The following is an internal report, which has not been reviewed. A verbatim transcript will be available in approximately two weeks, sent to the Division and posted on the FDA website at http://www.fda.gov.dockets/ecomments. Slides shown at the meeting will be available at the same website.
I certify that I attended the
Johanna Clifford, MS, RN, BSN Nathaniel Katz, M.D.
All external requests for the meeting transcripts should be submitted to the CDER Freedom of Information office.
Anesthetic and Life Support Drugs Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and
Research met on
Anesthetic and Life Support Drugs Advisory Committee Members Present (voting):
Janice Bitetti, M.D., Madelyn Kahana, M.D., Steven Shafer, M.D., Mary Beth Bobek, Pharm.D., Vera Bril, M.D., and Carol Rose, M.D.
Anesthetic and Life Support Drugs Advisory Committee Consultants (voting):
Jeff Balser, M.D., Peter Kowey, M.D., Thomas Fleming, Ph.D., Eric Holmboe, M.D., Dan Roden, M.D., Terese Horlocker, M.D., James Eisenach, M.D., Stephanie Crawford, Ph.D., M.S. (Drug Safety and Risk Management), Robert Dworkin, Ph.D., David Wlody, M.D., and James Gillett, Ph.D. (Patient Representative).
Acting Industry Representative (non-voting):
Charles McLeskey, M.D.
Marek Malik, M.D., Ph.D.
FDA Guest Speakers:
Arthur Simone, M.D., Ph.D., Nancy Chang, M.D., Mehul Desai, M.D. and Lester Schultheis, M.D., Ph.D.
Robert Meyer, M.D., Bob Rappaport, M.D., and Nancy Chang, M.D.
Open Public Hearing Speakers:
Bruce Cullen, M.D. – American Society of Anesthesiologists
T.J. Gan, M.D - SAMBA
Abu Alam, M.D. – Akorn, Inc.
The Committee discussed the evaluation and communication of risk related to QTc prolongation by Droperidol (inapsine) Akorn, Inc. The members and the invited consultants were provided the background material from the FDA prior to the meeting.
The meeting was called to order at by Nathaniel Katz, M.D., M.S. (Committee Chair). The Committee members, consultants, and FDA participants introduced themselves. The conflict of interest statement was read into the record by Johanna Clifford, M.S., R.N., B.S.N. The agenda proceeded as follows:
Opening Remarks Bob Rappaport, M.D., FDA
Inapsine: Basis for Approval Arthur Simone, M.D., Ph.D., Medical Officer
Droperidol since 2001: FDA Risk Assessment Nancy Chang, M.D., Medical Officer,
Prospective Controlled Study of QTc Proglongation by Mehul Desai, M.D., Medical Officer
Droperidol in Healthy Volunteers DCRDP, FDA
QTc Prolongation: Controversies, Consensus, Case Histories Marek Malik, M.D., Ph.D.
Professor of Cardiac Electrophysiology
Department of Cardiological Sciences
Droperidol Study Proposals Lester Schultheis, M.D., Medical Officer
Open Public Hearing
Committee Discussion – Continued
Questions to the Committee:
There have been cases of Torsade De Pointes reported following the use of droperidol at doses within and below the labeled doses. These events are consistent with the pharmacologic effects of droperidol reported in preclinical models and in human studies at 0.1 mg/kg and higher. Data demonstrating safety and efficacy at droperidol doses lower than approved, yet commonly used, have not been submitted to the Agency.
1. Given this, would additional information on any of the following be essential to clinicians in order to use droperidol safely:
a. QTC effects of droperidol at labeled doses
b. QTc effects of droperidol at lower than labeled (i.e., < 2.5 mg.)
c. Metabolic pathways for droperidol, and effects of metabolic inhibition on QTc prolongation by droperidol
d. Other information (e.g. risk-reduction strategies, preclinical data, drug-drug interaction)
The first two questions are jointly addressed under question 2.
2. If yes to any of the above, please discuss the strategy you believe would be most appropriate to obtain these data. If a study or studies are recommended, discuss the following issues:
a. Populations to be studies (e.g., volunteers, patients, pediatrics, susceptibles)
b. Doses to be studied
c. Endpoints (e.g. mean QTc, QTc outliers in a larger populations, actual cardiac events, PK/PD drug interactions)
d. Study size and design
e. Minimally acceptable QTc assessment methodologies (e.g. 3-lead automated monitors?)
f. Any other data (e.g. comparison with alternative drugs, effects of co-administration with drugs that may potentiate QT effects, pharmacogenetic data)
The committee agreed that further data would need to be pursued and suggested various trial designs to include primary endpoints, methodologies, patient populations, etc addressing concerns of the effect on QTc and what doses could be maximally achieved in a clinical trial setting. It was acknowledged that it would be challenging to ethically administer high doses of droperidol in a clinical study or to make a determination of risk without using a surrogate, such as QTc., The design of the study would incorporate analysis of the dose response and efficacy of droperidol, giving the doses that the population can tolerate. Some of the committee felt that there should be an assessment of the risk of low doses of droperidol in addition to doses higher than normally used in the perioperative setting, such as normally recommended for these types of studies. In addition, potential underlying genetic polymorphisms should be investigated to determine if there are patients at genetic risk can be identified. The need for funding of such studies was also discussed and led to the suggestion of partnering with the American Society of Anesthesiologists to retrieve some of the data that the agency is requesting.
Among the study designs discussed was the in vitro cardiac wedge model, which results in a concentration response relationship for TdP, which can be used to inform a study in humans. A case controlled study was also suggested as an alternative design, collecting the cases of TdP and comparing that population with those that did not develop TdP. However, concerns were expressed about limitations of a case controlled model in determining the magnitude of risk of rare events. Another possibility includes observational study designs looking at the risk factors, whether they be concomitant medications or conditions. Such study designs, if done properly might provide useful information.
Although the committee agreed that there was a dose dependent prolongation of the QT interval with the use of droperidol that might occur even at the lower doses, there was discussion as to the actual risk of prolongation of the QT and the ideal measurement and analysis methodologies. It was suggested that agents that have a QT effect that is within single digits at multiples of the usual dose or at maximal metabolic inhibition, risk is probably minimal. The cardiology experts felt that in an otherwise healthy individual with a short baseline QT interval, even substantialQT prolongations of 40-50 ms are unlikely to lead to Torsades. Therefore, if a study was done on a population of healthy individuals, using a high dose in order to try to predict the risk in sensitive individuals, and the drug didn’t have a double-digit effect on the QT, this would be reassuring. Basic PK/metabolism data would also be required. There is a need for additional data on QTc and genetic predisposition of the population, and it is necessary to perform these studies using the highest clinically tolerable dosing. There was some debate about if a volunteer trial would result in dosing as high as what might be more appropriate in a clinical setting.
In summary, the committee agreed that that there is a need for additional data regarding whether the drug can be given safely and under what conditions. The committee also discussed the need for safety and efficacy data specific to doses of 0.625 and 1.25 mg, which are currently off label, to be submitted to the Agency for review. In obtaining these data, various options were provided that included laboratory studies, as well as human volunteer or clinical studies, documenting the true endpoint of TdP or a surrogate such as QTc interval, and correlation with pharmacokinetic and pharmacogenetic data in humans.
3. Based on the available clinical and pre-clinical data and the settings and circumstances of current use, how should the labeling
reflect safe use?
Recognizing the disparity between the way the drug is used clinically and the labeling, the committee found general agreement that there is very little pre-clinical or clinical data to review for safe use. They felt that the issue would also require very careful regulatory scrutiny of the data provided to the agency justifying the efficacy of the smaller doses. Further, they emphasized that evidence of efficacy preferably be demonstrated in a prospective trial. Alternatively, the agency might consider review of a literature-based submission to modify the current label, although there was some concern as to whether the data can be adequately assessed using this mode. It was urged that any contemplated literature-based submission should include a comprehensive presentation of available data rather than an ad hoc retrospective choice of studies based on the results that they report. However, until the data are received and presented to the agency in an appropriate manner, there is no way to revise the current labeling, either with respect to the boxed warning or to the labeled indications and dosing recommendations.
4. In addition to QTc data, what else should the Agency consider in making a risk benefit assessment for droperidol used in the setting of surgical and diagnostic procedures.
Clarification was provided that the boxed-warning is a mandated regulatory action in response to the nature of the associated adverse event and not the risk of the event. It was agreed that given the paucity of data supporting the safety of droperidol with respect to its potential for delayed cardiac repolarization, the Agency was justified in alerting the community to such a risk and in the manner in which this was done. It was also agreed that until the Agency receives appropriate safety data, any further action would be premature.
If the Agency receives the “substantial evidence” supporting approval of droperidol at doses less than 2.5 mg., should the label be revised to remove the currently indicated doses of 2.5 mg or higher?
From a clinical anesthesia perspective doses of 2.5 mg and higher are not widely used. However, the fact remains that there would need to be additional data submitted to approve the lower doses. Interventions to obtain such data should involve a PK study with intensive EKG monitoring, ideally with identification of which compartment corresponds QTc effect, in addition to some of the designs previously mentioned.
5. Are there other modes of risk communication that should be considered in addition to those that have already been implemented?
The FDA discussed the modes of risk communication already utilized. These included an FDA talk paper, the labeling changes, and the “dear healthcare provider” letter. In addition, the Agency has made a concerted effort to maintain a dialogue with the anesthesia and emergency medicine communities via publications and responses to articles in trade journals. The committee suggested clarifying to the medical community that the boxed warning applies to the labeled use of droperidol, as there still remains much misunderstanding of the meaning and implications of the boxed warning. In addition, the committee suggested that FDA clarify its position that the data is lacking to support approval of the smaller doses. A suggestion was made to establish a regular communication with one of the anesthesia trade journals to providing some insight on the procedures and policies of the FDA.
The meeting was
adjourned at approximately