CONTENTS Dry, Dr. Laurence R., general and vascular surgeon, and editor and publisher, Attorney's Medical Advisory Letter, Knoxville, TN... Julien, Robert M., Ph.D., staff anesthesiologist, St. Vincent Hospital and Lisbon, Dr. Alan, assistant professor of anesthesia, Harvard Medical School, and cochairman, respiratory-surgical intensive care unit, Beth Morrisey, Dr. Michael, Westchester Plastic Surgical Associates, Yonkers, Peck, Carl, M.D., Director, Center for Drug Evaluation and Research, Food and Drug Administration, accompanied by Dr. Paula Botstein, Deputy Director, Office of Drug Evaluation I; Philip G. Walters, M.D., Acting Director, Division of Surgical-Dental Drug Products; David Scally, M.D., Reviewing Medical Officer, Division of Surgical-Dental Drug Products; Gerald A. Faich, M.D., Director, Office of Epidemiology and Biostatistics; Janet Arrowsmith, M.D., Medical Epidemiologist, Office of Epidemiology and Biostatistics; and Thomas Scarlett, chief counsel/general counsel, Food and Drug Division, Office of the HHS Walta, Dr. Douglas C., Gastroenterology Clinic and Providence Hospital, Weiss, Hon. Ted, a Representative in Congress from the State of New Wolfe, Dr. Sidney M., director, Public Citizen Health Research Group, Letters, statements, etc., submitted for the record by: Botstein, Dr. Paula, Deputy Director, Office of Drug Evaluation I, Center for Drug Evaluation and Research, Food and Drug Administration: Information concerning reporting obligations.... Sawyer, Hon. Thomas C., a Representative in Congress from the State of Page 1 14 FDA'S REGULATION OF THE NEW DRUG VERSED THURSDAY, MAY 5, 1988 HOUSE OF REPRESENTATIVES, HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE OF THE COMMITTEE ON GOVERNMENT OPERATIONS, Washington, DC. The subcommittee met, pursuant to notice, at 9:30 a.m., in room 2154, Rayburn House Office Building, Hon. Ted Weiss (chairman of the subcommittee) presiding. Present: Representatives Ted Weiss, Thomas C. Sawyer, John Conyers, Jr., Nancy Pelosi, and Jim Lightfoot. Also present: James R. Gottlieb, staff director; Daniel W. Sigelman, counsel; Gwendolyn S. McFadden, secretary; and Mary Vihstadt, minority professional staff, Committee on Government Operations. OPENING STATEMENT OF CHAIRMAN WEISS Mr. WEISS. The Human Resources and Intergovernmental Relations Subcommittee of the Government Operations Committee is now in session. Today the subcommittee will hold an oversight hearing on the Food and Drug Administration's [FDA's] regulation of Versed [midazolam hydrochloride] Injection, a new drug manufactured by Hoffmann-La Roche Inc. FDA approved Versed on December 20, 1985, for preoperative sedation, induction of general anesthesia, and conscious sedation for diagnostic and endoscopic procedures. Since FDA has approved Versed, it has received 70 domestic reports of serious respiratory and cardiac reactions to the drug, including 36 deaths. Most of these cases have occurred in connection with the drug's use for conscious sedation during endoscopies. Unfortunately, it appears that many of the safety problems presented by Versed were preventable. Studies published in the early 1980's revealed that the initially approved Versed doses were dangerously excessive, and, prior to United States marketing, several European nations-Switzerland, the United Kingdom, West Germany, and Sweden-approved the drug at lower doses than were recommended in Versed's original American labeling. Our investigation has uncovered no evidence that FDA knew of any of this when it approved Versed. FDA is apparently approving potentially toxic new drugs for use by millions of people without familiarizing itself with important and relevant safety information, including informa tion in the published medical literature. This is obviously an untenable and unacceptable situation. Versed was apparently promoted directly to physicians as basically another, albeit improved, version of injectable Valium, another Hoffmann-La Roche product for conscious sedation that was losing its patent protection. In fact, for its first 12 years on the U.S. market, Versed was not only packaged in the same solution concentration as Valium, it was recommended for conscious sedation at doses comparable to those for Valium. Yet, by the early summer of 1986, shortly after U.S. marketing began, Hoffmann-La Roche had concluded that Versed is three to four times as potent as Valium, but did not adequately warn physicians about this until almost 2 years after FDA approval. The subcommittee's investigation has also unearthed evidence that Hoffmann-La Roche did not promptly report to FDA important Versed-related safety information in its possession, including reports of a number of Versed-associated deaths as well as important U.S. clinical trial data. Much of this evidence was plainly revealed by an examination of records obtained from FDA's own files. The subcommittee looks forward to the agency's testimony on what actions, if any, it has taken to investigate these important matters. Let me state for the record that we would have welcomed the manufacturer's testimony on this and other topics pertinent to our review, but we were advised, through counsel, that the manufacturer elects not to appear. [The subcommittee's invitation to the manufacturer to present testimony, and the manufacturer's response, are in app. 1, p. 119.] Today will mark the third hearing in 2 years where the subcommittee will present to FDA evidence suggesting that a drug manufacturer may have seriously violated legal reporting requirements. With each case that we review, we have become increasingly concerned that serious reporting lapses by pharmaceutical companies may have reached epidemic proportions within some segments of the industry. At the very least, FDA has not been receiving information vital to protecting human health and safety. If FDA is to continue to enjoy the confidence of the American public, it simply must do a far better job of ensuring that it has the information required to regulate new drugs. Let me, at this point, call on our distinguished ranking minority member, Mr. Lightfoot, for his opening statement. Mr. LIGHTFOOT. Thank you, Mr. Chairman. I look forward to today's hearing examining the Food and Drug Administration's regulation of Versed, which is a commonly used sedative/anesthetic drug in use since 1986 for preoperative sedation, conscious sedation, and induction of general anesthesia. Like the hearing held one year ago on the drug, Suprol, today's hearing should provide us with additional insight into FDA's drug approval process and surveillance system. The American public places a great deal of trust in the FDA to make sure that the drugs they use are safe and effective and adequately labeled. At the same time, the American public counts on the FDA to approve beneficial drugs in a timely fashion and to closely monitor these drugs once they reach the marketplace. These are important tasks and ones, which, in my opinion, are not taken lightly by Commissioner Young or his staff. Today's review of Versed enables us to examine FDA's drug approval process and surveillance system to determine whether they are working properly. I look forward to hearing Dr. Peck's testimony describing the steps the agency took to approve this drug, to monitor it after approval, and to address the adverse drug reactions that occurred. FDA's actions will help determine whether the public's interest in having access to safe, effective, and beneficial drugs are protected. Thank you, Mr. Chairman. Mr. WEISS. Thank you very much, Mr. Lightfoot. Before I recognize and introduce our very distinguished panel, let me indicate that today is going to be a very hectic day on the House floor, where debate continues on the Department of Defense authorization legislation. We will, doubtless, be interrupted from time to time for recorded votes on the floor. I hope that we can keep the breaks to a minimum, but we will just have to see how events develop. As a result of the floor activity and because members have other commitments that they must honor, members of the subcommittee will be coming in and leaving as their schedules mandate. I am sure that a number of them will be participating with us in the course of today's hearing. We have been joined by another of our distinguished subcommittee members Mr. Sawyer. Mr. Sawyer, do you have any opening comments you would care to make? Mr. SAWYER. Mr. Chairman, I have an opening statement but rather than read it, I would rather listen to what our panel has to say. So, with your permission, I would just insert it into the record. Mr. WEISS. Without objection, that will be done. Thank you very much. [The opening statement of Mr. Sawyer follows:] OPENING STATEMENT OF HON. THOMAS C. SAWYER Mr. Chairman, I would like to commend you for holding this hearing, indeed for the series of hearings you and your subcommittee have held, on the issue of drug regulation, health, and patient safety. It is often difficult to analyze with such medical detail and specificity issues like drug regulation in a political forum such as the U.S. Congress. You have managed to oversee an exceedingly complex issue area with professionalism and compassion. I am concerned by some of the preliminary reactions by patients to the recently approved drug, Versed. It would be a tragedy if all the reasonable precautions were not being taken to protect patients who have had Versed prescribed to them. There is an implicit trust between patient and doctor when a drug is prescribed that demands responsible care and precision by all those involved in deciding the condition of the drug's dispersal. I look forward to hearing the testimony of today's witness. Mr. WEISS. We have a distinguished panel of physicians appearing before us today, who have had experience with the drug in question. We have with us: Dr. Laurence R. Dry, a general and vascular surgeon, and editor and publisher, Attorney's Medical Advisory Letter, Knoxville, TN; Dr. Robert M. Julien, M.D., Ph.D., staff anesthesiologist, St. Vincent Hospital and Medical Center, Portland, OR, and formerly, associate professor, departments of anes |