came with the red flag on it, would it have probably gone to file 13 also, or not?

Dr. WALTA. No; the big red warnings when they come out, get everybody's attention. They recognize that something has happened to this product that made the FDA either force the drug company or encourage the company to communicate to us that there's a problem. A red warning gets my attention.

Mr. LIGHTFOOT. Would it be safe to say then, that's a legitimate warning device or tool or however you want to characterize it, to get people's attention?

Dr. WALTA. It's effective for me.

Mr. LIGHTFOOT. Would anybody else care to comment on that, because as I say, what we are trying to do is to try to find out ways to make sure that you all have the information that you need.

Dr. MORRISEY. I read them both, but I believe that if they had come to your office and detailed you, they should have come back and detailed you again on the hazards of this drug as soon as they knew it.

Dr. Walta had an incident in May and mine was in July, 3 months later. I mean, they did nothing in the meantime. However, the minute that this incident happened I called Hoffmann-La Roche. I spoke to Dr. Alan Bass and I told him that I wanted him to come and look into this and file the papers with the FDA.

He told me at that time, he was extremely busy and could not come out to Long Island because he was investigating other cases. I told him I wanted him out there as soon as possible, and I wanted him to bring executives with him and not salespeople. I wanted to discuss this case with him and I wanted them to report it to the FDA.

He came out about 2 weeks later. I met with him and a nurse. We went over the entire case. He was going to file the papers with the FDA and send me a copy. He never sent me a copy. At that time, he said he had a large number of reactions and he said probably it's time for us to go back to good old Valium. That was his direct words to me.

The drug company should have communicated that to us at the time they had their first incident.

STATEMENT OF DR. SIDNEY M. WOLFE, DIRECTOR, PUBLIC

CITIZEN HEALTH RESEARCH GROUP, WASHINGTON, DC

Dr. WOLFE. If I could comment on this issue, red warning letters as opposed to information for doctors. I also am an internist. I am licensed in the District and I get tons of such mail as well. FDA has policies, regulations, that require if there is really new, important information about dosing and other things that warn about a drug, that it really should go out in a red warning envelope for the very reason that there may be one of those for every hundred or thousand of the other kind of drug promotional mail. That's the only way you are going to grab the attention of somebody who is getting 50 pounds of mail a week.

So, I think that the fact that this was buried in such an obscure form prevented many physicians such as Dr. Walta and others,

from learning about the changes that the company was well aware of at the time but wanted to keep to themselves.

Mr. LIGHTFOOT. Are you saying that the first Dear Doctor letter that was sent out was not put in the type of form that you are accustomed to receiving, that it didn't go into enough detail, or whatever?

Dr. WOLFE. Yes; if you look at the form of the November letter, when they finally lowered the dose for other people and so forth, a red warning compelling you to look at it. Unfortunately, this is after huge numbers of people had already died, and too late to warn many of the doctors. So, there is clearly a difference.

Mr. LIGHTFOOT. Huge numbers of people, how many have died that you are aware of?

Dr. WOLFE. Well, I was reflecting on the fact that Dr. Julien and Dr. Walta say that just in the Portland area alone they are aware of seven deaths. The entire State of Oregon is something like 2.6 or 2.7 million people. In other words, it is barely over 1 percent of the United States.

I would stake my reputation on the fact that there are well over 100 deaths from this drug, even though the actual number reported to the FDA from respiratory depression is only 36. The FDA frequently throws out the figure that only 1 in 10 adverse drug reactions get reported.

I, alone, have been called concerning nine deaths from this drug. In a number of those instances when I asked, I was told that these had not yet been reported to the company or to the FDA. The circumstances in which these deaths are occurring are tragic. The physicians are very upset.

I have never been called, in the 17 years that we have been doing this work and have worked on dozens of different drugs, I have never been called by more physicians about the fact that they were not adequately aware of the dangers of a drug and, therefore, had done things that have resulted in the death of a patient.

I think that the actual number of deaths is well over 100. If a systematic survey of hospitals where most of these have occurred is done, I would bet that figure would be equal if not exceeded.

Mr. LIGHTFOOT. If you say 36 deaths have been reported――
Dr. WOLFE. To the FDA, right.

Mr. LIGHTFOOT. To the FDA, I would assume that the responsibility of reporting deaths would fall upon the hospitals or those people who administered the drug, or were involved with that patient at the time of death. How come the other 70-some cases that you say are out there haven't been reported? Why aren't they being reported?

Dr. WOLFE. In this country, unlike some European countries, reporting of adverse drug reactions on the part of a doctor or hospital is not mandatory. If the company finds out about these, the company is required to report them.

In fact, something like three-quarters or 80 percent of the average reactions which are reported to the FDA, come from the company, originally told about them by the doctors and hospitals. The FDA, in the last couple of years, has been making a major effort to get doctors to report more adverse drug reactions. I still think that

they would answer, if you ask them later in the morning, that only a small fraction of adverse drug reactions get reported.

Doctors are worried, hospitals are worried that even though the reporting is entirely anonymous, that the reporting might somehow result in malpractice actions brought against them. They also believe at some point or other, the FDA knows about this and they have already had a few reports and so forth. There are a number of reasons, but I think that it is clear that only a fraction of adverse reactions get reported in this country.

Mr. LIGHTFOOT. Perhaps my logic is flawed, but if I were a physician and in our litigious society where everybody is out to sue everybody for anything, if I lost a patient and I thought the drug was the cause of it, I would think that's the first thing I would do is to report that to protect myself in case that it did get to a jury trial; that it wasn't my treatment and it wasn't the way that I administered the drug, it was the drug itself.

I can't quite follow why people aren't reporting these incidents? Dr. WOLFE. I can't either. Just last week, there was a hearing concerning Accutane, also made by Hoffmann-La Roche, in which it was clear to everyone at the hearing-perhaps with the exception of Roche-that only a fraction of the birth defects that had been caused by this drug had been reported.

We have heard this over and over again. Your logic, I think, is correct. But, I think that if a doctor keeps good records and shows, for example, that he or she was giving a dose that was within the recommended range, that in and of itself would be a protection against a malpractice suit and would turn it into a product liability suit whether or not they report it.

I don't think that a doctor would be held at fault in a malpractice proceeding for having failed to report it to the FDA or the company. Within the company, the people to whom these deaths are reported are often the sales people who are visiting doctor's offices. Here, you have heard this morning of sales people totally unaware, because the company didn't tell them, about all the deaths that had occurred up to a point.

So, the whole process of interaction between the sales people and the doctors is somewhat flawed here, because they weren't informed by the company.

Dr. WALTA. Just one point. In my instance, my intent to report it was my concern that I never wanted to ever have this happen to me again. It was a terrible experience. If the drug were at fault, I didn't know that at the time. I didn't understand what happened. But if it were at fault, I wanted it stopped.

If the drug were the reason, I wanted it investigated and that's why we called Roche as well.

Mr. LIGHTFOOT. My reaction would be like yours, I would think. That's why I can't understand why these other cases haven't been reported. It makes it difficult, on the other hand, if you don't know what is going on out there to react to it in that respect.

I see that my time has expired. Did you want to respond to that, Dr. Morrisey?

Dr. MORRISEY. I reported it for the similar reason, that I wanted the drug investigated because I knew that there was something wrong with the drug.

I did not want to speak to any more salespeople. When I spoke to the product liability people at Hoffmann-La Roche, they stated that I asked them why their salespeople were not more knowledgeable. They said they put 400 to 600 people just on the staff and that these people were not as trained as well as they would like them to be trained, and that's probably one of the reasons that detailing was so-shall we say, slipshod.

As far as drug followup and sending out letters, the automobile company does a better job than the drug companies because they send out recall notices, they send out followup recall notices, and then sometimes they will call you if it is an extreme problem. Mr. LIGHTFOOT. Thank you, Mr. Chairman.

Mr. WEISS. Thank you very much, Mr. Lightfoot.

Dr. Dry, you are a general and vascular surgeon; is that correct?

STATEMENT OF DR. LAURENCE R. DRY, GENERAL AND VASCULAR SURGEON, AND EDITOR AND PUBLISHER, ATTORNEY'S MEDICAL ADVISORY LETTER, KNOXVILLE, TN

Dr. DRY. That is correct, sir.

Mr. WEISS. Aren't you also the editor and publisher of the Attorney's Medical Advisory Letter?

Dr. DRY. I am. It's a publication that is primarily directed to risk managers and hospital attorneys, and attorneys that are interested in both sides of the medical malpractice.

Mr. WEISS. In October 1986, your newsletter published an article on Versed which concluded that Versed is "a very dangerous drug if improperly used and improper use is openly invited with current packaging." In fact, didn't you write that the company had made a 'gross error"?

[The article referred to is app. 1, p. 136.]

Dr. DRY. That is correct.

Mr. WEISS. You further wrote that midazolam-that's the chemical or generic name, right?

Dr. DRY. Yes.

*

Mr. WEISS. "* * is 3 to 4 times as potent as Valium but is marketed in the same dilution, 5 mg/ml. This means that each 5 mg. of midazolam is equivalent to 15-20 mg. of Valium and physicians used to using Valium may easily overdose patients with the newer drug * The packaging of the drug in the 10 mg. ampules and syringes (equivalent of 30-40 mg of Valium) by its manufacturer, Roche, was a gross error." That's an accurate quotation; is that correct?

* *

Dr. DRY. That's correct.

Mr. WEISS. In reporting a fatal respiratory reaction to Versed, one doctor noted Versed patients in other hospitals in his area "going into respiratory and cardiac arrest" and wrote "that because of the similarity of size and total milligrams of dosage of this product and Valium, physicians are prescribing this product as they would Valium." [The report from this doctor is in app. 1, p. 138.] Is this what concerned you?

Dr. DRY. Yes, it is. I think by the time we had written this article, there were plenty of reports out to suggest that Versed was quite a bit more potent than Valium.

Mr. WEISS. Would it surprise you to learn that by October 1986, the same month in which your article was published, Roche was aware of the problem of endoscopists using Versed as they had Valium?

Dr. DRY. The company had been pushing this drug very vigorously for use in endoscopies and in use in physicians offices. I am sure that they had had some bad experiences at that time that they knew about.

Mr. WEISS. We have a tape of an October 18, 1986, meeting between Roche officials and consulting anesthesiologists, in the course of which a Roche official stated that "we're finding that what they're [i.e., endoscopists] doing is * trying to mimic their use of Versed as they had with injectable Valium and we're getting into trouble."

Why did you think the packaging of Versed was so dangerous? Dr. DRY. Versed was packaged as though it was Valium and it isn't. It's three to four times as strong. When an endoscopist, who is basically unfamiliar with the drug but who has been told it's the greatest thing since white rice decides to use the drug, he is going to look at the package insert, he's going to look at the size of the ampule.

Oftentimes, it is not a doctor who is doing the injecting, it's either a technician or a nurse in an endoscopy situation. The typical modus is to assume that the proper dose is a vial or a predrawn syringe. That's why I said that the packaging invited disaster. It invites you to use one ampule, which is a whopping dose for most people.

Mr. WEISS. We are now going to put technology to the test. Yesterday the House failed when our electronic computer broke down. On October 18, 1986, 7 months after U.S. marketing of Versed began, Roche officials met with several anesthesiologists on Roche's Advisory Board on Versed. By this time, Roche had received reports of over one dozen deaths associated with the use of the drug. We are now distributing a transcript of selected excerpts of the tape recording of that meeting that was obtained from HoffmannLa Roche. [The transcript of these excerpts is in app. 1, p. 141.]

Without objection, the entire tape and transcript will be placed into the record.

[The transcript of the tape is in app. 1, p. 142.]

Mr. WEISS. If you will, please play the tape. You will be hearing the voice of someone from Roche named Mary.

[Tape recording was played.]

Mr. WEISS. That is a tape of a meeting on October 18, 1986. Dr. Wolfe, what is your reaction to the tape?

Dr. WOLFE. I don't know if people were able to hear the electronic record of it. I guess the main thing that is running through my mind right now-and I may not be as articulate as I would like to be-what if the families of people who were killed by this drug heard Roche and its consultants laughing essentially about the fact that the drug was marketed at too high a dose which resulted in a lot of deaths.

I mean, on one hand, the company is bragging about having sold $15.2 million worth of the drug and then says that we would have sold even more if we had known how powerful a drug it was. In