FDA Drug Screening Measures Under Intense Scrutiny

SEN. CHARLES GRASSLEY:

One of my concerns is that the FDA has a relationship with drug companies that is far too cozy.

SUSAN DENTZER:

That criticism, voiced by Iowa Republican Sen. Charles Grassley, has the ring of familiarity at the Food and Drug Administration.

But officials there also encounter the opposite critique, that FDA is the pharmaceutical industry's biggest speed bump in marketing new drugs.

That view, too, emerged at a Senate hearing last week from another Republican, Oklahoma's Don Nickles.

SEN. DON NICKLES:

Maybe one of the results, if we give FDA a real hard time they're going to be real cautious and all of a sudden the time length for approval of drugs is going to get longer and drugs are going to be more expensive.

There's lives at stake on both ends of the drug-approval process.

SUSAN DENTZER:

The FDA has a dual role in that complex process, approving new drugs for sale, then overseeing their safety.

As a result, the agency has come under harsh scrutiny of late. Earlier this year, FDA was caught up in controversy over an apparent link between antidepressants and suicidal thinking and behavior in some teens and children.

Some analysts accused FDA of downplaying some of its scientists' concerns, and moving too slowly to warn about the drugs' risks.

Now the FDA is under fire for its role in monitoring the blockbuster painkiller Vioxx. The drug was pulled off the market in September by its manufacturer, Merck.

The company's own study showed Vioxx doubled the risk of heart attacks and strokes. FDA Safety Officer David Graham spoke at last week's hearing.

DR. DAVID GRAHAM:

I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx.

Simply put, FDA and the Center for Drug Evaluation and Research are broken.

SUSAN DENTZER:

Other FDA officials have taken strong issue with graham's criticisms. Dr. Sandra Kweder heads FDA's Office of New Drugs.

DR. SANDRA KWEDER:

That is not the FDA I know.

There was a drug safety reviewer on Vioxx, for example, that worked on a daily basis combing through adverse event reports and working with the new drug review division on this drug, just like we have for every drug.

SUSAN DENTZER:

But many at the FDA agree that there are problems, stemming in part from the agency's structure.

One issue is figuring out how to forge consensus among the frequently dissenting scientific views within FDA. Kweder says that process is being addressed.

DR. SANDRA KWEDER:

Disagreement is part of science.

However, we will implement the system in a more formal manner to absolutely ensure that scientists who don't believe they are being heard have an extra measure to ensure that.

SUSAN DENTZER:

A second concern is whether the process of approving drugs takes precedence over the process of overseeing their safety. Critics like Graham say it does.

DR. DAVID GRAHAM:

The organizational structure within CDER is entirely geared towards the review and approval of new drugs.

When a serious safety issue arises post-marketing, the immediate reaction is almost always one of denial, rejection and heat.

They approved the drug, so there can't possibly be anything wrong with it. This is an inherent conflict of interest.

SUSAN DENTZER:

This week, an editorial in the Journal of the American Medical Association called for a radical solution: Setting up an new drug safety board that would operate outside the FDA.

And FDA itself has called for an independent study of its drug safety oversight.

JIM LEHRER:

Ray Suarez takes it from there.

RAY SUAREZ:

Is the FDA Doing a good job of protecting the public while approving new drugs?

And what changes can be made to improve the system?

We get two views. Dr. Jerry Avorn is an associate professor of medicine at Harvard Medical School, and an international expert on medications.

He is the author of a new book, "Powerful Medicines: The Benefits, Risks and Costs of Prescription Drugs."

And Dr. Brian Strom is the director of the Center for Clinical Epidemiology at the University of Pennsylvania School of Medicine. He is an expert in the field, and has sat on several committees advising the FDA.

Dr. Avorn, is the FDA drug-screening machinery working properly?

Are we getting safe and effective drugs to the public and protecting the public from unsafe ones?

DR. JERRY AVORN:

I think it's fair to say in light of both the Vioxx experience and also the experience we've had with other drugs in the recent past that, no, the system is not working well at all.

RAY SUAREZ:

And what would you say is the cause of that? What is flawed about how the process is working that leads you to something like what you refer to, the Vioxx incident?

DR. JERRY AVORN:

Well, as the piece just indicated, there's an enormous focus within FDA about approving drugs quickly and getting them on to market. And that's okay if it's done well.

But then the attention of the FDA really drops off.

And the vigilance disappears when it comes to requiring and analyzing the data that we need to be able to learn about the safety of the drugs once they're in widespread use.

RAY SUAREZ:

Dr. Strom, is the FDA doing its job properly, getting safe and effective drugs to the public and protecting it from unsafe ones?

DR. BRIAN STROM:

I think given the circumstances FDA operates under, it does a remarkably good job.

Clearly there could be improvements. Things could be better. I guess we'll talk later about it.

But I think it's very important that the public realize that a safety problem like Vioxx doesn't necessarily mean the system is broken. Every drug has toxicities.

Every drug has safely safety problems inherent in it.

And we make as a society a risk- benefit judgment about whether or not to have a drug available.

As a physician I make a risk-benefit judgment about whether or not to prescribe a drug for a patient, knowing its toxicity, knowing its potential benefit. All drugs have safety problems.

RAY SUAREZ:

Well, at the beginning of your answer you said "under the circumstances." What circumstances does the FDA work under that limits their ability to regulate what drugs get to the public?

DR. BRIAN STROM:

Oh, I think there are a number of places and I would love to see the Office of Drug Safety greatly strengthened.

They have limited resources and limited staffing. They have limited regulatory ability.

When a company, for example, commits to be a post marketing surveillance study, the FDA has a very limited ability to enforce that commitment afterwards.

And those are all powers that FDA needs to have in order to be able to properly regulate.

RAY SUAREZ:

Wasn't that the trade-off during the 1990s, making the system work more quickly on the front end and putting more emphasis on the post market surveillance?

DR. BRIAN STROM:

I think that's exactly the tradeoff that was made.

I think that there was some effort made with that in order to strengthen the back end, as you refer to it, after the drug is marketed.

I think there's a lot more effort that needs to be done there in order to strengthen that even better.

Once again I think people at FDA do an enormously good job but I think a better job could be done if they were resourced even better and given greater powers accordingly.

RAY SUAREZ:

Well, Dr. Avorn, where did those pressures come up from to speed up the approval process on the front end in order to put more emphasis on how the drug works once it's in general circulation?

DR. JERRY AVORN:

Well clearly it's greatly in the interest of the drug manufacturers to have drugs approved speedily.

And certainly if it's an important breakthrough product, we want to have that drug approved speedily to get it to the people.

On the other hand, when the user fee act was first put in place in which the companies pay FDA to review their own products, the original plan was not one dime of that could be spent looking at safety problems that came up afterwards.

It was all about speeding up and not enough about catching the problems once they were discovered when drug was in the marketplace, and as Dr. Strom indicates, we currently do have a kind of atrophied component of post marketing surveillance.

RAY SUAREZ:

But you talked briefly about that model of using the user fees. That is, having the pharmaceutical companies themselves pay for their own regulation.

Does this set up two opposing forces that just aren't reconciling properly?

DR. JERRY AVORN:

Well, it's an odd way to fund a regulatory structure that you have the agency paid for by the industry that it's regulating.

The argument was that this would save money for the government but that's awfully shortsighted because it's at a great cost to have that kind of culture within the FDA that our salaries are eventually paid by the drug manufacturers.

That was probably a very short- sighted way to save money for the government.

RAY SUAREZ:

Dr. Strom, how does that work in your view? Is it a viable model?

DR. BRIAN STROM:

I certainly agree with Dr. Avorn, it is an odd way to fund it.

I am much less concerned about that conflict of interest than by the atrophy of the post marketing surveillance part.

The nature of the User Fee Act, as Dr. Avorn mentioned, it initially forbade FDA… FDA was not allowed to use any of those funds after marketing, which obviously doesn't make any sense.

If you're going to market drugs earlier, you want to strengthen the post marketing surveillance.

I think there are people who are concerned about having FDA funded by these user fees. It is an odd system.

On the other hand, I have certainly never seen any problem that has been generated with it.

I've worked a lot with industry; I've worked a lot with FDA. I can tell you FDA can be very stern with industry and industry can be very scared of FDA in response.

I certainly see no evidence of coziness and no change that came about because of the User Fee Act.

I think the big change was that the new drug branch got expanded and the post marketing surveillance branch did not.

RAY SUAREZ:

Well in our taped report, Susan Dentzer featured the testimony of Dr. David Graham, I think arguably blockbuster testimony.

He named several drugs by name, talked about the potential for other Vioxx's out there. Dr. Strom, what do you think? Are there?

DR. BRIAN STROM:

I think there is guaranteed to be other Vioxx's out there.

I think we don't do the public a service when we focus on one drug or five drugs and say they have problems that they have safety issues. The public has to understand that all drugs have safety issues.

No drug is safe whether you're talking about a prescription drug or over the counter drug or certainly an herbal drug that people take on their own.

We know they have toxicities and when you're dealing with a new drug, we know they have toxicities that are as yet undiscovered.

Fully 51 percent of drugs have major new safety problems discovered after the drugs are marketed. And those are the ones we know about.

To me the Vioxx's are a success not a failure. Those are the ones we found out about. I worry more about the ones we haven't found out about.

RAY SUAREZ:

Dr. Avorn, what about that, the idea of a discovery like that of Vioxx shows that the machinery as set up is a viable one — that the system works?

DR. JERRY AVORN:

I couldn't disagree more.

I think we have very ample evidence that there were worries about Vioxx going back to 1999 and 2000, and the FDA failed grotesquely in not demanding that the manufacturer look into those questions the very moment they were first raised.

Instead years and years and years went by; millions of people took the drug. FDA did not require Merck to do the studies that it needed to require them to do in the year 2000 and 2001.

Merck failed to do those studies on its own. And I don't think that demonstrates the works. I think it demonstrates some real problems with the system.

RAY SUAREZ:

What do you do now, Dr. Avorn? Does this call for a major overhaul of the methods that we use to approve drugs for the market?

DR. JERRY AVORN:

I'm afraid it does. There have been a number of cases over the last couple of years. Vioxx is not an anomaly.

In "Powerful Medicines," I talk about three or four or five instances in which we discover that there were major problems with the drug years after in some cases the Europeans had taken the drug off the market.

We need to do a much different job and perhaps we can't have it within the same agency.

Maybe we do need to have a separate group approving a drug and another group saying, let's look at the safety so that there isn't this conflict within the same agency.

RAY SUAREZ:

And how about you, Dr. Strom, the idea that has been suggested to take the approval process out of the hands or big parts of it out of the hands of FDA, what do you think of that?

DR. BRIAN STROM:

I think it would be useful to have an agency outside of FDA but not the approval process.

I would suggest that there really are four changes that are needed.

One of them is that the Office of Drug Safety needs to be strengthened, FDA needs to be strengthened.

It needs to be given more regulatory authority after drugs are marketed.

The second is I would recommend that for the first few years after marketing we have a conditional approval process; that the companies have to come back to FDA after those few years with additional safety information in order to get an unconditional approval.

Third, I would recommend that during those three years direct to consumer advertising should not be allowed.

Part of the problem is Congress has unleashed the marketing arms of the drug companies to grossly overuse drugs.

And when a drug is new, almost surely there are still safety problems as yet unknown.

The drug should only be used by people who really need the drug.

The fourth thing I would recommend is we do need an external body. I would not remove from FDA the regulatory authority.

I think the external body needs to have a complementary role. One of them is basically an autopsy type of role, a post mortem role; when there's a problem look back at the problem and say, could we have done anything different?

The other role it would have is a whole set of roles that FDA doesn't and can't now do and shouldn't now do, like educating the public, like educating physicians, not to overuse drugs not to overuse new drugs.

The biggest problem we have in this country is not the rare adverse reaction to the new drug. The biggest problem we have is inappropriate use of drugs.

Whether it's new drugs that become blockbusters prematurely and have side effects we haven't discovered, or old drugs that we know very well what the toxicities are but are killing thousands or tens of thousands of patients because we're not using them correctly.

RAY SUAREZ:

Let me turn to Dr. Avorn and see if you heard anything you like in that list of suggestions.

DR. JERRY AVORN:

I think there's a number of things that Dr. Strom said that make a great deal of sense, and we clearly do need to have a better way of doing the so-called autopsies on drugs.

On the other hand I think if we did a better job of approving drugs and learning more about them before they were marketed, we would perhaps not need to do as many autopsies on drugs or on patients.

We need to figure out a mechanism for getting better data before the drug is approved.

Right now a company has to demonstrate only that its drug is better than a sugar pill in many cases for it to be marketed.

And I as a doctor don't want to know is it better than a sugar pill; I want to know is it better than what I could otherwise used.

And that is not at all part of FDA's mandate. We need that kind of study. Industry will not do it voluntarily because very often the drugs are not much better than the drugs we have on the market.

RAY SUAREZ:

What about Dr. Strom's suggestion that there be something in between full general release and test release?

He posited this idea that a drug could go into limited release and we could learn more… even more about it before it goes into this fullest final form?

DR. JERRY AVORN:

I think that makes a great deal of sense. Medicine is all about learning.

And we're never going to know everything we need to know. As Dr. Strom said when a drug is first released even if the studies are adequate, as they are not currently.

So we do need this period of learning. That's exactly the period when we don't want to have direct consumer ads saying everybody on the planet should be taking this.

RAY SUAREZ:

Dr. Avorn, Dr. Strom, gentlemen, thank you both.