dangerous prescription
homethe fdainterviewsdiscussion
interview: paul seligman, m.d., m.p.h.

Why is it necessary to monitor medications after they're approved?

First of all, there's an entire life cycle of a drug, if you will. It starts out from the very early days, when a pharmaceutical manufacturer basically develops a chemical or an entity that they feel might be of benefit, or treat a particular indication.

The fundamental point is that no drug  even having gone through this long period of development, testing, and review  is 100 percent safe.

So there's a long, long period of medicine development prior to its being received for review at the FDA. But the fundamental point is that no drug --even having gone through this long period of development, testing, and review -- is 100 percent safe. Every medication has a potential side effect, or potential for causing a more serious adverse event.

For that fundamental reason, we continually need to keep track and monitor the safety of products once they have been approved and marketed.

You mentioned that all medicines can have side effects. How serious are the side effects that all medicines can have? Can every medicine hurt somebody -- even gravely?

When you go to the pharmacy and pick out medicine that's sold over the counter, you'll notice that on the side of the label are adverse events and warnings to the consumer. Depending on how the product is used, any medication has potential serious side effects and can harm the consumer. It's why we spend so much time trying to understand the conditions of use, and why we try to understand the circumstances under which someone might be harmed by a medicine.

photo of seligman

Since July 2001, Paul Seligman has been the director of the Office of Pharmacoepidemiology and Statistical Sciences and director of the Office for Drug Safety in the FDA's Center for Drug Evaluation and Research. The Office for Drug Safety monitors the safety of drugs after they go on the market, and receives as many as 1,000 MedWatch alerts a day. In this interview, Seligman explains how his office manages these alerts and how it conducts risk management when adverse events are reported. This interview was conducted on Nov. 4, 2002.

In the vast majority of instances, medicines are there for the benefit. In fact, we approve drugs because we feel very strongly that the benefits far outweigh the risks of that particular product. But used incorrectly, used with another medication that might cause an interaction -- there's just a whole variety of circumstances that could lead to a potential problem of any medicated use.

So at the time a drug is approved by the Food and Drug Administration, what do we actually know about safety and efficacy? How much has it been tested? How many people has it been tested [on]? How thoroughly do we understand it?

There are a variety of phases that each drug goes through in its development. Usually all drugs require an early phase, where it's tested in animals. Then, if it's demonstrated that it not only produces the desired effect, but is also not producing unusual side effects or adverse events in that animal population, it moves on to the second phase, where it's tested in a limited number of individuals.

After it goes through that second phase and, again, we review carefully the Phase II data, the drug is then approved for testing in a wider population. These clinical trials are done on a fairly limited selected number of individuals, usually for the indication that the sponsor or the manufacturer is seeking approval -- usually on volunteers, usually on individuals who are relatively healthy, and may only have that one illness or disease for which the drug is going to be indicated.

The size of the population can range anywhere from three individuals to 3,000 -- again, depending on what the drug is going to be used for, how commonly it's going to be used, and what information is needed to ensure that the benefits and safety of the drug can be appropriately understood.

So it's hard to say how big a study one should do, because it depends on the drug, its indication, and its potential side effects.

What don't we know about a drug at the time it's approved?

There are a lot of things that we don't know about a drug at the time that it's approved. First of all, because of the limited number of people who were studied during the clinical trial phase, rare adverse events are often difficult to pick up during that phase.

For example, for a serious side effect that occurs once in every 10,000 prescriptions, if you have a clinical trial that only studies 350 individuals in three separate arms, it may be very difficult to understand or to pick out that piece of critical information.

Once a drug is marketed and used in tens [of thousands], hundreds of thousands, or even millions of individuals, it's more likely for that rare adverse event to occur.

There are also lots of other things that we don't know at the time a drug is approved. For example, it's hard to fully characterize the entire range of use of a particular medication, once it is on the market.

The general population is a complex one. People have many underlying illnesses. They use many different kinds of drugs. They have many different kinds of diets. They use different kinds of dietary supplements or herbal medicines. All of the potential interactions, underlying illnesses -- co-morbidities, as they are called -- can contribute to the underlying risk profile of the drug, and can result in an unintended or unpredicted adverse event. ...

How can those side effects, or adverse events, range in severity?

Adverse events or side effects can range in severity from -- nausea [and] headache are the kind of things you often are warned about on the side of a medication bottle -- to things that are serious and life-threatening that can lead to hospitalization or even death. So they range across the entire span of potential effects. Even what we could consider the minor side effects are important to us, because they often result in consumers not taking important medications for which they can receive benefits.

So it's important for us to understand, not only the serious ones, but some of the less than serious adverse events that may influence the way the consumer uses a medication and achieves the greatest benefit for using a pharmaceutical agent.

How does the Food and Drug Administration find out about adverse events or side effects?

The Food and Drug Administration finds out about adverse side effects primarily through its collected voluntarily reported cases of an adverse event. The vast majority of these come to the manufacturer or sponsor of the pharmaceutical agent. Ninety percent of the reports that we receive at the FDA come through that route -- from a physician, pharmacist, health care institution, or other provider who reports to the manufacturer, who follows up on that case and then reports to the FDA.

If an adverse event is serious -- which means it could cause death, it resulted in hospitalization, or was potentially life-threatening or prolonged the hospitalization -- the manufacturer has a legal responsibility to report that case to the FDA within 15 days of receipt. For all other adverse events that are reported to the FDA, the manufacturer, again, has a responsibility to report those to us on a quarterly basis for the first three years after a drug is approved, and then annually thereafter.

The other 10 percent of the reports that we receive come directly to us through our MedWatch program. These reports are from physicians, consumers, anyone who wishes to report an adverse event. Again, 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 medicine once it's been marketed, without the voluntary reporting by astute clinicians and health care providers, who recognize that a particular illness is being caused by the medication that they're taking.

So a vital component to our post-marketing surveillance in this country is the voluntary compliance and active engagement by the health care community in recognizing and reporting adverse events.

So, in other words, the Food and Drug Administration doesn't actively go out and try to find out about adverse events? They're not trying to investigate them?

We actively investigate an adverse event when it's reported to us. But the only active part of our program is that we do work with health care provider groups and others to encourage reporting. We attend conferences, meetings. We have a Web site that actively encourages promoting. We really rely on the public health spirit and the ethical duty of health care providers to report these adverse events to us.

Of all the real adverse events or side effects that occur in the real world, what percentage actually ever get reported, either to the pharmaceutical companies or to the FDA?

A variety of studies have looked at the rate at which the FDA receives adverse event reports. Commonly, we say that between 1 percent to 10 percent of all adverse events are reported to us. These are based on studies that have gone back as many as 20 years, where attempts have been made to actively promote physician reporting, and compared what active promotion of reporting does compared to what was the reporting made prior to that act of promotion.

In addition, there have been a variety of studies looking at hospitals, ambulatory care settings, nursing homes, to understand the rates of medication errors or rates of adverse events. Again, [it's been] demonstrated fairly consistently that we receive somewhere between 1 percent to 10 percent of all adverse events that occur.

There also have been studies that have looked at serious adverse events. For many of those, the actual reporting rate is somewhat higher. Again, depending on the nature of the adverse event and the drug, we may receive somewhere between a third and a half of those serious reports, compared to the 1 percent to 10 percent of all reports.

What does it mean that the Food and Drug Administration doesn't become aware of all of the adverse events that occur, particularly the serious ones?

The FDA doesn't need 100 percent reporting to determine whether or not there's a problem with a drug, once it has been marketed. We hope that there are not selective biases in our passive surveillance system, so that we are picking up the key and serious reports, which we need to get information to make a regulatory decision or to understand what the problem is with a particular drug in the post-market environment.

So we're fairly confident that with the level of reporting that we're receiving now, that we're picking up the most important side effects and serious events that will help us understand whether a drug is getting into trouble in the post-marketing environment.

How does the whole process by which the Food and Drug Administration monitors drugs work?

We have on our staff at the FDA approximately 50 safety evaluators and epidemiologists, who, on a daily basis, review the adverse events that we received on the prior day, particularly those that are of a serious nature. We follow up certain kinds of adverse events up in great detail.

We receive approximately 1,000 reports every day at the FDA. Those are entered immediately into our adverse event reporting system. Then they are triaged to the safety evaluators electronically. Those events pop up on their computer screen. They review those events, look for those that are serious or important, and make a decision as to whether they need to request further information on those cases, having reviewed the narrative of that particular case. Each safety evaluator is assigned a certain series of drugs in their domain.

So adverse events are getting distributed to people who have the expertise in that area?

Right. Our safety evaluators are trained pharmacists, usually with advanced degrees in pharmacy. They tend to focus on a limited number of drugs. They're constantly looking at the reports that they're receiving and comparing them with reports that they've received in the past days, weeks, months, or years, to determine whether or not there's a pattern that merits their further or closer attention.

Our safety evaluators also will often follow up directly with the reporter of a particular case to get more information, to assess whether or not the adverse event that's reported is related to the drug in question.

We process also approximately 500 consultations every year. The divisions in the FDA that were responsible for the approval of the drug are also very interested in monitoring its safe and effective use in the post-marketing environment, and they are constantly asking us for updates of the safety profile of the drug. What do we know in the last quarter and year, particularly, about a newly marketed product?

We often receive requests from our office of compliance, if there are issues related to the recall or a manufacturing problem that's associated with a particular drug. Similarly, we've received consults from our controlled substances staff if there's a question related to the abuse potential, or how a drug is being utilized.

So in addition to looking at adverse events, we also look at drug utilization patterns, as well. What kinds of practitioners are [prescribing] the drug? How often is it being prescribed? In what populations is it being used? Is it being co-prescribed with other kinds of medications?

So we look at, not only the adverse event reports; we look at drug utilization patterns. We respond to consults, as well as citizens' petitions from outside organizations, who may have a particular concern about an individual or cluster of adverse event reports. ...

You're getting 270,000 adverse event reports a year? But how many are the serious kinds?

Of the 278,000 adverse event reports that we receive every year, approximately 30,000 of them are of the serious nature. So, as I indicated earlier, if we have 1,000 overall reports received every day, about a third of those are of the serious nature.

How do serious adverse events reports rise to the level of, "Hey, we're really concerned about this drug?" Does it take one case? Does it take 10? Does it 50? How does that work?

We look at every serious adverse event report with a tremendous deal of care. There are a couple of things that we look at. First of all, was this a serious adverse event that we knew about at the time of marketing? Given that no drug is safe, and given that each drug has a different adverse event or toxic profile, there are certain situations where we might expect serious events, adverse events.

For example, oncologic drugs -- drugs that are used to treat cancer. We know that a lot of these drugs have very serious side effects. They're anticipated and expected as part of the treatment.

Those that we anticipate that are part of the label and are occurring at the frequency that we would anticipate when used in a population are an important enough concern. But [they] are clearly less of a concern than those that we either did not anticipate, that were not part of the label, [or] that occur at a frequency far greater than what we had anticipated at the time the drug was approved. Those are the kinds of things that we ask our safety evaluators to look at carefully.

So an unanticipated adverse event, [or] an adverse event that's occurring far more frequently than we had anticipated are two signals that tell us that we need to pursue more information and greater investigation.

How does something become a signal -- because one event doesn't necessarily mean you're worried about it?

... Clearly, one case, if it's unusual, unanticipated, indeed may be a signal to pursue further investigation, to try to uncover whether there are additional cases. Again, it depends on the drug, whether it's something we've observed before, how serious it is, what the potential public health impact is of that signal.

Let me give just an example, but a drug that's, for instance, used over the counter, that's commonly used in the population. If we discover a medical error, a dosing error, for example, because a parent either misread a label or misused the product, that one case may tell us that there is a more serious problem going on out there that needs to be addressed.

If we observe, for example, in a pharmacy, that a drug is substituted for a drug of a similar-sounding name, that one case, in and of itself, may signal to us that there is a problem with a look-alike or sound-alike drug product that needs to be addressed.

So what we're really looking at, in any situation, is whether or not there is something that can be prevented; whether there is an adverse event or a problem that has occurred that public health authorities, that physicians, that pharmaceutical sponsors can intervene on to prevent further harm. That's the issue for us. ...

Is one event serious enough to take a drug off the market? Or is there something you have to see -- a certain pattern, a certain percentage of people who were using something?

I think there's no easy answer to that question, because each drug, and its indication, and its use is specific. An over-the-counter drug -- we would like to think are those drugs that have the lowest risk profile, that are the safest for use, because any individual can make their own decision about when to take those. [That's] a different kind of drug product than those that are used to treat serious or life-threatening illnesses.

So we evaluate each drug on its own merits, if you will. How is it being used in the population? What is it indicated for? What do we know about its toxic profile, both prior to marketing and subsequent to marketing? What other alternatives for medications are there out there? Are there substitutes that have equal benefit, but lower risk?

We look at every drug and every circumstance individually. Is the drug being utilized appropriately by the medical community? Is it being utilized appropriately by consumers? Are there ways that we can change those utilization patterns in order to improve, not only the benefit, but also to lower the risks of that medication?

These are all the kinds of factors that we consider and think about in our ongoing and continuous review and reassessment of the market status of a particular product. ...

If you see that there's a problem with a drug, does it immediately come to mind that you're going to take the drug off the market? Or are there other things that you consider before considering that step? What's the course of events?

The options that are available to the FDA when we see that there's a problem with a drug are a wide spectrum. One is to change the warnings that accompany the drug on the label. Second is to highlight those warnings in what we call a "black box," which [is] put up in front of the label and puts a black box around that warning in bolded letters. One is to change the way the drug is being prescribed or utilized by the medical profession. We also look at the way the consumers are utilizing the particular drug product.

So there are a whole host of potential options that exist, depending on the circumstances. Sometimes, if the problem is occurring because two drugs have a similar-sounding name, or the names look alike, or there's confusion in dose, we would work directly with the manufacturers to consider changing the way the drug is named, or the dosages are printed on the bottles.

So it really fundamentally depends on the nature and seriousness of the problem. There are a whole host of essentially risk management steps that range from changing the label, educating providers, educating consumers, [and] restricting distribution of the product that will allow us to ensure that the risks are essentially minimized and the benefits are maximized for that particular therapy.

Does the FDA impose that to the pharmaceutical company, and say, "You must change your label?" Or does it have to be negotiated? I imagine pharmaceutical companies don't like to change anything; change is bad, unless it says more people can use it.

No. It's always in the interest of the pharmaceutical company, the manufacturers to ensure that their products are beneficial to the public, and impose the least risk or safety hazards to their consumers. So they take seriously these reports, as well. When we receive them, we discuss them with a sponsor. We talk about the weight of the evidence that exists, and the need for inclusion of this information on the label, or the need for development of either an education program or other strategies to effectively manage the risk of the drug.

These are always discussions that we have with the manufacturer. Often, we have public meetings, in what we call advisory committees, to also advise the FDA on what further risk management steps might be taken when we learn about a problem post-marketing.

So there are a variety of venues that we can use to make decisions about whether to strengthen warnings, strengthen the education of consumers or providers, or to limit the way the product is being distributed in order to ensure that its benefits are maximized and risks are minimized.

Then when does a drug have to get taken off the market, and why?

Most withdrawals in the United States are voluntary withdrawals that the manufacturer decides to engage in. Those decisions are generally complex ones that involve not only the risks of that particular medication, [but] whether there are other therapies available that work as well. So the withdrawal is really sort of the last step in a process. It really is rarely applied. ...

In the end, when does a drug have to be taken off the market? Or are you heavily pressuring the company to voluntarily take it off the market?

A drug needs to be taken off the market when the benefits no longer exceed the risks of that drug, and all available avenues to manage those risks have been exhausted.

Is it inevitable that some drugs are going to get approved, and then later have to be taken off the market?

I think historically that appears to be the case; that indeed, as we learn, at the time a drug is approved, we don't have all the information that we would like to have. We simply can't have all the information, because certain side effects are particularly rare, because we don't understand the full manner in which a drug will be utilized in the population. It's likely that, at some point in the future, we will have additional information that would indicate that, indeed, a drug -- the benefit for that no longer exceeds its risk.

New products are always being developed, and often, the marketplace speaks with its feet, if you will. [If] physicians recognize that a new product for a particular indication has a safer profile, they will begin to use that newer product, as opposed to an older product.

On the other hand, older products that have been around for a long time, and have been on the market for a long time, have clearly -- physicians and patients have accumulated a lot of experience. So there's no need to change to a new product if the old one works just as well. ...

How alarmed should the public be that a number of drugs have been taken off the market fairly recently? It seems like more than usual. Or maybe there are more drugs on the market to consider?

If you look historically at the rate at which drugs have been removed from the market, you'll find that it has been fairly steady. Although it may appear that the rate is higher, because there have been a series of high-profile removals, the reality is that very few drugs get removed from the market. This rate hasn't changed over time.

The consumer needs to understand that the FDA's mission is to ensure that drugs are safe and effective before they are approved for marketing; that the vast majority of medications meet that very high standard prior to their approval; that we are dedicated, once a drug has been approved for marketing, to keep a close eye on what's happening in the post-marketing environment; and [we] respond quickly and aggressively when we find that there are problems with a particular medication.

We have, in this country -- and I think, throughout the world -- achieved extraordinary benefits from the use of pharmacologic agents. As a society, we are living longer. We live longer for a whole variety of reasons. But clearly, medicines have had an important role and impact in, not only the quality of our lives, but the longevity of our lives. That, in large measure, is due to the benefits that we receive and the high quality of the medications that we, as a nation, receive.

What, if anything, would you do to improve the system? You've been here for a while now, so you've had enough time to see how it works. How could we feel even safer?

I think we have just reached an historic agreement with the pharmaceutical industry that was codified by Congress in the third round of the Prescription Drug User Fee Act, which, for the first time, gives us prescription drug fees for use in post-marketing surveillance.

There's always room for improvement. A number of areas that we're going to focus on in the coming years is understanding more thoroughly how drugs are utilized once a product is marketed, and the degree to which utilization can change the risk profile of a drug once it has been marketed. That's one area that we can certainly focus on.

As part of this emphasis on risk management, we're going to continue to encourage manufacturers to thoroughly assess and understand not only the safety profile, but how drug utilization patterns post-marketing may influence the safety of a particular drug. Drug utilization is clearly one area that we want to focus on.

The other is, for lack of a better term, what I would call "applied research." Understanding how physicians receive information and make decisions about therapeutics has always been an important issue in safe pharmacotherapy.

Understanding how consumers make decisions, and how to influence their behaviors to ensure safe medication use is another area of great interest of mine, and I think an area that the FDA will be continuing to place greater emphasis on.

So I think understanding drug utilization, and understanding how physicians and consumers use medications to ensure their greatest benefit and to limit those risks are two areas where we could improve FDA's processes. ...

Why do we need to know about the way physicians and consumers actually use the products that they prescribed? What are they doing wrong?

I think consumers have an important role in the safe use of medications. They are ultimately the individuals who make the decision about what they take.

But we recently had an advisory committee meeting, looking at over-the-counter analgesics, or pain relievers. One product that we were looking at was acetaminophen, which is a commonly used medication. In the course of that advisory committee, based on some of the adverse event reports that we received, [we found] that consumers frequently use multiple acetaminophen-containing products unwittingly, not realizing that the pain reliever that they're taking may also have acetaminophen in it, as well as a cold preparation or other combination products that they can readily buy over the counter.

So consumers need to actively read the label, understand what they're taking, look at the information that is provided to them by the pharmacy, listen carefully to what the physician is saying, ask questions of the physician. Whenever they receive a new medication, ask the physician, "Will this be a problem, because I'm taking the following medications?" or, "I use the following herbals," or, "I'm taking the following over-the-counter medication."

Frequently, in the course of a clinical encounter with the physician, the doctor won't have all that information. So it's really incumbent upon the consumer to take charge a little bit; make sure that they are reading the label, because those labels are there for them; reading the patient information, and talking to their physicians about other products that they may be taking could potentially interact with the prescription that they're currently receiving. ...

Why was Baycol removed from the market? In retrospect, was it a mistake to have approved it?

Baycol was voluntarily withdrawn from the market by its pharmaceutical sponsor. It was withdrawn following reports of a muscle condition, rhabdomyolisis. This muscle condition occurs as well with other blood-lowering, cholesterol-lowering agents, or statins.

One of the problems that was observed with Baycol was that it was prescribed with another class of cholesterol-lowering agents, the fibrates, that the rate of rhabdomyolisis was elevated or higher. There were numerous other statins on the market to treat this particular condition.

We had been in discussions with the manufacturer about the highest dose of that particular drug which seemed to be causing the greatest number of rhabdomyolisis cases. In the course of that discussion, the sponsor determined that they wanted to withdraw the drug from the market. So that was really their decision.

At the time, we were most concerned about the highest dose of that particular drug, and also its co-prescribing with another cholesterol-lowering agents that seemed to be responsible for the greatest number of these rhabdomyolisis cases.

So what happened? There had been attempts made to manage the risk. So was this just a case where there just wasn't a safe way to use it?

I think the attempts that had been made to manage the risk prior to its withdrawal included "Dear Doctor" letters or letters to health care professionals, informing them of the risks associated with the combination therapy of this particular drug with the fibrates. We already know that these kinds of letters -- in general, not just for this drug -- have somewhat limited effectiveness in changing physician behavior.

But again, the sponsor looked at the weight of the evidence that had accumulated at the availability of other medications to treat this condition, and made a decision that they wished to withdraw the marketing of this particular medication.

So from the FDA's point of view, it didn't have to get completely withdrawn? They could have kept a weaker version of it on the market?

Again, we had looked at the evidence, and found that the higher doses were responsible for the greatest number of these cases, as well as the co-prescribing of that medication with another agent. This particular medication is still on the market in other countries, and is still being used at the lower doses. But, again, the company, for its own reasons, chose to withdraw in this market in the United States, as well as in the European markets. ...

So was this a triumph for the FDA, in a way, of doing what it's supposed to be able to do -- to pick up these problems, present them to the manufacturer, and say, "You know, we've got to do something about this?"

Well, I think withdrawal is really just, as I mentioned, the tail end of a long process to understand the risks and benefits of a drug and to effectively manage those risks.

We take our job very seriously, because, not only do we have a concern for the public health, but we are part of the public, as well. We take these medications individually, and our families take them.

Every time a medication requires greater risk management efforts or the ultimate risk management step, which is withdrawal, it indicates to us that the process is working as it should work. We're attentive to problems. We are constantly vigilant of problems that might occur with a particular medication, and [that] the appropriate steps are being taken to ensure that we're protecting the American public, and those who take these medications.

When a new drug comes on the market, does the manufacturer have to be able to prove it's safer than things that are already on the market, or a little more effective, or any better in any kind of way? Or does the FDA not have anything to say about that?

The FDA evaluates each drug individually to look at its efficacy and its safety, and makes its approval decision based on the data and the studies done for that particular drug.

So if a competing drug comes on the market, and the newer drugs aren't necessarily better, they don't have to be? Is that what you're saying?

Newer drugs don't have to be better, and there's a good reason for that. Not every individual responds to the same drug. So the degree to which we could have therapeutic alternatives on the market that are safe and effective, the better the average physician can treat a patient. Some people respond to one drug better than another.

So there is a role, an important role for therapeutic alternatives. People often call these "me-too drugs," and complain that there is really no role for these other drugs of similar effect and similar benefit. ...

I want to ask you about Pondimin, fenfluramine, Redux.

It was sort of before my time. The only comment that I would have is that we often talk about these drugs as "lifestyle drugs." But the reality is that they are really treating conditions that are important to the health and welfare of individuals.

Obesity is not a lifestyle choice. It's a serious medical condition, and it's a difficult medical condition to treat. It requires a combination of approaches, including pharmacologic approaches, changes in one's diet, changes in one's exercise patterns or levels of physical activity.

So these are important agents, as well. For years, as a society, we have not wanted to talk about things like anxiety or depression. The degree to which patients are now willing to talk about those conditions with their physicians, and to utilize pharmacotherapy in a way that improves their ability to function in social situations and work situations, is of potentially tremendous value.

So I'm not a fan of that term "lifestyle drugs," because there are medications that do improve and can improve the quality of our lives.

I sometimes read about people who have criticized those drugs. What they've said is, in many cases, just that they're not treating serious enough problems to merit the risks that's involved.

That's why we continually reassess the benefit and the risks associated with these drugs, and why we look at how efficacious they are. Are they achieving they benefit that we hoped to achieve?

Indeed, as we gain more experience with the drug, that balance often shifts. At some point, indeed, it becomes obvious to us at the FDA and to others that the risks exceed their benefits, and it's no longer appropriate to have that drug generally available.


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posted november 13, 2003

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