other words, if people hadn't started dying from this drug, the sales would have been even higher. In fact, one of the reasons that people died was that it was promoted as equally powerful or equally potent with Valium when, in fact, it was known to be three or four times more powerful.

I think that the first part of the tape is as telling as anything, where the Roche person is saying that one of the foremost things in the back of our mind was that we knew we had to get the product Versed on board and into your hands before generic diazepam became a stronghold.

In other words, the drug Valium, is coming off patent and now generic Valium is available for one-half or one-third as much, the kind you would inject. Before that happened and people had switched to a less expensive version of Valium, this company wanted people to sort of get into the easy transition from Valium to Versed; same vial, same concentration, 5 milligrams per mil; by and large the same dosage but it just has a lot of advantages.

This is one of the more grotesque things I have ever heard. When we filed our petition in February asking for this drug to be stopped in its use by anyone other than anesthesiologists, we speculated that the fact that the patent had expired had caused this huge rush. I must say that I am still shocked, as cynical as I am, to hear this kind of tape where people are laughing about how this drug was so successfully pushed by taking on so many detail people as you just heard, that they didn't even know some of the problems with the drug.

Mr. WEISS. Dr. Walta, I would appreciate your reaction to the tape, as well as and Dr. Morrisey's and Dr. Julien's.

Dr. WALTA. As a physician you have to rely upon a lot of different things and a lot of people being credible to you in the things you do. You rely upon your equipment, you rely upon your nurse, you rely upon staff and you rely upon the drug companies to give you the correct information. You recognize that everything that you do has risks.

For me, I am sitting here fuming. I, as a physician, relied upon the Government, the FDA and I relied upon the drug company to put something into my hands and communicate to me that this is what it does and this is its effect. If it is found out beforehand, before I have an episode like which happened to me-which I take incredibly personal-makes me lose my trust. It makes me furious. I didn't like the episode that happened to me. It affects the way I feel every time I sedate a case, this comes back. This has been mulling in my mind a long time, and it's not humorous and it isn't funny. It makes me furious.

Mr. WEISS. Dr. Morrisey.

Dr. MORRISEY. This tape that I just heard is devastating, that people should sit and laugh because they made $15 million and they couldn't make $40 million. And now, if we can put the drug in the correct dosage we can make more money. The idea of putting it out as the same as Valium so that we can have the people switch over, it's shocking.

Mr. WEISS. Dr. Julien, as the tape demonstrates, by October 18, 1986, Roche and several of its consultants considered Versed to be three to four times as potent as Valium. When do you first recall

that Roche alerted physicians, either in a Dear Doctor letter or the drug package insert, that Versed was three to four times as potent as Valium?

Dr. JULIEN. That information first became disseminated to practitioners in late 1987, approximately September, October, November 1987.

Mr. WEISS. Dr. Walta, did the recommended doses of Versed for conscious sedation at the time that you used the drug in May 1987 reflect its being three to four times as potent as Valium?

Dr. WALTA. In May 1987, it wasn't appreciated that it was three to four times as potent as Valium.

Mr. WEISS. Dr. Morrisey, did the detailmen ever tell you that Versed was three to four times as potent as Valium, or indicate that you generally need only one-quarter to one-third of the dose you would need for Valium?

Dr. MORRISEY. No. They told us it was a similar dose to Valium. Dr. WALTA. Can I interrupt for 1 second?

Mr. WEISS. Please.

Dr. WALTA. For the drug to be effective, it needs to have some safety limits. The medication that we gave our patient was the amount necessary for her comfort. We didn't recognize that we had no safety limit. To say the drug was three to four times as potent is one thing, but when I use it and it doesn't work at the lower dose, that means that the drug isn't very useful for our procedure.

If we are only allowed to give a small increment and not get the beneficial effect from it, we won't use the drug. If somebody told me it was three to four times more potent and you aren't going to get the benefit from it, I wouldn't use the medicine.

Mr. WEISS. Dr. Lisbon.

STATEMENT OF DR. ALAN LISBON, ASSISTANT PROFESSOR OF ANESTHESIA, HARVARD MEDICAL SCHOOL, AND COCHAIRMAN, RESPIRATORY-SURGICAL INTENSIVE CARE UNIT, BETH ISRAEL HOSPITAL, BOSTON, MA

Dr. LISBON. The problem with the drug is that it has a very steep dose response curve. What that means is that there is very little margin on either side of the doses for any kind of difference in the way the patient will react to that. There is no margin of safety with the drug because it has such a steep dose response curve.

Mr. WEISS. Tell me what you mean by steep dose response curve. Dr. LISBON. In other words, compared to a drug like Valium which does not have a steep dose response curve, which has a flatter dose response curve; with Valium there is much more variation in the amount of drug that you can use with safety.

With a drug like midazolam, it's a very steep curve, so that a little bit too much, because it is so potent, will have somebody stop breathing or run into other cardiovascular and respiratory complications.

Mr. WEISS. Dr. Morrisey.

Dr. MORRISEY. There's also a latent period built into this drug. You can get a reaction when a patient reacts to the drug, they become sedated. All of a sudden they will get more absorption of the drug or there will be a change. They will have a tonic reaction,

chronic reaction, they will have a fit and then become apneic. This will happen sometimes 5 or 10 minutes later from the drug.

This is what is bothering a lot of anesthesiologists, because the drug is basically out of their control.

Mr. WEISS. In early 1987, more than 1 year after the drug was approved, Roche for the first time included the following statement in the Versed package insert. "For ease of titration, Versed may be diluted with 0.9 percent sodium chloride or 5 percent dextrose in water to 2 to 5 times the original volume." [An excerpt from the January 1987 package insert containing this statement is in app. 1, p. 195.1

Dr. Julien, in your judgment, was this labeling changed sufficient to ensure safe use of the drug?

Dr. JULIEN. No. This was grossly inadequate, because it places the onus for drug use entirely on the physician, attempting to take it off the manufacturer. The concentration available to us still was associated with a high incidence of problems associated with the presentation.

It should not have been up to the physician to have to translate that drug or transform that drug himself into something that is safe to use. That should have been done by the manufacturer.

In addition, many people in endoscopy or bronchoscopy or other nonanesthesiologists, don't have the fluids readily available to them to make these dilutions. In addition, you then have in your work area, two different syringes. You have the original company syringe plus you have one that you have had to dilute up, and that adds an additional problem of having two different concentrations available for what we call syringe swaps or making a mistake and grabbing the wrong syringe and injecting it.

The company was totally wrong in not making that dilution themselves and in trying to tell us that we are, indeed, the ones that should have been smart enough to figure it out.

Mr. WEISS. Dr. Julien, I understand that you are not only an anesthesiologist but also a well-published Ph.D. pharmacologist who has closely followed European developments concerning Versed for several years; is that correct?

Dr. JULIEN. Yes, sir.

Mr. WEISS. Prior to its approval by FDA, was the drug marketed in Europe only in the 5 mg/ml. concentration originally available in the United States?

Dr. JULIEN. No, sir. According to the information that I had heard, the British Government had required the company in England to change, I believe, to a 2 milligram per cc. concentration. It was well recognized in Europe from approximately 1982 or 1983, that indeed the drug was different from Valium and was much more potent.

The Europeans were light years ahead of us in recognizing this problem.

Mr. WEISS. Dr. Dry, how many endoscopies have you performed over the years?

Dr. DRY. Several thousand, at least.

Mr. WEISS. On the basis of your experience with these procedures, were you concerned when you prepared your article on Versed about the drug's use in endoscopy settings?

Dr. DRY. Yes. Particularly there, where it is an unstructured environment, there is no resuscitation equipment immediately available. The people that are giving the drug are typically not physicians. They are either untrained technicians or nurses.

Not that a nurse isn't perfectly adequately qualified to resuscitate or to check the patient's blood pressure and respirations, but they may not have the same information about the drug. They think that they are dealing with something that is identical to Valium, and the rest is history.

Mr. WEISS. Your article, as indicated, was dated October 1986, which means that it would have had to have been prepared before September 1986. Now, by that time, had either FDA or HoffmannLa Roche publicized the drug's association with serious cases of respiratory arrest, including deaths?

Dr. DRY. Not to my knowledge.

Mr. WEISS. Yet, you wrote that the "errors" made in packaging the drug "will cost some lives before packaging of the drug is corrected" and that "no warning in the package insert can be deemed sufficient to counteract the disasters invited by current packaging of the drug!" [This statement is in app. 1, p. 137.] On what basis did you make this statement?

Dr. DRY. Actually, Dr. Lisbon and I wrote that article together. We had done some research of both in terms of finding older articles that suggested this, but also checking with people in our institutions to find out whether they had any problems with the drug and they had some.

The drug was mostly used in anesthesia, I believe, in both of our institutions. The anesthesiologist certainly recognized that the drug was more potent than Valium.

Dr. LISBON. The information was available in the British literature. The European literature was full of references to midazolam, and it discussed how potent the drug was. We knew at the time that we wrote the article, that there was probably in some range of 15 percent incidence of apnea or stoppage of breathing with the drug.

Mr. WEISS. What does Versed do to the respiratory system that, in your judgment, necessitates close patient monitoring?

Dr. LISBON. Like all benzodiazepines or drugs like this, it is a respiratory depressant which means that it slows the amount of ventilation that an ordinary patient would take. Aside from this, there are some other problems with a drug like midazolam. That is that if you make some people hypoxic or you deprive them of oxygen, then there are various physiological responses that people have. A drug like midazolam-and there are papers that show this particularly about midazolam-blunts these kind of responses that people in endoscopy for example, are used to looking for. [One such paper, by Alexander & Gross, is in app. 1, p. 196.] When most people become hypoxic or they are deprived of oxygen, their pulse rate goes up. There are studies in the literature that show if you have given these people midazolam, then their pulse rates don't go up, as you would expect them to do.

Mr. WEISS. Your hospital, Beth Israel Hospital in Boston, is among the most prestigious in the Nation. What is the status of the drug's use for endoscopies at Beth Israel?

Dr. LISBON. Our hospital does probably somewhere between 3,500 to 4,500 endoscopies of all sorts per year. With very small exceptions, the endoscopists at our hospital do not use midazolam. They continue to use diazepam or Valium and Demerol, if they need it.

Mr. WEISS. Dr. Julien, I understand that in France the recommendation has been that Versed only be administered by an anesthesiologist. [Correspondence from France establishing this fact is in app., 1, p. 202.] Would this be a practical alternative for endoscopies?

Dr. JULIEN. No, it would not, sir. At this point, there is neither the manpower in the country to provide anesthesiologists for all this, nor can our society-especially through the Medicare system-fund it. It is just too expensive.

Mr. WEISS. Your review of midazolam cites a 1983 British study by Whitwam et al regarding use of Versed for conscious sedation for endoscopies. [The review referred to is in app. 1, p. 206.] What does that study suggest about doses of the drug for conscious sedation? [The published study by Whitwam et al. is in app. 1, p. 218.] Dr. JULIEN. These studies in 1983, and the studies were actually conducted over the period of 1981 and 1982, point to appropriate dose of approximately 0.07 to 0.10 milligrams per kilogram total dose. This dose is at least 50 percent below that which was promoted in this country.

Mr. WEISS. Dr. Wolfe, I understand that your February 12, 1988, petition to FDA cites additional studies published in the United Kingdom regarding Versed's use for conscious sedation. [The petition referred to is in app. 1, p. 222.] At what dosage level did those studies, all published before FDA approval, show adequate sedation?

Dr. WOLFE. It is particularly interesting that the Food and Drug Administration has not yet responded to our petition. It was filed in February of this year. The purpose was to stop the use of this drug except by anesthesiologists, the reason being that when an anesthesiologist is taking care of a patient the patient is usually intubated. There is a tube, as earlier described, into their respiratory system so that if something happens with the drug, immediately something can be done about it, as opposed to the conscious sedation use where a patient isn't usually-at least at the start-intubated and where it is much more risky.

As you just heard, to have an anesthesiologist be there in addition to the gastroenterologist or whoever else is doing it, is just not feasible which is why I suspect at Beth Israel they mainly don't use this drug at all for conscious sedation.

We have been able to find, in addition to studies that we cited in our petition, a total of six studies all in the published literature before the drug was approved in this country, showing that low doses of this drug-low, meaning around the level approved in Britain-were effective. We found a total of six studies published before 1985 in which low doses of this drug, midazolam, were effective and were better than Valium in terms of making people forget. The point is that these studies were apparently not relied upon by the Food and Drug Administration which approved the drug at a much higher dose. The studies were relied upon by authorities in