The FDA Exposed: An Interview With Dr. David Graham, the Vioxx Whistleblower

[Guest guest]

http://www.newstarget.com/011401.html

 

The FDA Exposed: An Interview With Dr. David Graham, the Vioxx

Whistleblower

 

 

Friday, October 07, 2005

The FDA Exposed: An Interview With Dr. David Graham, the Vioxx

Whistleblower

The following interview with Dr. David Graham (senior drug safety

researcher at the FDA) was conducted by Manette Loudon, the lead

investigator for Dr. Gary Null. This interview contains jaw-dropping

insights about the corruption and crimes that take place every day

inside the Food and Drug Administration. This is no outside critic,

either: these are the words from a top FDA employee who has worked at

the agency for two decades. If you've ever wondered how the drug

industry could pull off the greatest con of our time -- and turn the

human body into a profit-generating machine -- you're about to learn

the shocking answers in this interview.

 

This interview is reprinted here with permission from Dr. Gary Null.

Parts of this interview also appear in Dr. Gary Null's Prescription

For Disaster video documentary, which is available at the Gary Null

website and is a must-see video for anyone who wants to know the truth

about the pharmaceutical industry and the FDA.

 

MANETTE: Dr. Graham, it's truly a pleasure to have the opportunity to

interview you. Let me begin by asking you how long you've been with

the FDA and what your current position is?

 

DR. GRAHAM: I've been with the FDA for 20 years. I'm currently the

Associate Director for Science and Medicine in the Office of Drug

Safety. That's my official job. But when I'm here today I'm speaking

in my private capacity on my own time, and I do not represent the FDA.

We can be pretty certain that the FDA would not agree with most of

what I have to say. So with those disclaimers you know everything is okay.

 

MANETTE: On November 23, 2004 PBS Online News Hour Program you were

quoted as making the following statement. " 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

Research (CDER) are broken. " Since you've made that statement, has

anything changed within the FDA to fix what's broken and, if not, how

serious is the problem that we're dealing with here?

 

DR. GRAHAM: Since November, when I appeared before the Senate Finance

Committee and announced to the world that the FDA was incapable of

protecting America from unsafe drugs or from another Vioxx, very

little has changed on the surface and substantively nothing has

changed. The structural problems that exist within the FDA, where the

people who approve the drugs are also the ones who oversee the post

marketing regulation of the drug, remain unchanged. The people who

approve a drug when they see that there is a safety problem with it

are very reluctant to do anything about it because it will reflect

badly on them. They continue to let the damage occur. America is just

as at risk now, as it was in November, as it was two years ago, and as

it was five years ago.

 

MANETTE: In that same PBS program, you were also quoted saying, " The

organizational structure within the CDER is currently geared towards

the review and approval of new drugs. When a serious safety issue

arises at post marketing, the immediate reaction is almost always one

of denial, rejection and heat. They approved the drugs, so there can't

possibly be anything wrong with it. This is an inherent conflict of

interest. " Based on what you're saying it appears that the FDA is

responsible for protecting the interests of pharmaceutical companies

and not the American people. Do you believe the FDA can protect the

public from dangerous drugs?

 

DR. GRAHAM: As currently configured, the FDA is not able to adequately

protect the American public. It's more interested in protecting the

interests of industry. It views industry as its client, and the client

is someone whose interest you represent. Unfortunately, that is the

way the FDA is currently structured. Within the Center for Drug

Evaluation and Research about 80 percent of the resources are geared

towards the approval of new drugs and 20 percent is for everything

else. Drug safety is about five percent. The " gorilla in the living

room " is new drugs and approval. Congress has not only created that

structure, they have also worsened that structure through the PDUFA,

the Prescription Drug User Fee Act, by which drug companies pay money

to the FDA so they will review and approve its drug. So you have that

conflict as well.

 

MANETTE: When did that go into effect?

 

DR. GRAHAM: The Prescription Drug User Fee Act came into play in 1992.

It was passed by Congress as a way of providing the FDA with more

funds so that it could hire more physicians and other scientists to

review drug applications so that drugs would be approved more quickly.

For industry, every day a drug is held up from being marketed,

represents a loss of one to two million dollars of profit. The

incentive is to review and approve the drugs as quickly as possible,

and not stand in the way of profit-making. The FDA cooperates with

that mandate.

 

MANETTE: And what about those new drugs? Are they any better than what

already exists on the market?

 

DR. GRAHAM: It's a myth that is promulgated not only by industry but

also by the FDA itself. It's a misperception that our lawmakers in

Congress have as well and they've been fed this line by industry.

Industry is saying there are all these lifesaving drugs that the FDA

is slow to approve and people are dying in the streets because of it.

The fact is that probably about two-thirds to three-quarters of the

drugs that the FDA reviews are already on the market and are being

reviewed for another indication. So, for example, if I've got a drug

that can treat bronchitis and now it's going to be used to treat a

urinary tract infection well, that's a new indication. But it's the

same drug and we already know about the safety of the drug. There is

nothing lifesaving there. There is nothing new. There is nothing

innovative. A very small proportion of drugs represent a new drug that

hasn't been marketed before. Most of those drugs are no better than

the ones that exist. If you want to talk about breakthrough drugs –

the ones that really make a difference in patients' lives and

represent a revolution in pharmacology – we're talking about maybe one

or two drugs a year. Most of them aren't breakthroughs and most of

them aren't lifesaving, but they get treated as if they were.

 

MANETTE: Are you at liberty to discuss some of the problems your

colleagues are finding with other drugs and if so, how widespread is

the problem?

 

DR. GRAHAM: I'm really not at liberty to talk about things that

pertain to my official duties at the FDA. I can talk in my private

capacity, but I can't talk about material that would be confidential.

What I can say is that there are a number of other scientists within

the FDA who have also worked with drugs that they know are not safe,

even though the FDA has approved or allowed them to remain on the

market. They face some of the same difficulties that I do. The

difference is that either the problem isn't as serious in terms of the

numbers of people that were injured or that it's a fatal reaction –

they're not willing to expose themselves to retaliation by the FDA -

and retaliation would surely follow.

 

MANETTE: Do you think we should have any confidence in the FDA and if

so, can you elaborate on what they do that you feel benefits the

American people?

 

DR. GRAHAM: In terms of confidence in what the FDA does, there are two

things that the FDA determines when it looks at a drug: it determines

whether or not a drug is safe and it determines whether or not it's

effective. Regarding the determination of drug effectiveness, I think

the FDA does a pretty good job. If the FDA says that the drug will

have a particular effect, probably for many of the patients who take

the drug it will actually have that effect. If the FDA says a given

drug will lower blood pressure and you're somebody who has high blood

pressure, there's a good chance that the drug will have an effect that

lowers your blood pressure. That has to do with the rigor with which

they force the drug companies to establish that the drug actually has

an effect.

 

On the safety side, I think that the American public can't be very

confident. They can have some confidence because it turns out that

most drugs are remarkably safe. But, when there are unsafe drugs, the

FDA is very likely to err on the side of industry. Rarely will they

keep a drug from being marketed or pull a drug off the market. A lot

of this has to do with the standards that the FDA uses for safety.

When they look at efficacy, they assume that the drug doesn't work and

the company has to prove that the drug does work. When they look at

safety it's entirely the opposite. The FDA assumes the drug is safe

and now it's up to the company to prove that the drug isn't safe.

Well, that's a no-brainer. What company on earth is going to try to

prove that the drug isn't safe? There's no incentive for the companies

to do things right. The clinical trials that are done are too small,

and as a result it's very unusual to find a serious safety problem in

these clinical trials. Safety flaws are discovered after the drug gets

on the market.

 

MANETTE: I read somewhere that a drug only has to be better than a

sugar pill

 

DR. GRAHAM: Right. The standard that the FDA uses to approve a drug is

primarily " does the drug work? " That's what they call efficacy. Most

often, they'll compare the drug against something called a placebo or

a sugar pill. It's basically something that doesn't have a medical

effect. The assumption is that the drug will be no different than the

sugar pill. The FDA puts the onus on the drug company to conduct a

clinical trial to show that the drug is different from a sugar pill.

The way the FDA's approval standards are, the drug does not

necessarily have to have a very great effect in order to be approved.

The drug might lower your blood pressure by just a few millimeters of

mercury, but the FDA will say we can approve it because it does lower

your blood pressure.

 

Now, would that be a benefit or are there other drugs out there – many

other drugs – that patients could take instead that would lower their

blood pressure by 10 or 15 or 20 millimeters? The FDA doesn't really

care about that. What happens is the drug gets marketed. You've got

two drugs that are out there – one drug that effectively lowers your

blood pressure a substantial degree and another drug that barely

lowers your blood pressure at all. The company that has that second

drug markets it like it's this breakthrough medicine. It lowers your

blood pressure and they have all these glitzy ads, direct-to-consumer

advertising. Lots of patients and lots of doctors will use that

medication. What happens in the process is these patients are actually

in a sense being denied a more effective treatment because the FDA

doesn't require that drugs that come on to market be at least

equivalent to, or better than, the drugs that are already there. All

they have to do is be better than a sugar pill.

 

MANETTE: When you consider the financial impact your whistle blowing

has had on the pharmaceutical industry do you have any fears that your

life may be in jeopardy?

 

DR. GRAHAM: I have tried not to think about that. In the work that

I've done I've never really thought about what the financial impact

would be on any particular company. I put that out of my mind because

my primary concern is whether or not the drug is safe. If it's not

safe, how unsafe is it and how many people are being hurt by it? In

terms of when I identify an unsafe drug, to me it doesn't really

matter what drug company it is. I've helped to get ten different drugs

off the market, and they're from ten different drug companies. It's

not a vendetta against any particular drug company. I have to hope

that the drug companies don't take it personally. I'm just a scientist

doing my job and I have to leave the rest to God to protect me.

 

MANETTE: Has anyone tried to silence you and stop you from becoming a

whistleblower?

 

DR. GRAHAM: Prior to my Senate testimony in mid-November of 2004,

there was an orchestrated campaign by senior level FDA managers to

intimidate me so that I would not testify before Congress. This

intimidation took several forms. One attack came from our acting

Center Director who contacted the editor of the Lancet, the

prestigious medical journal in the United Kingdom, and intimated to

the editor that I had committed scientific misconduct and that they

shouldn't publish a paper that I had written showing that Vioxx

increases the risks of heart attack. This high-level FDA official

never talked to me about this allegation. He just went directly to the

Lancet.

 

The second attack was from other high level FDA officials who

contacted Senator Grassley's office and attempted to prevent Senator

Grassley and his staff from supporting me and calling me as a witness.

They knew that if they could disarm Senator Grassley that would

neutralize me.

 

The third attack came from senior FDA officials who contacted Tom

Devine, my attorney at the Government Accountability Project, and

attempted to convince him that he should not represent me because I

was guilty of scientific misconduct; I was a bully; a demigod; and a

terrible person that couldn't be trusted. These people were posing as

whistleblowers themselves ratting on another whistleblower. Some of

these senior level FDA officials were in my supervisory chain and are

people I work for. They were involved in a coordinated attempt to

discredit me and to smear my name and to prevent me from giving testimony.

 

There's one other thing that happened the week before I testified. The

Acting Commissioner of the FDA invited me to his office and offered me

a job in the Commissioner's Office to oversee the revitalization of

drug safety for the FDA if I would just leave the Office of Drug

Safety and come to the Commissioner's Office. Obviously he had been

tipped off by people in the Senate Finance Committee who are

sympathetic to the FDA's status quo that I was going to be called as a

witness. To preempt that, he offers me this job, which basically would

have been exile to a fancy title with no real ability to have an

impact. This was a conspiracy and it was coordinated and there was

collaboration among senior level FDA officials. What a mess!

 

MANETTE: All of these attacks backfired on them. Tell us a little bit

about that.

 

DR. GRAHAM: Well, Senator Grassley and his staff quickly realized that

what they were saying about me was fabricated. The editor of The

Lancet also realized that what the high level FDA officials were

saying to him was a pack of lies. He sent emails to them saying it

looked to him as if they were trying to interfere with his editorial

process. He was very savvy to what these people were doing. Tom

Devine, as he said publicly, was very interested in doing the right

thing. He said, " We don't want to protect somebody who's a lawbreaker

and who really isn't representing the truth so produce your evidence. "

They had no evidence because there is no evidence. But I produced my

evidence. I showed him all the documentation, all the emails, and the

reports that I've written. They flunked every test and I passed every

test.

 

In all of the criticism I have received relating to Vioxx and drug

safety, they've never attacked the work or the science that I've done

or the results that I've come to. What they've done is call me names.

The ad hominem attack is the last refuge of the indefensible. They

don't have an argument that's substantial. They know that they're

vulnerable. They know that they've disserved the American people. The

FDA is responsible for 140,000 heart attacks and 60,000 dead

Americans. That's as many people as were killed in the Vietnam War.

Yet the FDA points the finger at me and says, " Well, this guy's a rat,

you can't trust him, " but nobody is calling them to account. Congress

isn't calling them to account. For the American people, it's dropped

off the radar screen. They should be screaming because this can happen

again.

 

MANETTE: On CNN with Lou Dobbs you said that there was a certain

" culture " that exists at the FDA. Can you explain what you meant by that?

 

DR. GRAHAM: The FDA has a very peculiar culture. It runs like the army

so it's very hierarchal. You have to go through the chain of command

and if somebody up above you says that they want things done in a

particular way well, they want it done in a particular way. The

culture also views industry as the client.

 

They're serving industry rather than the public. In fact, when a

former office director for the Office of Drug Safety criticized me and

tried to get me to change a report I'd written on another drug – Arava

– he said to me and to a colleague who was a coauthor on this report

that " industry is our client. " I begged to differ with him. I said,

" No, industry is not the client, it's the American people, the people

who pay our taxes. That's who we're here to serve. " He said, " No!

Industry is our client. " I ended the conversation by saying, " Well,

industry may be your client, but it will never be my client. "

 

Another aspect to the culture at the FDA is that it overvalues the

benefits of drugs and undervalues the risks of drugs. And so the FDA

will always say to you, " Well, we're leaving this drug on the market

because the benefits exceed the risks. " Well, the FDA has never

assessed the benefit of any drug that it's ever approved. It works on

what's called efficacy. Does the drug work or not? Does it lower your

blood pressure or does it lower your blood sugar? Not: Does it prolong

your life? Does it prevent you from having a heart attack? Those are

benefits. All they focus on is efficacy.

 

For example, ask the FDA why on earth they didn't ban high dose Vioxx

after the VIGOR Study showed in early 2000 that it increased the risk

of heart attack by 500 percent? High dose Vioxx was approved for the

short-term treatment of acute pain. What earthly benefit was there

that exceeds a 500 percent increase in heart attack risk? Ask the FDA

to produce its benefit analysis that shows that the benefits exceed

the risks. It doesn't exist. The FDA has never looked at benefit. The

FDA just says to the American people, " The benefits exceed the risks.

Trust me. Believe me. " If you held the FDA to its proof the American

people would see how badly served they've been by the FDA and its

culture that belittles safety in the drug companies' interest.

 

If the FDA were to pull a drug due to safety issues, it would hurt the

marketing of the drug. It might also call into question why they

approved the drug in the first place. Therefore, you get this culture

of cover-up, this culture of suppression, this culture of denial, and

this culture that demonstrates above all else that industry is the

client and not the American people.

 

MANETTE: Have your peers turned against you?

 

DR. GRAHAM: No. I've been very fortunate. Tom Devine at GAP has told

me that the experience of a typical whistleblower is that they'll have

the support of their peers but the peers will be so afraid of

retaliation that they won't express that support in public. I've had a

very different experience. I've been basically embraced by my peers as

someone who has said what they want to say and what they wished they

had been able to say and that they recognize as the truth. They're

really proud of the fact that I've said it and they're not afraid to

be seen with me. They're not afraid to work with me. I've been pretty

fortunate in that way.

 

Now with management it's been another story. Upper management avoids

me and doesn't talk to me. I could be walking down the hall and I'll

say hello, and they'll act like I'm not there. They don't give me

interesting work assignments. They don't call me in to consult on

things that I should be consulted on even though I am the senior

epidemiologist in the Office of Drug Safety with more experience than

any of the other people there. I'm looked up to by the scientific

staff because of that expertise. Basically, I feel like I'm in the Gulag.

 

MANETTE: How do you cope with that going to work each day?

 

DR. GRAHAM: It's difficult. It's a mind game. They're hoping that I'll

just become very frustrated and disillusioned and leave or that I'll

slip up in some way so that they can take some sort of action against

me. As Tom Devine at GAP has said, I have to be Saint David. I can't

afford to make any mistakes. That's very difficult and it is a little

bit discouraging. But I've been a target of retaliation in the past.

You take ten drugs off the market well, no good deed goes unpunished

at the FDA. I've experienced retaliation with many of those other

episodes but not as severe as what I've experienced with Vioxx. This

is the first time that my job was actually in jeopardy and where the

FDA actually intended to fire me. That was stopped only because

Senator Grassley intervened. He put the heat on the FDA and told them,

" Lay off. This guy has told the truth. He's helped America. Whose side

are you on? "

 

MANETTE: Were there any warnings that Vioxx was a problem? Did you see

the disaster coming?

 

DR. GRAHAM: I think that I was afraid that there would be a disaster,

but I only became aware of this with the publication of the VIGOR

Study, which was this large clinical trial that was done that showed

that Vioxx increased the risk of heart attack five fold. That study

was published in November of 2000. It was written, performed, and paid

for by industry. What industry concluded was not that Vioxx increases

the risks of heart attack, but that the drug they were comparing it

against – Naproxen – decreased the risk of heart attack. I knew that

was not a sustainable argument. There was no way that Naproxen was

that protective against heart attacks. Clearly Vioxx was the problem.

I knew that Vioxx was on the road to becoming a blockbuster drug (20

million users). All the ingredients were there for a disaster.

 

The FDA is responsible in so far as it could have prevented much of

the damage, heart attacks, and deaths simply by banning the high dose

Vioxx back in mid 2000 when they knew the results of the VIGOR Study.

But the FDA did nothing for almost two years. They were " negotiating "

with the company over a label. What did the label accomplish? Nothing!

Before the label 17 or 18 percent of people who took Vioxx took the

high dose. After the label change 17 or 18 percent were still taking

the high dose. High dose use didn't change at all. People didn't read

the label, and if they read the label they wouldn't know what to do

anyway because it was very confusing. The right thing to do would have

been to pull the high dose off the market because there is no benefit

for short-term relief of acute pain that exceeds this risk. The FDA

made bad decisions based on its culture and its institutionalized

biases that favor industry, and as a result thousands of Americans

died. Americans and Congress should be screaming bloody murder. They

should be beating on the doors of the FDA demanding change.

 

MANETTE: It's estimated that over 200,000 people a year die from

prescription drugs. Do you see this as a serious problem and do you

think many of these treatments are more dangerous than the disease itself?

 

DR. GRAHAM: Death from adverse drug reactions is one of the leading

causes of death in the United States. It turns out that most of these

adverse reactions are actually what are expected in the sense that

they are an extension of the drug's action. For example, we know that

drugs for diabetes can lower your blood sugar. If you're more

sensitive to the drug than the normal person and it lowers your blood

sugar too much, causing you to have a seizure while driving your car

and you get killed, well, you died from an adverse drug reaction, but

it wasn't something unexpected.

 

The blood thinner Coumadin is another example. That drug provides a

benefit, but it is also responsible for probably more deaths than any

single drug currently marketed. But it has a recognized benefit and

there aren't other drugs to do what it does or to do what it does

well. So physicians accept that there are patients who are in a

serious situation and who might die without the drug, so they take it.

 

Yes, drugs cause a lot of harm. Unfortunately, we haven't quantified

the benefits. For most of these drugs it's more belief. It's faith. We

have faith that they'll confer a benefit, but the FDA hasn't

demonstrated that they confer a benefit. We're getting much better at

quantitating the risks. In the future what we need to do is just take

the risks and look hard and dispassionately at what the real benefits

are. If the benefits aren't there we shouldn't be having discussions

about labeling the drug. You need to weed the garden patch of drugs

that aren't doing what they're supposed to do. The FDA has not been

very good about that; it likes to cultivate all these weeds.

 

MANETTE: In a perfect world what role do you see the FDA playing in

our nation's health?

 

DR. GRAHAM: In a perfect world, I think the FDA would need to be

restructured. If it were restructured properly, I think that it could

actually provide a great benefit to the public health. I would

recommend several changes. First, I would separate safety and

post-marketing from the pre-marketing. I would create a separate

center for product safety. Actually, Senator Grassley and Dodd have

recently introduced legislation to create an independent center for

post-marketing safety that would serve to protect the American people

from unsafe drugs. This isn't happening now.

 

On the pre-marketing side, the FDA needs to pay greater attention to

safety. They need to have larger clinical trials. They need to compare

drug products against other drugs that treat the same indication

rather than comparing a drug against a sugar pill. What we want in the

end are drugs that actually have better benefit.

 

The FDA also needs to determine the post-marketing benefits of a drug.

I've done that for several drugs. How many people are actually

benefiting? How many people are living longer versus those who are

having their lives shortened? Only when you have that kind of

information can you make rational decisions about a medication. The

times when I've done the benefit analysis, I've been chastised,

criticized and suppressed by the FDA. These benefit analyses should be

done as a matter of routine.

 

There is a lot that the FDA could do to improve, but the changes

aren't going to happen on their own. Congress is going to have to make

them happen. There's an expression, " the zebra doesn't change its

stripes nor the leopard its spots. " The FDA isn't going to change the

way it does business; changes will have to be imposed from outside.

 

MANETTE: How you do feel about direct-to-consumer advertising?

 

DR. GRAHAM: Direct-to-consumer advertising in general is a great

disservice to the American people. We see wonderful ads of people

demonstrating their health, whether they're skating across the ice or

doing their Tai chi. Madison Avenue knows that a picture is worth a

thousand words, so they convey an image, a message, and it makes an

impression on patients and on physicians. It creates needs or desires

where there really isn't a need or a desire.

 

There was a recent study in The Journal of The American Medical

Association that showed that if patients mentioned a drug that they've

seen on television to their physician they were much more likely to be

prescribed that drug by the doctor. Drug companies know this. That's

why they do it. Would the Vioxx disaster have been as great and as

large in the absence of direct-to-consumer advertising? I submit that

the numbers would have been far lower than what they were.

Direct-to-consumer advertising is part of what made Vioxx a

blockbuster drug. It helped to rev the market up to get people to want

to use the drug.

 

Clearly, direct-to-consumer advertising does not serve the American

people well. Madison Avenue is smarter than the most intelligent

American. That's why they make so much money and that's why the drug

companies go to them to sell their products. We're not living in a

neutral world where the information we're getting is objective and

unbiased. It might be that the average American, given all the data,

all the facts, and all the information in an objective way could make

an intelligent, rational decision. But we don't live in that kind of

world. We live in a world where what we're seeing is a visual image of

these people being vital and healthy and cured of their illnesses. And

it's all because of this little pill that they're taking. A patient

with that condition says, " I want to be just like that person. " So

they go to the doctor and say, " I want that pill. " Are their lives

changed? Maybe some people's lives are changed, but I think most aren't.

 

MANETTE: What do you think people hear when they're watching the ad

and after the ad they list all the possible side effects?

 

DR. GRAHAM: I don't think it registers. You have the visual image that

conveys one message. Then you have the voice that's speaking over this

pictorial being shown telling you what this drug is good for. Then at

the end the auctioneer gets on and says, " You know this drug could

cause…, " and they rattle off 25 different things in three seconds.

You're lucky if you hear anything. I don't think that people come away

with it and they certainly don't come away with any sense of how

likely it is to happen because the visual image overpowers anything

that gets said.

 

It's the same with the ads that appear in magazines. Companies are

required to put some of the labeling in the ad. You have the ad on the

one side – that's the picture. It shows this person being healthy

because they take this pill. The fine print is all on the next page.

People aren't going to read the fine print. It's the same thing with

labeling for physicians. Physicians don't read product labels. Where

do they learn about drugs? They learn about drugs from the detail

person from the drug company or from other colleagues who have used

the drug. They're not learning it from the labeling.

 

MANETTE: Do you think there is a criminal cover-up going on between

the FDA and Big Pharma to approve dangerous drugs that sicken and kill

Americans?

 

DR. GRAHAM: I have no knowledge of criminal activity and I'm sure

there are legal standards for what's criminal and what's not. I do

think that there is an institutional bias at the FDA that says we will

look for a way to say " yes " to the approval of any drug that comes

down the pipe. If a drug is so bad that they can't find a reason to

approve it, they won't. But, if there is any way that they can approve

the drug, they will. The way this is done is by what's called the

" indication. " Why is it that you're going to take the drug? Maybe

you're going to take it because you have high blood pressure. Maybe

you'll take it because you have high cholesterol. That's the

indication. A company may come in with a drug and want to get it

approved for five different indications. One of them is a really

insignificant indication that affects a very small number of people.

The main indication might affect millions of people. The drug doesn't

show efficacy for that major indication, but they're able to somehow

or another approve the small indication.

 

So the drug gets approved for this narrow indication, but the FDA and

the drug company both know that it's going to be used for that other

indication. It's going to be used " off-label. " Then, the FDA turns

around and says that they don't regulate the " off- label " use of

drugs. No. But, they aid and abet it. They allow it to happen and in

many instances " off-label " use of a drug product is a public health

threat. The FDA has a responsibility to protect the public health. The

FDA should be intervening, but they don't. In my own experience I have

seen multiple examples where I've heard people say, " We can't ask a

company to put that in the labeling because the company will say no. "

Or, " We can't do that because that will decrease their marketing.

We've got to try to approve this drug. Let's see if we can give them

this small indication. At least it's giving them something. You've got

to find a way to say yes. "

 

That is the typical attitude of the FDA culture. I think Congress is

partially responsible for that because when they issued the PDUFA, the

Prescription Drug User Fee Act, what they were really saying was, " We

want you to review these drug applications more quickly because you're

keeping lifesaving medicines from the American people. " That's the

line they were fed by Big Pharma. So they pressure the FDA and the FDA

gets the message. It's a really pernicious system. I think it's

unfortunate. There are many people from the FDA who have examples that

they unfortunately can't talk about. They'd lose their job and maybe

get thrown in prison because you can't discuss confidential and trade

secret information. But the fact is these things happen at the FDA and

there have been multiple examples in the past where one could see

evidence of that.

 

MANETTE: Did your faith as a devout Roman Catholic play any role in

the decisions you made to put your career on the line to report the truth?

 

DR. GRAHAM: It did in so far as my faith forms my conscience. It's

sort of my sense of what's right and what's wrong and what I am and am

not responsible for. I was in a situation here with Vioxx where I was

invited by Senator Grassley's office to testify. I could have told

them no, but then they would have subpoenaed me. So of course I went

peaceably. I was faced with this dilemma. Should I lay it on the line

and tell them the way it really is or do I kind of downplay it? There

are ways of doing that.

 

What I concluded was that I'm now being given the opportunity to tell

the truth to the people who are in a position to actually make a

difference. I can't make a difference. I can't change the FDA, but

Congress can. If I don't tell them the truth, then I'm now

responsible, in part, for future deaths. I don't want to become a

co-conspirator with the FDA in what happens with Vioxx because tens of

thousands of people were injured or killed because of the FDA's

disregard for safety. If I keep quiet about that, now I'm part of the

problem. I'm one of them, and at that point then my conscience asks

me, " You know what the truth is, are you going to speak it or aren't you? "

 

So I went ahead and did that and prayed that it all works out well for

me personally. That I have a job and I'll be able to support my

family, that I'm protected from retaliation, that maybe some good will

come out of that. My faith plays a role, but it wasn't a direct

teaching of the church. You have to do x, y and z, but it's the faith

as I've internalized it. My conscience is formed by the voice of

Christ speaking internally to me. That's what the conscience is; it's

the voice of God speaking to each and every one of us about what's

right and what's wrong. I knew what was right. If I walked away from

that nobody else would have to do anything. I'd be beating myself up

because my conscience would condemn me. So yes, faith plays a part in

every thing that I do. It's not saying I'm a saint, because I'm not.

But I can't separate who I am from my religious faith. It's all part

of the same person.

 

MANETTE: Do you think Congress genuinely wants to fix the problems at

the FDA or are too many politicians influenced by the pharmaceutical

industry?

 

DR. GRAHAM: I don't know what Congress will do in the end. My hope is

that they will act decisively to reform the FDA and make the American

people safer by having strong post-marketing. Will that happen or not?

I don't know. I think there are many people in Congress who see this

as a serious problem and who very much want to see a change. I think

at the same time there are other people who don't think it's such a

bad problem, and many of those people honestly believe that. For those

people I'd say they haven't seen the evidence so they don't really

understand how bad the problem is. There are undoubtedly some people

who are influenced by industry. Does that influence their judgment in

the end? I don't know. They'd probably say no, it doesn't. Maybe at a

conscious level it doesn't. But we have the same phenomenon in the

scientific world where we look at research studies that are funded by

industry and studies that are funded by government, by National

Institutes of Health or the Medical Research Council in the United

Kingdom. Multiple studies have been done that have shown that if your

study is funded by industry you are much likelier – about five times

more likely – to come up with the result that's favorable to the drug

company than if your study on the same subject is funded by an

independent body unrelated to the company.

 

Now, are the researchers who did this study biased? Are they

consciously cheating and manipulating the data and everything else?

No. I don't think that's happening at all, but the fact is if the

study is funded by industry it's much more likely to be favorable to

industry. Without attributing bad motivations to the scientists doing

those studies all I can do is point to a strong correlation.

 

With Congress I would be concerned that there could be a strong

correlation there because Pharma is very bright. They fund as many

politicians as they can. They get to the Republicans and the

Democrats. Look at the funding on the major committees, the Health,

Education, Labor and Pension Committee in the Senate or the Oversight

and Investigations Subcommittee in the House. The Wall Street Journal

reported recently that many people on these committees are funded by

industry to a substantial degree. Industry knows how to exercise

influence. What we have to do is overcome that influence with

evidence, and then rely on the fact that at the end of the day the

Congress will do what's best for the American people.

 

Will that happen? I don't know because then it gets embroiled in

politics. You know, Republicans versus Democrats, the left versus the

right, conservatives versus liberals. Yet, what we're talking about is

public health and public health is nonpartisan. I can say this with

certainty. For every member of the House of Representatives somebody

in their district died because of Vioxx. Somebody in their district

had a heart attack because of Vioxx. For every Senator in the Senate,

many more people in their state died because of Vioxx or had a heart

attack because of Vioxx. It doesn't matter whether it's a red state or

a blue state. Those are human beings and what we're talking about is

public health. What I'm hoping is that Congress will respond. There is

a problem and the evidence is overwhelming, but we'll just have to

wait and see.

 

MANETTE: What are you thoughts on President Bush's attempt to pass

tort reform, which would protect most pharmaceutical companies from

lawsuits except in the most egregious cases?

 

DR. GRAHAM: I think it's dangerous and wrong for the following

reasons. We already have an FDA that's been neutralized by industry

and sees industry as its client. The Center for Drug Evaluation and

The Office of New Drugs dominates drug safety so that the drug safety

is not independent. Drug safety can't protect the American people. So

government now isn't going to protect the average citizen from the

consequences of unsafe drugs. The only alternative they have left is

the legal system – the tort system. It's not a wonderful system. It

would be much better if we had effective post-marketing regulation so

that we could get bad drugs off the market before they hurt more

people, but that's been neutralized. All that's left to people now is

the courts. That's the only way we have of getting companies to change

their behavior.

 

What tort reform will do is remove that threat as well. It's basically

giving companies immunity because now the people who are injured by

the drugs can't recover damages that might actually mean something to

industry. I mean $250,000 for damages; they blow that in one ad

campaign. To them that's nothing. But a lawsuit for multiple millions

of dollars has more of an impact. Now, is that optimal? No. But the

fact is that since we have a regulatory agency that doesn't regulate

and we have a public health agency that doesn't protect the public, we

have thousands of people who are being injured by products that the

FDA knows are unsafe. The FDA knew there was a problem with Vioxx.

They knew it was a big problem back in mid 2000 yet did nothing about it.

 

There has to be a system in place that reins companies in. If the FDA

isn't going to exercise control over companies, then who will? How

will it happen? I don't think that working through the courts and

lawsuits is a particularly effective way of doing it; but it's the

only recourse we have now, and that will be removed as well. You can

demonize the trial lawyers but I think that there are patients who are

severely injured by drugs. The defense is, " It's on the labels so

we're protected. " The problem is that nobody reads the labels so how

do they protect anyone? The FDA should be making those decisions.

 

MANETTE: What can you tell us about all the antidepressants on the

market that millions of children are taking?

 

DR. GRAHAM: In early 2004, SSRI antidepressants and suicidal behavior

was a big safety issue. The FDA had suppressed a report written by a

colleague of mine in drug safety and had prevented him from presenting

this information in an advisory committee meeting. That information

leaked to the media, embarrassing the FDA because it had been caught

suppressing very important information – that most of the

antidepressants don't work for treating children. Someone in my

supervisory chain initiated a criminal investigation to identify the

person who had leaked this information to the media. It turns out that

the investigation ordered by these FDA officials was illegal. They

broke federal laws – at least two or three federal laws – in ordering

this investigation.

 

I think it's well established that depression is very common in

adolescence. With the antidepressants that we have on the market right

now only one of them has been shown to work in children and that's

Fluoxetine or Prozac. All the other SSRI antidepressants are no better

than sugar pills. However, if you were to read the labeling for these

drugs it doesn't point that fact out so patients think one SSRI is as

good as another. This is another way that the FDA has betrayed the

American public and has betrayed the public health.

 

With the SSRI and antidepressants what the FDA should have insisted on

was a signed informed consent at the time a child was going to be

treated. That informed consent would say three things. One, these are

the antidepressants that are available. Only Fluoxetine has been shown

to work for depression in children. All the other drugs are no better

than placebo. That's point two. No better than placebos. No better

than sugar pills. Third, all of these drugs appear to have the ability

to increase the risk of suicidal behavior. As a parent, if I see that

in writing and the psychiatrist or GP is going to write the

prescription and put my child on some drug other than Fluoxetine, I

can say, " Doc, why are you putting my child on a drug that doesn't

work in kids. "

 

The FDA didn't want patients to have that information so they refused

to have signed informed consent. The companies didn't want the

patients to have that information because all of a sudden the

" off-label " use of these drugs would dry up. So whose interest was

being served there?

 

MANETTE: How do you feel about taking the approval process out of the

hands of the FDA?

 

DR. GRAHAM: Well, where would you put it? If you put it somewhere else

they're going to eventually become co-opted the way the FDA has been

co-opted. I think the most that we could probably hope for is to try

to disassociate the industry pressures from the approval decision. You

have to change the culture of the organization, and you have to change

the incentives in the organization. The culture and the incentives

that the FDA operates by would have to be changed, and Congress can do

that through legislation and by establishing different standards for

how a drug gets approved. Not only do you have to show that the drug

is effective, but you've got to show that it works as well or better

than other drugs that treat that indication. You've got to prove to me

that the drug is safe, not that the drug is harmful because you're

never going to prove to me that the drug is harmful. You set up

stringent standards of evidence that might lead to the approval of

safe drugs that actually have benefits to the population.

 

Then pair that up with an independent post marketing regulation.

Currently, the pre-market people who approve the drug decide what

happens after it's on the market. If the drug needs to come off the

market, they're the ones who have to say yes at the end of the day.

The people at the FDA who approved the drug, the Office of New Drugs,

they are the single greatest obstacle when it comes to removing unsafe

drugs from the market. I can vouch for that from personal experience.

What you have to do is you have to take that responsibility and power

away from them and put it with the group who sees their mission as

serving the public and protecting the public health from unsafe drugs.

I think if you do those two things you'd be a long way towards getting

the FDA on the right footing.

 

Also, it would probably be beneficial not to have the FDA's funding

come from industry. He who pays the piper calls the tune, and we now

have a captured agency. Industry underwrites more than 50 percent of

the Center for Drug Evaluation's budget. When industry yanks the chain

whose neck is going to get tugged? The Center for Drug Evaluation! If

industry isn't happy with them and the funding dries up what are we

going to do? We're going to have to let half our people go. The

program is going to shrink. Congress is going to be jumping up and

down on our back. So it's a captured agency and America is not well

served when industry is calling all the shots. Yes, industry has a

right to make a legitimate profit from marketing products that help

the American people. But you shouldn't have a situation that just

basically leaves the American public defenseless. And that's what we

have right now. We're virtually defenseless.

 

MANETTE: Are there other Vioxx's out there? Do you think this will

repeat itself at this high profile level?

 

DR. GRAHAM: At this current moment I don't think there are other drugs

out there that are as bad as Vioxx in terms of the enormous numbers of

people that were hurt. During my Senate testimony I did mention that

there were five other drugs that I thought the FDA really needed to

reevaluate because in my estimation the benefit to risk was misjudged.

After I named those five drugs the FDA was in the media saying that I

did junk science and that these drugs were safe and effective and that

I was a crackpot. However, recently the FDA announced that they were

going to take Bextra off the market. Well, Bextra was one of the five

I mentioned. They announced that with Acutane they were going to

impose a restricted distribution system. Well, I had recommended a

restricted distribution system 15 years ago. The major problem with

Acutane is that it's just so widely overused that it causes an

enormous amount of potential harm to pregnancy exposure. If we

restricted the use of the drug to the small number of women who really

need it each year, the problem would be pretty much resolved. But the

FDA didn't want to do that because it would interfere with company

profits. If you restrict the distribution and only one-tenth of the

people who are getting it now are getting it tomorrow, profit will

drop 90 percent. Of course companies aren't going to go along with

that and the FDA isn't going to do anything that's going to harm

corporate profit.

 

After my Senate testimony the FDA announced that they can look at

other drugs – not only the other three of the five that I mentioned.

There are other drugs on the market that I prefer not to talk about

that the FDA knows are killing people. Ten or 100 people a year are

dying because of the use of a particular drug or being hospitalized.

Hundreds or maybe thousands of people are being hospitalized each

year. For some of those drugs the benefits do exceed the risks. For

others, it's clear that more could and should be done and maybe that

means restricting the distribution of the drug's use or maybe it means

banning an indication for the drug saying the drug should not be used

for particular indications. Maybe it would be something like with the

SSRI's where I believe there should be signed informed consent so that

parents will know that the drug the doctor is prescribing for their

son or daughter actually doesn't work in children.

 

I think that there are many things that can be done that haven't been

done. There are other unsafe drugs out there, and the nature of our

business is that a drug could be approved tomorrow that turns out to

be the next Vioxx and we won't know until it happens. Then the

question is, how quickly do we identify the problem and how quickly do

we take effective action against it? We're pretty good at identifying

these problems quickly. Where the FDA falls flat on its face is that

there is a long period of time in which it does nothing. Then what it

normally does is woefully inadequate and ineffective and as a result

the body count mounts and that needs to be changed. Maybe Congress

will change that.

 

MANETTE: Let's talk about incentives. When you say incentives what do

you mean? For example, working at the FDA, is their pay somehow based

on how many drugs they approve?

 

DR. GRAHAM: Currently, the performance evaluations for managers at the

FDA are built around the drug review. How many reviews did they get

done? Did they meet their PDUFA deadlines? It looks bad if you miss

your PDUFA deadlines. The unspoken mores – what's the expected – is

that you're going to approve as many of these drugs as you can. There

has to be an overwhelming reason for you not to approve. Frequently

what will happen is that these medical officers in their review will

recommend that a drug not be approved and they get overruled by the

higher ups because the higher ups are answering to a different set of

incentives. You have to change that. A lot of that comes from the

leaders. What I want to see is does the drug really make a difference?

Is it beneficial?

 

There are many classes of drugs where we've got 10 or 15 members of

that class. They all lower your blood pressure. They all lower your

cholesterol. Another one comes along and the FDA feels its obligation

to approve it. Why? Maybe the standard should be that for the drugs

that come later in a class, they've got to show that they're actually

better than the drugs on the market because we've already got these

other drugs that work. That would create incentives maybe within

industry to develop drugs that are better than the ones that are

already there. Currently, the way the incentives are for industry,

it's safer to do a " me too " drug, another drug in the same class.

 

MANETTE: Do you think that the FDA should not be partially funded by

industry?

 

DR. GRAHAM: I think that PDUFA funding for the FDA is a mistake.

 

MANETTE: Can you explain that a little more clearly because most

people don't know what PDUFA funding is?

 

DR. GRAHAM: The drug companies pay a substantial amount of money to

the FDA at the time that they bring a drug application for approval in

order for the FDA to review the drug. Basically it's a tax. It's a

fee. Industry pays the fee, and the FDA will review the drug

application. But the real expectation is from the company: " We've paid

our money, now approve our drug. " That's basically how the FDA reacts

as well. I think that the funding for the FDA should be independent of

the industry that it's regulating and I think in the scientific field

there's good evidence to support this notion. Industry money is

influencing the decisions that get made, and it creates this incentive

structure. You have this culture, you have these expectations, you

have pressure from Congress. All of them come to a head at the FDA and

all of those incentives are in the direction of " approve the drug. "

That's what happens so I believe that the FDA is unduly influenced by

industry and that undue influence is in part the result of industry

money funding the FDA operations.

 

MANETTE: Dr. Graham, thank you for your commitment to your convictions

and for sharing insights that drove you to save many lives.

 

DR. GRAHAM: You're welcome. I hope I've helped.

 

 

 

Overview:

 

* The FDA Exposed: An Interview With Dr. David Graham, the Vioxx

Whistleblower

 

Source: http://www.newstarget.com/011401.html