FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
MEETING OF THE
ANESTHETIC & LIFE SUPPORT DRUGS ADVISORY COMMITTEE
Holiday Inn
ATTENDEES
COMMITTEE MEMBERS:
NATHANIEL P. KATZ, M.D., Chair
Assistant Professor of Anesthesia
JOHANNA CLIFFORD, M.S., R.N., B.S.N.
Executive Secretary
Advisors and Consultants Staff (HFD-21)
Center for Drug Evaluation and Research
Food and Drug Administration
JANICE BITETTI, M.D.
Assistant Professor of Clinical Anesthesiology
The
MARY BETH BOBEK, PHARM.D., Consumer Representative
Director, Cardiovascular Pharmacotherapy
Department of Cardiac Services
VERA BRIL, M.D.
Medical Director, Clinical Neurophysiology
University Health Network
Room 11-209, General Division
Toronto, Ontario
MADELYN KAHANA, M.D.
Professor of Pediatrics and Anesthesiology
The
Department of Anesthesia and Critical Care
ATTENDEES (Continued)
COMMITTEE MEMBERS: (Continued)
CAROL ROSE, M.D.
Assistant Professor
Department of Anesthesiology
STEVEN L. SHAFER, M.D.
Professor of Anesthesia
VA
531 Miranda Avenue
Palo Alto, California
CONSULTANTS:
(Voting)
JEFF BALSER, M.D.
Chairman, Department of Anesthesiology
Room 504,
STEPHANIE CRAWFORD, PH.D., M.S.
(Drug Safety & Risk Management Advisory Committee Member)
Associate Professor
ROBERT DWORKIN, PH.D.
Professor of Anesthesiology, Neurology,
Oncology and Psychiatry
Director of
Anesthesiology Clinical
ATTENDEES (Continued)
CONSULTANTS: (Voting)
JAMES
Professor of Anesthesiology
Department of Anesthesiology
Section on Obstetric & Gynecology Anesthesiology
THOMAS FLEMING, PH.D.
Professor and Chair
Department of Biostatistics
ERIC HOLBOE, M.D., F.A.C.P.
(Drug Safety & Risk Management Advisory Committee Member)
Assistant Professor of Medicine
Department of Internal Medicine
1074 LMP,
TERESE T. HORLOCKER, M.D.
Section Head, Associate Professor
Department of Anesthesiology
200
PETER KOWEY, M.D.
Chief, Division of Cardiovascular Diseases
LanKenau Medical Office Building East
DAN M. RODEN, M.D.
Professor of Medicine and Pharmacology
Chief, Division of Clinical Pharmacology
RRB 532C
23rd and Pierce
ATTENDEES (Continued)
CONSULTANTS: (Voting)
DAVID J. WLODY, M.D.
Director, Obstetric Anesthesia
Department of Anesthesiology
PATIENT REPRESENTATIVE: (Voting)
JAMES GILLETT, PH.D.,
216 Rice Hall
ACTING INDUSTRY REPRESENTATIVE: (Non-voting)
CHARLES McLESKEY, M.D.
Global Medical Director/Global Marketing Director
Anesthesia/Sedation
Abbott Laboratories - PPD/GPRD
Department 96R, Building LFCP4-4
GUEST SPEAKERS:
MAREK MALIK, M.D., PH.D., D.SC., D.SC. (MED), FACC, FESC
Professor of Cardiac Electrophysiology
Department of Cardiological Sciences
FOOD AND DRUG ADMINISTRATION STAFF:
NANCY CHANG, M.D.
MEHUL DESAI, M.D.
ROBERT MEYER, M.D.
DR. MARTIN POLLOCK
BOB RAPPAPORT, M.D.
LESTER SCHULTHEIS, M.D., PH.D.
ARTHUR SIMONE, M.D., PH.D.
ATTENDEES (Continued)
ALSO PRESENT:
ABU ALAM, PH.D.
BRUCE F. CULLEN, M.D.
T.J. GAN, M.B., F.R.C.A.
C O N T E N T S
AGENDA ITEM PAGE
CALL TO ORDER
by Dr. Nathaniel Katz 8
OPENING COMMENTS
by Dr. Terese Horlocker 8
INTRODUCTION OF THE COMMITTEE 10
CONFLICT OF INTEREST STATEMENT
by Ms. Johanna Clifford 13
OPENING REMARKS
by Dr. Bob Rappaport 16
INAPSINE BASIS FOR APPROVAL
by Dr. Arthur Simone 21
DROPERIDOL SINCE 2001
FDA RISK ASSESSMENT
by Dr. Nancy Chang 39
PROSPECTIVE CONTROLLED STUDY OF
QTc PROLONGATION BY DROPERIDOL IN
HEALTHY VOLUNTEERS
by Dr. Mehul Desai 77
QTc PROLONGATION: CONTROVERSIES,
CONSENSUS, CASE HISTORIES
by Dr. Marek Malik 90
DROPERIDOL STUDY PROPOSALS
by Dr. Lester Schultheis 134
OPEN PUBLIC HEARING
by Dr. Bruce F. Cullen 160
by Dr. T.J. Gan 166
by Dr. Abu Alam 183
QUESTIONS FOR DISCUSSION 201
P
R O C E E D I N G S
(
DR. KATZ: Good morning. I wonder if everybody could make their way to their seats.
My name is Nathaniel Katz. I will be co-chair of the meeting today.
Welcome. Let me begin by welcoming everybody to this meeting of the Anesthetic & Life Support Drugs Advisory Committee. This meeting will be about the use of droperidol.
I would like to give a special welcome to Terese Horlocker, who was the chair of this committee before I became chair, and she has kindly agreed to join us today and to actually chair this meeting since droperidol is more within her area of expertise as an anesthesiologist than it is in mine as a neurologist. So we're grateful to her for agreeing to join us.
Terry, would you like to make any introductory comments?
DR. HORLOCKER: Thank you. It's certainly an honor to be here, and I'm looking forward to a truly educational session. Also as an anesthesiologist, I'm very interested in the outcome of these proceedings. Droperidol has been around since 1970, but the ongoing case reports of prolonged QT leading to torsade de pointes, as well as some of the clinical investigations led to the FDA placing a black box warning in December of 2001. That action took away one of our major front line drugs for the treatment and prevention of nausea and vomiting, as well as a great rescue medication, or at least severely limited its use. So it's not surprising that this caused a lot of controversy within the anesthesia commission. However, the FDA has always promised to convene an advisory committee panel to discuss these proceedings, and thus here we are today.
In my opening comments, what I want to do is to say to the advisory committee we are not here to discuss the relative efficacy and risk of the other antiemetic drugs. We want to focus on droperidol. And as you've all reviewed your questions, we want to really focus on the labeling and also what recommendations we can make to the FDA to make this drug as safe as possible to administer to our patients.
Thank you.
DR. KATZ: Thank you very much.
Let me just remind everybody around the table of a couple of different mechanical issues here. When you do want to speak, just raise your hand later during the discussion, and Dr. Horlocker will recognize you, more or less, in the order that your hand goes up. We'll try to be as fair as possible about that, given the need to make sure that the discussion is on point.
When you do speak, you have to press this little microphone button in front of you where it says "mic," and when you're done speaking, you need to turn it off unless you want everybody to hear all your whispered comments that you make to your neighbor. And it creates a lot of feedback, so try to remember that, and we'll remind you.
With that, what I'd like to do, since many of us don't know each other and Dr. Horlocker has not met some of you, I'd like to go ahead and have everyone around the table introduce themselves. So if we could start at that end please.
DR. MEYER: I'm Dr. Bob Meyer. I'm the Director of the Office of Drug Evaluation II in the Center for Drugs at FDA.
DR. RAPPAPORT: I'm Bob Rappaport. I'm the Director of the Division of Anesthetics, Critical Care, and Addiction Drug Products in the Center for Drug Evaluation and Research.
DR. CHANG: Nancy Chang, same division. I'm the medical team leader for anesthetics.
DR. RODEN: Dan Roden, clinical pharmacology and electrophysiology at Vanderbilt.
DR. KOWEY: Peter Kowey.
I'm one of your other token cardiologists for the day. I'm Professor of Medicine at
DR. SHAFER: Steve Shafer, anesthesiologist and clinical pharmacologist at Stanford, UCSF, and anesthesiologist at the Palo Alto VA Health Care System.
DR. HOLMBOE: Eric Holmboe.
I'm a general internist from
DR. KAHANA: Madelyn Kahana. I'm a professor of pediatrics and
anesthesiology at the
MS. CLIFFORD: Johanna Clifford. I'm the Exec Sec to this meeting.
DR. HORLOCKER: Terese Horlocker, Mayo Clinic, co-chair.
DR. BRIL: I'm Vera Bril. I'm a professor of neurology at the
DR. ROSE: I'm Carol Rose. I'm an anesthesiologist at the University of
Pittsburgh Medical Center, and I have a particular interest in anesthesia for
electroconvulsive therapy at Western Psychiatric Institute and Clinic in
DR. BITETTI: I'm Janice Bitetti. I'm on the faculty at
DR. WLODY: I'm David Wlody. I'm an anesthesiologist at the State
University of New York Downstate Medical Center in
DR. CRAWFORD: Good morning. Stephanie Crawford, University of Illinois, Chicago, College of Pharmacy, and also a guest member from the Drug Safety and Risk Management Advisory Committee.
DR. BOBEK: Mary Beth Bobek,
DR. EISENACH: Jim Eisenach,
anesthesiologist, Winston-Salem, North Carolina.
DR.
BALSER: Jeff Balser, Chair, Anesthesiology
at Vanderbilt, Nashville, Tennessee.
DR.
GILLETT: Jim Gillett, Professor of
Toxicology and patient rep for Esophageal Cancer Awareness Association, Cornell
University.
DR. McLESKEY: Charlie McLeskey, anesthesiologist by training. I work for Abbott Laboratories, and I'm the industry representative to the committee.
DR. KATZ: Thank you very much, everybody, and with that, Johanna Clifford will read the conflict of interest statement.
MS. CLIFFORD: The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
Based on the submitted agenda and information provided by the participants, the agency has been determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.
Dr. Nathaniel Katz has been granted a waiver under 18 U.S.C. 208(b)(3) for consulting with two competitors on unrelated matters. He receives between $10,001 to $50,000 a year from each firm.
Dr. Dan Roden has been granted a 208(b)(3) waiver for consulting on unrelated matters for a firm that manufactures a competing product. He receives less than $10,000 a year. Also, for serving as an expert witness for a competitor on an unrelated matter, he receives greater than $50,000 a year. Dr. Roden has been granted a waiver under 21 U.S.C., section 355(n)(4) for owning stock in a competitor worth greater than $50,000, but less than $100,000.
DR. RODEN: My wife owns the stock.
MS. CLIFFORD: Okay, thank you.
DR. RODEN: In a blind trust.
MS. CLIFFORD: Thank you.
Dr. Robert Dworkin, who will be joining us later, has been granted a 208(b)(3) waiver for consulting with five competitors. He receives less than $10,000 a year from each firm. Also, Dr. Dworkin is a speaker for a competitor on unrelated matters. He receives from $5,001 to $10,000 a year.
Dr. Peter Kowey has been granted a 208(b)(3) waiver for consulting with four competitors on unrelated matters. He receives less than $10,000 a year from each firm. Also, Dr. Kowey is a member of a competitor's speaker's bureau. He lectures on unrelated matters and receives greater than $10,001 a year. Lastly, Dr. Kowey is a consultant to a competitor firm on unrelated matters. He receives greater than $10,000 a year.
Dr. Thomas Fleming has been granted a 208(b)(3) waiver for consulting with five competitors on unrelated matters. He receives less than $10,000 a year from each firm.
Dr. James Eisenach has been granted a 208(b)(3) waiver because his employer has a contract with a competitor for a study of an approved competing product. This study is funded for less than $100,000 a year.
Dr. Janice Bitetti has been granted a waiver under 21 U.S.C., section 355(n)(4) for owning stock in a competitor valued between $5,001 to $25,000 a year.
A copy of these waiver statements
can be obtained by submitting a written request to the agency's Freedom of
Information Office, room 12A-30 of the
We would also like to note that Dr. Charles McLeskey is participating in this meeting as the acting industry representative acting on behalf of all regulated industry. Dr. McLeskey is an employee of Abbott Laboratories.
With respect to FDA's invited guests, Dr. Marek Malik has reported interests that we believe should be made public to allow the participants to objectively evaluate the comments. Dr. Malik has received research grants, consulting fees, and speaker's fees from a number of pharmaceutical companies; however, he has never received any grants, consulting or speaker's fees related to the product at issue or its competitors.
In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.
Thank you.
DR. BALSER: My conflicts of interest were submitted a few weeks ago, but were not read.
MS. CLIFFORD: Thanks, Dr. Balser. We'll take a look at that.
DR. KATZ: With that, I'll turn the meeting over to Dr. Horlocker, who will be chairing the meeting for the rest of the day.
DR. HORLOCKER: Dr. Rappaport, would you like to make your opening comments?
DR. RAPPAPORT: Good morning. Dr. Katz, Dr. Horlocker, members of the committee, and invited guests. Thank you for participating in this meeting today.
The purpose of today's session is to enlist your assistance in determining the best path forward for our ongoing risk analysis of the cardiovascular toxicity of droperidol, an important product in the anesthetic armamentarium.
As you are aware, in March of 2001,
Janssen discontinued marketing of droperidol internationally except in the
Shortly after the withdrawal was announced, the division held teleconferences with both Akorn and Janssen representatives and was informed of an existing internal analysis that had been performed by Janssen. We requested and received that document, and after review, we performed an internal review of our own postmarketing safety database for droperidol, as well as a thorough literature review. Those reviews led us to the conclusion that a real signal for an association between QT prolongation, torsade de pointes, and droperidol did indeed exist.
We held numerous telecons with Akorn, as we attempted to find ways to establish and evidence-based data set that would allow us to assure safe use of the drug and to avoid removing this widely administered product from the market. Although we were unable to fully achieve this goal, based on a clear demonstration of significant QT prolongation and torsade, the absence of a clear safety margin or clear prevention and management strategies and the existence of alternative treatments, we chose to take the relatively conservative approach of a labeling change. In doing so, we also took into account the long marketing history of the drug, the importance of the drug to the community, and the use of relatively low doses in current practice. Thus, following our regulatory mandate to communicate serious safety signals to practitioners on an urgent basis, the agency placed a boxed warning on droperidol labels in November of 2001.
Due to the necessity for us to act on an urgent basis, we did not convene a meeting of this committee prior to instituting the changes in the label. And although in retrospect, it may have been prudent for us to have communicated more effectively at that time, the intensely negative responses to the label changes from some members of the medical community were not ignored.
In addition to publication of an article outlining the reasons for our action, we committed to conducting a pharmacokinetic/pharmacodynamic study to evaluate the dose-related effects of droperidol on the QT interval. You will hear a detailed presentation of that study later this morning from one of the original investigators who is now a medical officer in the Cardio-Renal Division of the agency.
Unfortunately, that study was discontinued prematurely due to significant neuropsychiatric adverse events and was therefore inconclusive.
Since the results of that study became available, we've been exploring the options for obtaining additional data that would satisfy the regulatory standards for a demonstration of safety and efficacy at doses lower than those currently labeled, as well as data that would clearly define the risks associated with use of the product in general. This task has turned out to be far more challenging than we had suspected and, indeed, it's not even clear to us at this time whether there is a reasonable path or if further efforts are even warranted.
The presentations today will focus not only on the cardiotoxicity profile of droperidol, but also on our efforts thus far to find an appropriate study design to fully elucidate that profile and the limitations that are inherent in the exploration of any low incidence, high morbidity adverse event.
Dr. Malik, one of the international medical community's leading experts on QT prolongation, will present the current thinking on evaluation and assessment of this often drug-induced toxicity. FDA staff will provide you with a history of the original product approval, a detailed portrait of the agency's assessments and actions since March of 2001, and the current status of our evaluation of risk assessment for this product.
In addition to seeking your assistance in determining the most appropriate way for the agency to proceed with a significant public health concern, we will also be asking you to provide us with advice on how we might best communicate to the medical community the risks of cardiovascular toxicity that are associated with droperidol. There have been cases of torsade reported following the use of droperidol not only at the labeled doses, but also at the commonly used, unapproved lower doses. The literature establishes a clear relationship between droperidol and QT prolongation.
What further evidence, if any, is necessary in order to provide practitioners with a clear picture of the risk/benefit ratio for this product?
If more data is required, how may this best be obtained?
Based on the available data, is the current level of safety information in the label appropriate?
And are there other modes of risk communication that should be considered?
These are some of the questions you will be asked to address later today. Please keep these questions in mind as we chronicle this complex and often frustrating story for you.
And thank you again for your participation. I believe that we have a stimulating and challenging day ahead of us, so I'll end here and I'll turn the meeting back to Dr. Horlocker.
DR. HORLOCKER: Thank you.
We'll proceed with our next speaker who is Dr. Simone.
DR. SIMONE: Good morning and welcome. I'm Art Simone, a medical officer in the Division of Anesthetic, Critical Care, and Addiction Drug Products. Together with Dr. Nancy Chang, anesthetics team leader in the division, we will present the history of droperidol from the submission of the new drug application to the placement of the boxed warning on the label.
Specifically, my goal is to provide the historical context of its approval from a regulatory, clinical, and safety perspective with emphasis on use of droperidol to prevent and treat perioperative nausea and vomiting. It is our hope that these presentations go beyond mere descriptions of FDA actions and provide some insight as to the basis for these actions.
Let us begin then with the new drug application for Inapsine. McNeil Laboratories submitted its NDA in June of 1968, including studies which it felt supported the claims of safety and efficacy for three general indications: for sedation or tranquilization in the perioperative setting, including all phases of anesthetic care; neuroleptanalgesia, which is a tranquilized, stress-free state induced so patients may undergo and tolerate surgical and diagnostic procedures; and for prevention of nausea and vomiting.
Pharmacokinetic data regarding absorption, distribution, metabolism, and elimination in humans was not submitted with the NDA. Rather, a rat study of the elimination of tritiated droperidol was provided. However, even that was limited in its scope. A determination of all metabolic products was not performed, and metabolites that were detected were not assessed from a toxicology perspective. While this would constitute a serious deficiency by today's standards, it was acceptable in the 1960s.
The clinical studies submitted for agency review were, for the most part, conducted shortly after the 1962 Kefauver-Harris amendments to the federal Food Drug and Cosmetic Act. These amendments included requirements by sponsors to show their drug products were efficacious, as well as safe, in essence, enabling the FDA to perform risk/benefit analyses of new therapeutic agents.
The submitted studies were completed prior to the agency's issuance of a guidance on adequate and well-controlled studies which provided FDA's understanding and interpretation of how the amended act was to be implemented. With this in mind, let us look at the clinical portion of the NDA.
McNeil provided the agency with a total of 54 phase II and phase III trials that were to serve as the basis for findings of safety and efficacy. The trials were conducted by 50 investigators and included 2,906 patients. In each trial, droperidol was used either as an adjunct to anesthesia or as a component of neuroleptanalgesia. Most of the trials were uncontrolled. 17 percent of the trials had only 1 patient. Few had formal protocols, and most were anecdotal in nature.
The clinical data were presented in three parts. These included tabulated and analyzed data collected from the 1,824 patients in 44 trials who received droperidol related to their anesthetic care; data from 1,197 patients involved in what were described as special studies such as otologic procedures, pneumocephalograms in pediatric studies. 115 patients were common to both parts I and II. Lastly, investigators were polled as to their opinions of droperidol's safety and efficacy when used as a neuroleptanalgesic.
In the part I studies, some of the 44 trials included evaluation for prevention and treatment of nausea and vomiting in the perioperative period, generally limited from the time of admission to the holding area to the time of discharge from the recovery room. More than half the studies evaluated 10 patients or less. 5 of the studies included 70 or more patients.
Pertinent to current issues surrounding droperidol are the doses for which FDA has safety data. This slide provides a breakdown of the doses evaluated in part I studies. Although doses of less than 1 milligram were used, the number of patients receiving these doses were too small for the evaluation of safety and efficacy. In addition, many patients received doses at more than one period, further complicating the issue.
Routes of administration included intramuscular, intravenous, intravenous drip, and combination of an intravenous bolus and intravenous drip. The significant number of incidents of unreported routes of administration, which is listed in the last column, limits the usefulness of the data, particularly in the assessment of preoperative administration where there were 273 such cases.
Part II studies bring to the fore an interesting issue regarding safety monitoring. Even in the special study of epinephrine antagonism in which 5 patients were evaluated for the use of droperidol as an alpha adrenergic blocking agent, there was no electrocardiograph monitoring. Rather, manual intermittent blood pressure and pulse rates were assessed as the primary determinants of cardiovascular status. In the 1960's, use of ECG monitoring was the exception, not the rule.
Part III of the clinical data included a survey of investigators regarding their opinion of the drug's safety and efficacy. 98 percent found it to be both safe and efficacious. It may be argued by some that the percentage has changed only minimally in the 30-plus years that droperidol has been marketed.
Let us turn our attention now to the efficacy data for droperidol, such as they were, relating to the prevention and treatment of nausea and vomiting. The salient point for each of these studies is the dose or the dose range studied.
The NDA submission noted the results of two studies in particular and combined data from several other studies where incidence of nausea and vomiting were assessed. In the part II study of droperidol use during pneumocephalography, evidence suggestive if not fully supportive of efficacy was shown at a dose of 0.15 milligram per kilogram or 10.5 milligrams for the average 70-kilogram adult.
In a study comparing three pharmacological approaches to neuroleptanalgesia, including droperidol with meperidine, chlorpromazine and meperidine, and chlorpromazine used with fentanyl, droperidol significantly reduced the incidence of nausea and vomiting when given at a dose of 10 milligrams intravenously.
Lastly, an overall evaluation for nausea and vomiting during intraoperative and immediate post-operative periods ‑‑ that's in the recovery room ‑‑ was performed on a combination of several studies. An incidence of nausea and/or vomiting was found to be about 5 percent, with mean droperidol doses ranging from 5 to 7 milligrams.
That only one study, a prospective controlled trial provided the strongest evidence of efficacy is not the primary point to be made here. Rather, antiemetic doses tested ranged, for the most part, from 5 to 10 milligrams. Patients under 33.3 kilograms would have received less than 5 milligrams in the pneumocephalogram study, and that was the only study that would look at a dose that low.
Adverse event data for the part I trials included assessment made during the post-operative period; that is, the time in the recovery room. This table summarizes the cardiovascular events noted. These studies included the use of: droperidol alone; that is, other non-narcotic agents were used in the anesthetic; droperidol with Innovar, which is a droperidol and fentanyl fixed combination drug; and droperidol with fentanyl; or a combination of all three. So, indeed, it's droperidol, droperidol and fentanyl; droperidol and fentanyl; or droperidol and fentanyl; and droperidol and fentanyl.
Even during this limited time frame, on the order of about 1 hour postoperatively, and scant monitoring which was in place, a substantial number of events were noted.
Cardiovascular adverse events noted among all patients exposed to droperidol are included in this table. In some of the studies, the actual incidences of hypo or hypertension were not reported. In these cases, the number of events was treated as 1 and the plus sign was added to indicate the number was actually greater. Often cutoff values defining hypo and hypertension or brady- or tachycardia were not prespecified, introducing the possibility of inconsistent and arbitrary reporting of these adverse events. Interesting to note are the episodes of arrhythmia reported despite the lack of routine electrocardiographic monitoring.
The next slide summarizes patient fatalities. Deaths are listed by time of occurrence relative to surgery. There's a peak occurrence from postoperative days 1 through 4, but a relatively substantial number of cases occurred through the first 24 hours as well. In fact, the 9 of the 2,906 patients who died during the intraoperative and immediate postoperative period constitutes a death rate of .31 percent. If one looks at all deaths occurring up through postoperative day number 4, it's a rate of .96 percent.
In April of 1969, McNeil submitted
an amendment to the new drug application satisfying deficiencies noted by the
review staff, and in June 1970, Inapsine was approved for marketing in the
Indications on the approved label were listed as preoperatively during induction and during maintenance for sedation or tranquilization, for anti-anxiety activity, and for reduction of the incidence of nausea and vomiting.
The dosing was described as shown based on when it was to be used perioperatively. You will note that there are no dosing recommendations for postoperative use or for the prevention or treatment nausea and vomiting.
So where did this leave us at the start of the new decade? Data provided by the sponsor was extremely limited in its usefulness for a safety evaluation that is applicable to the current question at hand. There was substantial incidence of results that were described as "not reported." Some concerned the routes of administration. Others concerned safety outcomes. For example, in some of the nausea and vomiting evaluations, it was assumed that neither occurred because there were no reports of incidents occurring, and both were defined as adverse events. While this may not be a significant problem in and of itself, the scale to which it occurred, a total of 305 cases of no documentation for nausea and vomiting outcomes, raises concerns about the attention paid to gathering other safety and efficacy data.
Combining data from diverse protocols, especially large numbers of studies with small numbers of subjects, makes it difficult to derive meaningful dosing information and to discern possible safety issues. This is especially true when most of the data come from uncontrolled trials.
The mortality rates reported overall within the first 4 postoperative days and even within the first 24 hours following surgery are relatively high compared to the 1 in 10,000 mortality rates generally associated with anesthesia at that time. Without a control population, however, it is difficult at best to determine a role for droperidol in the increased mortality.
The same applies for the incidence of cardiac events that were seen, and although a case could be made that some of the serious adverse events were related to the patient's medical status preoperatively or to the nature of the surgeries they underwent, there is no way, without controls, to assess if droperidol added substantially to these risk factors.
The sponsor also included literature from European studies involving droperidol. Such studies may be used to support a finding of safety and/or efficacy, although they're not without their limitations.
Despite these concerns, which are much easier to raise retrospectively, the approval of droperidol in 1970 was made in accordance with the clinical and regulatory standards of the time. From the perspective of the practice of medicine in anesthesia in the early 1960's when the studies were done, the level of monitoring in anesthesia was such that risks associated with many drugs would be nearly impossible to detect by the standards in place and the equipment available at the time. Indeed, it would be another 16 years before the American Society of Anesthesiologists would promulgate its first standards for basic monitoring, including continuous ECG monitoring.
Similarly, our understanding of drug actions and interactions on the cellular level were limited. It would be years before the issue of QTc prolongation would become a consideration for all new molecular entities and for some older entities not heretofore evaluated.
The 1950s and 1960s marked the beginning of an era for the development of new anesthetic agents. Given the limited armamentarium of the time, a higher level of risk was acceptable in order to provide alternative agents in virtually all anesthetic drug classes. From a regulatory perspective, requirements for approval had recently been changed to include demonstration of efficacy. Safety evaluation was still evolving. Given the data presented, the practice of anesthesia at the time and the limited options for anesthetic drug products, a risk/benefit analysis supporting approval was not inappropriate.
Over the last three decades, the
clinical use of droperidol has evolved.
The introduction of new drugs with shorter duration of effect and fewer
side effects have significantly reduced the use of neuroleptanalgesics and
droperidol as a major component of balanced anesthetics. Nonetheless, droperidol has remained popular
as an antiemetic. Indeed, from 1998 to
2001, unit sales of droperidol in the
At the end of 2001, the labeled indications remained essentially unchanged from that of 1970. Droperidol was still only approved for use in the setting of an anesthetic to produce a tranquil state, induce or maintain a general anesthetic as an adjunct to regional anesthesia and as a neuroleptanalgesic agent.
Likewise, dosing information has also remained unchanged. For adults, starting doses were a minimum of 2.5 milligrams for all indications, and the lowest approved dose of 1.25 milligrams was reserved for supplementation purposes alone. There remains no labeled dose for the prevention or treatment of nausea and vomiting.
So where did this leave us at the turn of the century? We have a drug for which the FDA had no pharmacological profile for its use in humans and only scant information on its excretion in animals; a drug, which when used at labeled doses, is associated with cardiovascular events and mortality rates that by current standards suggest possible safety issues; a drug whose off-label administration constitutes a significant portion of its use; and a drug whose perhaps most popular use is indicated although at doses, specifically the .625 milligram dose, for which the sponsor has not provided evidence of safety or efficacy to the FDA for its evaluation.
My colleague, Dr. Nancy Chang, will be picking up the story from here. I'd like to thank you for your attention, and I'd be happy to address any questions members of the committee may have.
DR. HORLOCKER: Are there any questions or points of clarification? There will be a building of the story by Dr. Chang who will discuss things after 2001. So please limit your questions to the pre-2001 for Dr. Simone. Any questions?
DR. HOLMBOE: Would you please just clarify the mortality data that you showed? I'm concerned that you're showing mortality data without context. In other words, these were deaths, probably some related to the surgery, and it's not clear to me exactly how this relates to the use of droperidol.
DR. SIMONE: The fatality data is that for all patients that participated in the trials. Sometimes there was no analysis offered by the people conducting the trials as to the actual cause of death. The trials in which it was used do run a gamut from extraction of molars to thoracotomies and cardiac surgeries. So there were significant numbers that did occur in more complicated procedures where you would expect a higher death rate. But again, without a control study for comparison purposes, you don't know if the use of this drug seems to push the equation more towards one side or the other. So we have limited data to go by.
DR. HORLOCKER: Any other questions? Thank you, Dr. Simone. Dr. Chang. Oh, I'm sorry.
DR. RODEN: I was intrigued by the idea that the sales of this drug have doubled over a very short period of time, and I'd ask mostly my anesthesia colleagues around the table why has that happened.
DR. HORLOCKER: I would think it's because of the aggressive prophylaxis and treatment of postop nausea and vomiting, especially among the outpatient setting where that's such a point of patient satisfaction that we were very aggressive with trying to prevent nausea and then also treat it aggressively to facilitate discharge.
Does anybody else have other comments on that?
DR. RODEN: But this happened in the context of a drug that's never been studied at those doses and for which there's no data.
DR. HORLOCKER: I would actually differ with that, that there have been many studies. Droperidol is truly the gold standard, and then when ondansetron and some of the other serotinergic medications came out, they were compared against these lower doses of droperidol.
DR. RODEN: Will we get an opportunity to hear those data?
DR. BALSER: There are studies at these doses. I think what the speaker meant was that the drug company hadn't submitted those data. Am I not correct?
DR. SIMONE: That's correct. The agency reviews the information submitted to it by the sponsor.
DR. RODEN: Well, are we going to hear those data sometime today?
DR. SIMONE: There will also be a discussion by Dr. Chang regarding the use during this time period, and she may be able to address some of the other drugs used as well.
DR. CHANG: We're not going to directly present the data that have been published in the literature because those data have not been submitted to us. We haven't been able to look at those and scrutinize them in any sort of a thorough way.
The other point I would make with respect to use is that we have seen an increase in use with all antiemetics. This isn't isolated to droperidol. All antiemetics have been steadily increasing in use over that period of time.
DR. HORLOCKER: Yes, sir.
DR. SHAFER: Just for the record, Dan ‑‑ I don't think this is even in doubt ‑‑ there are probably in the area of 20, 30, 40 well-done, large studies with thousands of patients. So I don't think the effectiveness of droperidol as an antiemetic at these doses is in doubt.
DR. HORLOCKER: And as Dr. Chang will point out, we have documented efficacy but nobody has done the true risk analysis of this. So even if we have the efficacy, we don't have a comparative risk analysis at these doses. So having half of the answer is not really helpful in this situation.
Dr. Fleming.
DR. FLEMING: So I'm still confused by this. We're not going to see the data that establishes the efficacy at these very low doses, and if we're not, can somebody confirm that there are proper placebo controls or, if not, how is it that we interpret efficacy?
DR. SIMONE: The determination of safety and efficacy is something that's under the purview of the FDA and that's based on the information that's provided to the agency by the sponsor. So we only have information delivered to us by the sponsor with which to address these issues.
DR. CHANG: The determination of safety and efficacy has been made by the medical community, but that assessment has not been made by the FDA.
DR. HORLOCKER: Dr. Shafer, did you have an additional comment?
DR. SHAFER: Yes. I just want to comment when you said that they hadn't done safety, actually certainly all the studies that I'm aware of ‑‑ and again, there have been lots of them by our colleagues, including perhaps some people in the room here ‑‑ did in fact, document a pretty low incidence of safety problems. Now, whether there was a formal risk/benefit ‑‑ but certainly the studies didn't just report efficacy in the absence of any safety assessment.
DR. HORLOCKER: That's correct.
Dr. Eisenach.
DR. EISENACH: Well, yes, we did one of these studies 15 years ago with 400 subjects, and there are multiple studies that have been published in the last 15 years regarding low doses of droperidol in placebo-controlled and active-controlled trials. There is no doubt in the medical community from these well-controlled trials that these doses are effective.
Similarly, all these studies were done during the time of modern ECG monitoring and the ASA guidelines of the late '70s. Now, clearly, very large effects such as a torsade de pointes would have been reported as part of that database. So I think it's unfortunate that the FDA took the case reports of problems and reviewed those for us but didn't provide us with a summary of the published data so we had an idea of what the denominator is.
Another reason perhaps for this large increase was several recent meta-analyses and reviews which suggested that droperidol was equally or more active than more expensive alternatives.
DR. HORLOCKER: I'd like to limit the discussion right now to just points of clarification because Dr. Chang is going to elaborate on the 2001 experience.
DR. BRIL: Well, I just wanted to make a point about efficacy data and what we've been presented with. In similar situations, it's what's presented to the regulatory agency and the trials you present with the safety data collected in a manner that the agencies require that would lead to the balancing of those studies. So the medical community can be convinced of efficacy of different interventions for different disorders very clearly from trials, but although safety is collected, it may not be in the form that would be acceptable to the agencies and reviewable by them. So there's a whole body of opinion that may say this is an effective safe treatment for something, but it won't be labeled as such or approved as such. If you take some of these trials to the agency, then there are a lot of questions that arise because of the way they were run and things like that. So there's not a concurrence I think always with what happens.
DR. HORLOCKER: Dr. Chang, why don't you go ahead and we'll have a discussion after both your presentation and Dr. Simone's.
DR. CHANG: Good morning. I'm going to present to you a little bit of the agency's approach and the rationale behind that approach that led to the 2001 labeling changes for droperidol. I do want to emphasize that I am not trying to advocate a particular position or a particular action with respect to droperidol. The agency's approach to drug-induced QT prolongation has gone through a very rapid evolution in the last several years in response to an also very rapidly evolving science. So it's in that context that I'm going to present to you and as a group were going to present to you what we know about droperidol. I hope that we will be able to convey to you what a very difficult and complex regulatory issue this is, and I hope that you will take these issues into account as we try to work together and find the best path forward.
Probably the first major announcement of a potential problem with droperidol occurred in 1997 when the French agency announced that they were concerned about a number of sudden deaths related to droperidol. Now, these deaths were occurring in large part in patients who were getting very large doses. A lot of these patients were alcoholics. But nevertheless, the agency estimated an incidence of sudden deaths at 1 per 55,000 vials, and because of that concern, they issued a Dear Doctor letter and they made a change to their labeling.
In early 2001, we found out from the British that Janssen was going to discontinue marketing of droperidol worldwide. Again, this was related to a risk/benefit assessment by Janssen looking at specifically the concern of QT prolongation related to droperidol. They chose to stop marketing all forms of droperidol, both oral and IV, although in their statement, they said that their primary concern was the use of oral doses in chronic conditions. With this statement, this was what prompted us to do our own analysis at FDA.
I'm going to present to you first the results of our postmarketing spontaneous reports. These numbers are going to be somewhat different from some of the numbers you've seen elsewhere for a couple of reasons. One is that the numbers have been updated to October of 2003, and the other is that these particular search terms have been narrowed down from some of the earlier search terms that had been used. The largest contributor would be we have a large number of deaths related to droperidol that have not also been associated with one of these cardiac terms. That large number of patients has not been included in this particular analysis.
So the particular search terms we used here are QT prolongation, torsade de pointes, cardiac arrest, ventricular tachycardia, ventricular fibrillation, ventricular arrhythmia, and sudden death, and only those terms. Altogether from the time of marketing to October 2003, we had 89 events, 46 of which were fatal.
If you look at the QT and torsade cases only, we had 22 cases. At least 5 of them are fata