Dr. JULIEN. Because at the point of slurred speech, you can still see respiratory depression and decreases in blood oxygenation. In addition, the drug has a slower onset of action than you would expect. If you titrate patients to the point of slurred speech, they will continue to absorb additional drug into the brain for several minutes after that point, so they actually become more deeply sedated following the point where you intended to go.

Mr. WEISS. Dr. Lisbon, doesn't a recently published study by Alexander and Gross indicate that Versed may make it more difficult to detect serious losses of oxygen because it suppresses some of the clinical response, such as increased breathing, that normally signal such trouble? [The study referred to is in app. 1, p. 196.]

Dr. LISBON. Yes, it does. I believe I addressed that a little bit before.

Mr. WEISS. I think that you both said that oversedation is more difficult to detect, therefore, with Versed than with Valium; is that correct?

Dr. LISBON. That's correct also.

Mr. WEISS. Do you agree with Dr. Ronald Miller, a Roche consultant, that a Versed patient can be moving yet be heavily sedated and that "one trap a person unaware of [Versed's] pharmacologic properties can fall into is not recognizing that" such a patient can be undergoing "severe respiratory depression"?

[The paper in which Dr. Miller made this observation is in app. 1, p. 265.]

Dr. LISBON. That's correct. Many times when people are hypoxic or not receiving enough oxygen to their brain, they become agitated. Absolutely, at that time, the wrong thing to do is to inject them with more drug.

Mr. WEISS. Dr. Lisbon, has part of your concern been that Versed would be widely used for conscious sedation by nonanesthesiologists who would fall into such a trap?

Dr. LISBON. Yes, I have been very concerned about that from the beginning of usage of this drug in this country. I would like to see this drug limited to use by anesthesiologists in the hospital setting. Mr. WEISS. In your judgment, does the likelihood that many physicians, particularly endoscopists, administering Versed will not realize that their patients are already adequately sedated and do not need more of the drug enhance the importance of having the lowest, effective recommended total doses?

Dr. LISBON. Yes, sir.

Mr. WEISS. Do you believe that the problems that have apparently resulted from Versed were preventable, Dr. Lisbon and Dr. Wolfe?

Dr. LISBON. Yes, I do. I believe if we go back to the British literature, as far back as 1982, that the dosage is the correct dosage that should have been recommended in this country. The data were available and were available to both the company and the FDA.

Mr. WEISS. Versed was approved in December 1985. Dr. Wolfe, I understand that you have questioned the number of new molecular entities approved during that month; is that correct?

Dr. WOLFE. Yes. In 1985, FDA boasted of having broken the modern record for the largest of drugs approved, at least in the last 20 years. Thirty new drugs were approved in 1985. It is of interest

that 16 of them were approved just in the month of December; 2 of those 16 were suprofen, an arthritis drug which we petitioned and sued to have FDA take off the market and which has now been taken off the market worldwide.

Another of the drugs in the 16 of the month of December was this one. The drug had been pending at FDA for a long time, but maybe it should have pended a little longer and people would have focused on the fact that it was being approved at too high a dose. Mr. WEISS. On November 20, 1985, 1 month before Versed was approved, two Roche officials wrote that "we have learned recently that Versed will be FDA approved by January 1, 1986."

[Their November 20, 1985, letter is in app. 1, p. 273.] Would you have any comment on that, Dr. Wolfe?

Dr. WOLFE. Again, I don't like to overuse the word shocking. That essentially tells us that the company was informed by FDA prior to the time that this drug was approved late in December 1985, that they could count on it being approved by the end of the year. Somehow or another, it was going to get through the pipeline. I don't think that's a very healthy relationship between the company and the FDA.

Mr. WEISS. Thank you. Mr. Lightfoot.

Mr. LIGHTFOOT. Thank you, Mr. Chairman. I would like to, having been one who has enjoyed the joys of an endoscope and who has also gone through recent surgery, compliment you gentlemen on the work that you do. As my anesthesiologist said, anybody can put you to sleep. The important thing is that we can wake you up. I appreciate your efforts on that behalf.

Mr. Chairman, I would like to ask unanimous consent that we place in the record the Hoffmann-La Roche response to Dr. Wolfe's petition that was dated April 25, 1988, and was addressed to Commissioner Young at the FDA.

Mr. WEISS. Without objection, that will be done.

[The response referred to is in app. 1. p. 274.] In fact, without objection, we will place into the record a number of the documents that we have referred to in the course of these hearings.

Mr. LIGHTFOOT. Also, Mr. Chairman, the tape that we heard, could you enlighten us as to where that was obtained and under what conditions?

Mr. WEISS. Yes. I think that I indicated that Hoffmann-La Roche gave us that tape at our request.

Mr. LIGHTFOOT. I would also like to ask unanimous consent that the entire tape be put in the record. Having spent 18 years in the news business, I know it's pretty easy to pick out a sentence and have it misconstrued or the whole contents changed. I think it would give us a better feeling for what was actually trying to be accomplished at that particular meeting.

Mr. WEISS. Without objection, I have already requested that be done. I assume that you are talking about discussions relevant to this particular drug?

Mr. LIGHTFOOT. Šince we haven't had an opportunity to hear the tape, I would just request the entire tape be put in and we can go through it later.

Mr. WEISS. Without objection.

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

Mr. LIGHTFOOT. Dr. Wolfe, I notice that following the playing of the tape you were reading from your comments on a typed sheet of paper.

Were you aware of the contents of this tape before you heard it today?

Dr. WOLFE. The typed sheet of paper was the one that was given out by the staff. I was reading from the same sheet of paper that you were just given, which I have not seen before. This is the typed sheet of paper, and I was reading because I didn't hear it very well either.

The thing that the staff handed out about 2 minutes before the tape was played..

Mr. LIGHTFOOT. And, you had no prior knowledge of what was on the tape until you heard it?

Dr. WOLFE. That's correct.

Mr. LIGHTFOOT. The only reason that I ask is that we on the minority side only found out about this hearing last Tuesday, by reading about it in a trade journal. We weren't aware of who you gentlemen were going to be until yesterday morning. We understand that the FDA was not notified who would testify until this morning.

As you might have noticed, we received a transcript of the tape after all of you did, and that was the first that we had seen it as well. It makes it extremely difficult to ask the important questions that need to be asked under those conditions.

Dr. WOLFE. Let me just amend that somewhat. About 5 months ago or 6 months ago, before we filed our petition, I had called a number of anesthesiologists including anesthesiologists who apparently were there at that session when that tape was made. They had told me that the session had occurred, when it occurred, and the kinds of things that were discussed.

That is a different matter from actually having a copy of the tape or whatever. So I mean, I knew about the existence of the tape from some anesthesiologists who were fairly angry with the company for failing to pay any attention to them. I mean, one of the comments in that tape was we all knew how powerful it was. Obviously, that included the company too, but they didn't do anything about it.

So, I think that if the investigation goes further, a number of the advisors or consultants to this company will be found to be fairly angry at this whole turn of events and why the contents of that tape were kept secret.

Mr. WEISS. We will pick up where we left off. At this point, the second bells have rung for a vote. We will recess briefly.

[Brief recess.]

Mr. WEISS. This subcommittee is back in session. I have just one question, and then we will conclude with Mr. Lightfoot's questioning.

Dr. Wolfe, how do you respond to the argument that package insert instructions to titrate to desired sedation levels, not labeled total dosage ranges, are the key to determining proper dosage?

Dr. WOLFE. Titrate translated into English means be careful. I think that one of the things that has been brought out this morning that a little tiny bit extra of this drug, even if you are careful,

may make the difference between someone living and someone dying.

The labeling, when it originally came out, said that the recommended dosage range was 0.1 to 0.15 milligram per kilogram sometimes 0.2 as we have discussed before, as opposed to it being 0.07. If you contrast that with the current labeling which says as little as a milligram might work, what we are talking about is the difference between a range that is suggested of a total dose of seven to 10.5 milligrams when it first came out, and now they are telling us that as little as a milligram would work.

Even with a milligram you want to be careful. You want to be careful wherever you are, at the high or low end of the dosage range. It is a combination of carefulness and how much of the drug. I think that you need both the titrating kind of notion and some recommendation about where to start titrating, so to speak. I mean, I know a number of gastroenterologists, ones who I have worked with in the past, who tell me that some people can respond to as little as half a milligram or 1 milligram of this drug. Well, when it came out they were being told use seven to 10.5 milligrams.

I think that to omit the importance or underemphasize the importance of the range where you are supposed to get going as opposed to the titrating kind of thing, it's just misleading. People need as much information as possible. They also need, as has been brought out, the drug in the right concentration. In other words, they need it diluted as opposed to too concentrated. The drug is now available in a dilute dosage form but as I understand it, the company hasn't even recalled the more concentrated form which is more dangerous.

Mr. WEISS. Thank you very much. Mr. Lightfoot, I will now yield to you for your questioning.

Mr. LIGHTFOOT. Thank you, Mr. Chairman. One final question in the area we were discussing before we broke for the vote, and then we will move onto some other things.

In terms of the invitation to testify, so that we can clear the air on this particular issue as far as I'm concerned, would each of you mind telling us when you were asked to come to our hearing and when you accepted?

Whoever wants to start can go ahead.

Dr. DRY. I was contacted approximately a month or 5 weeks ago. Mr. LIGHTFOOT. Thank you, Dr. Dry.

Dr. JULIEN. I think mine was in that approximate range. It might have been-I think it was about 5 weeks ago, 5 to 6 weeks ago.

Dr. LISBON. I was contacted the first week in April.

Dr. MORRISEY. March 22, my notes show that I had been contacted.

Dr. WOLFE. Approximately 1 month to 12 months ago.

Mr. LIGHTFOOT. Dr. Walta.

Dr. WALTA. We had been in touch with the subcommittee for a long time, because our petition was filed in February. But it was probably about a month or so ago that I was actually asked to testify.

Mr. LIGHTFOOT. Thank you very much. One of the things we were discussing earlier deals with the detail people from the various pharmaceutical companies. They have a job to do, and I would assume that's a very legitimate portion of the operation because that's one way to get information out to physicians that a new drug is available in the market.

If I am hearing correctly, I get the feeling from what several of you said, that you may feel like there are some areas that aren't adequately being explained or that are making you uncomfortable. I know that you are deluged with just tons of material, and Dr. Walta, you mentioned earlier that lots of things go into file 13.

I recall during the years I was in the broadcasting business that on Monday morning much of my mail, I will have to admit, particularly if it came from a Senator or Congressman usually went into file 13 without being opened. But you do, after a while, set up a pattern of things that you identify that you do want to keep. You lay it on your desk to look at later in the week or when you have time.

We are getting back to the communications problem. Would you elaborate for us what role the detail person has in communicating with you from a company about a new drug that is on the market. I would be interested in any suggestions on how they could possibly do their job better, how these written communications could come to you maybe in a better manner so that they are more easily digested or brought to your attention or whatever. It appears that we have got an area that is just kind of foggy at this point.

Dr. WALTA. You are going to get only one man's opinion.
Mr. LIGHTFOOT. That's fine. That's what we want.

Dr. WALTA. I get deluged, as you might imagine. I select out the things that apply to me that I use and learn about it initially. I will try to get that information, not just from the drug company because their objective is to get me to use the medication. I like a more broad perspective on it.

The disturbing thing in this case was the fact that the representative-who is a hard working person-wasn't aware of the problem even after we had the episode happen. I would really hope that the company would inform their representatives who are trying to sell their products to the physicians, be better informed so after the fact they come in-are at least aware that in their own city where they are trying to sell the drug they have had at least three deaths and are sensitive to that and can facilitate or assist other physicians in avoiding the same ultimate outcome.

Mr. LIGHTFOOT. Excuse me for interrupting. You just said that the detail person, even after your incident wasn't aware. Did you meet with this individual and discuss it with them then?

Dr. WALTA. Actually, I was in a hospital and my partner said come in here and meet the representative from Roche. She doesn't even know what's going on. I went in and talked to her and she said, I wonder why I haven't been told. Our gentle encouragement was that you better go back and talk to your company.

Mr. LIGHTFOOT. Do you remember in what timeframe this was after your incident?

Dr. WALTA. It was probably a month and one-half. Of interest, as I did encounter her again a month ago or thereabouts, she still has