CHAIRMAN RELLER: Good morning. I'd like to welcome everyone to this meeting of the Anti-Infective Drugs Advisory Committee of the Food and Drug Administration.
I'm Barth Reller from Duke University Medical Center and will be chairing today's meeting.
At the outset of the meeting, we'd like to introduce those who are around the table and will be either guest speakers, consultants or members of the committee, and we'll begin at the end of the table with Dr. Diane Murphy.
DR. MURPHY: I'm Dr. Diane Murphy. I am the Director for the Office of Drug Evaluation-4, but presently on detail to the Office of Review Management. So I'm really being Mack Lumpkin this morning, and Dr. Kweder is being the Director of ODE-4.
DR. CHIKAMI: I'm Gary Chikami. I'm the Director of the Division of Anti-Infective Drug Products at the FDA.
DR. KWEDER: I'm Sandra Kweder. I'm serving as the Acting Director, Office of Drug Evaluation-4.
DR. MEYERHOFF: I'm Andrea Meyerhoff. I'm a medical officer in the Division of Special Pathogens.
DR. ARCHER: I'm Gordon Archer from Virginia Commonwealth University in Richmond, Virginia. I'm the Chair of the Division of Infectious Disease there.
DR. CHESNEY: I'm Joan Chesney from the University of Tennessee in Memphis, in pediatric infectious disease.
DR. O'FALLON: Judith O'Fallon, Mayo Clinic, statistician.
DR. SOPER: David Soper, Medical University of South Carolina in Charleston.
DR. CHRISTIE-SAMUELS: Celia Christie, University of the West Indies, Kingston, Jamaica, infectious diseases and epidemiology and child health.
DR. RODVOLD: Keith Rodvold, the University of Illinois College of Pharmacy and Medicine.
DR. PEREZ: Tom Perez, Executive Secretary for this meeting.
DR. WITTNER: Murray Wittner. I'm with the Albert Einstein College of Medicine and Professor of Pathology, Parasitology, and Tropical Medicine.
CHAIRMAN RELLER: I would also like to introduce our guests who will be speaking. Dr. Arthur Friedlander, and maybe you could help me out by introducing yourselves as we go down the table here.
DR. FRIEDLANDER: I'm Art Friedlander from USAMRID, Fort Dietrich, Frederick, Maryland.
DR. WALKER: David Walker, Chairman of Pathology at the University of Texas, and Director of the Center for Tropical Diseases.
DR. HUGH-JONES: Martin Hugh-Jones, Department of Veterinary Epidemiology at LSU Veterinary School, and I'm the coordinator for the WHO Anthrax Working Group.
DR. TAKAFUJI: I'm Ernie Takafuji from the Office of the Assistant Secretary of Defense for Health Affairs.
DR. DEITCHMAN: I'm Scott Deitchman. I'm an occupational medicine physician and senior scientist with the National Institute for Occupational Safety and Health, which is a part of the Centers for Disease Control and Prevention.
DR. BAYUK: Dr. Jim Bayuk. I'm the Office of Environmental Health and Preventive Medicine at the Department of State, Office of Medical Services. Our office represents the health care responsibilities for approximately 25,000 men, women and children that are part of our U.S. embassies and consulates overseas.
MR. WERTZ: I'm Mike Wertz with Eagle Group International. I'm the project manager for the Anthrax Vaccine Immunization Program at the Department of State, Office of Medical Services.
CHAIRMAN RELLER: Thank you very much.
We're most pleased to have our guests and consultants, members to discuss the important issues before us today in the interest of the health of the nation.
I'd next like to turn the meeting over to Tom Perez, who will make the necessary statements regarding this meeting.
DR. PEREZ: Good morning. The following announcement addresses the issue of conflict of interest with regard to this meeting and is made part of the record to preclude even the appearance of such at this meeting.
Based on the submitted agenda for the meeting and all financial interests reported to the committee participants by the committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest or the appearance of a conflict at this meeting.
We would, however, like to disclose for the record that Keith Rodvold, Pharm.D., previously participated in meetings of Bayer's Moxyfloxacin Pharmacy Advisory Board and that he previously participated in Bayer's Speakers Bureau.
In addition, Dr. Rodvold was a co-investigator in a pharmacokinetic study of the lung penetration of vivofloxacin and cipro.
Lastly, Dr. Rodvold was an investigator in a study of the effect of cardiopulmonary bypass on cipro disposition.
With respect to FDA's invited guests, there are interests which we believe should be made public in order to allow the participants to objectively evaluate the guests' comments. Dr. Arthur Friedlander would like to disclose for the record that he has received speaker fees from Bayer for educational lectures that he has given to physicians.
In the event that the discussions involve any other product or firms not already on the agenda for which an FDA participant has 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.
CHAIRMAN RELLER: Thank you, Tom.
I'd next like to take the opportunity to introduce Dr. Jonathan Moreno from the Center for Bioethics at the University of Virginia, who has joined us and is one of our guests for today's discussions, deliberations.
Now I should like to call on Dr. Diane Murphy whom you heard before is the Director of the Office of Drug Evaluation-4. Dr. Murphy will present opening comments and set the framework, the context into which this meeting is occurring.
DR. MURPHY: I wish to extend my sincere thanks to everyone who has made time in their schedule to be here today.
My task this morning is to delineate for the committee, in particular, but also for the discussants and the public, how this meeting is different because, as you will hear, this is not quite our usual situation. It is a unique situation.
So I'm going to -- my tasks are to go over how we got here. It's often important to understand what has happened, to understand the context of the situation. So I'm going to spend a minute doing that and review then what are the components of this meeting which we think are important for people to understand or different.
Next slide, please.
In 1998, there have been a number of presidential directives, but we'll focus on this one for right now concerning bioterrorism that orders federal agencies to significantly expand and better coordinate their steps to protect against the consequences of biological and other unconventional attacks.
We, of course, are a federal agency and wish to facilitate the ability of our population to have access to therapies that they would need in such an event.
Next slide, please.
The particular mandates or directions under the presidential order that were addressed at HHS, and this is quite a condensation of those bullets, were that HHS is to basically be involved in improving the nation's surveillance network, strengthening the medical response capacities, creating and maintaining a stockpile of pharmaceuticals for mass treatment, and expanding research into the disease agents and into improved treatment.
Next slide, please.
The research and development aspects do relate to FDA. As you will see, the agents that have been particularly targeted with an emphasis on anthrax, tularemia, and plague, and as you are aware this morning, the product which, along with input from national and academic and professional societies, and that has -- there has been numerous papers and publications in this area, and they are to develop the stockpile, the components of which that relate to FDA activities. This is a stockpile that will be deliverable within 24 hours, will cross interstate boundaries.
That left us at FDA with a number of options.
Next slide, please.
We have been working with a number of other federal agencies in trying to streamline the IND process for use in the event of a mass exposure. That is an ongoing process so that products that would be under study and not yet approved for the indication could be used, if necessary, in such a situation.
That is not why we're really here this morning. We're not talking about that process. We're talking about really Item No. 2.
We also have been involved in identifying marketed products which do not have the indication for treatment in the event of a bioterrorist event, but which may be appropriate for labeling, and what that means is we have looked at the products in the stockpile and have looked at those which do not have the indication in their label, and have proceeded to look at the evidence, the body of evidence that is available to see if it would be appropriate to consider labeling these, the product, and if not, whether the activities or studies would be needed.
And then last is another area that we continue to be involved in, which is identifying marketed products which may need additional other studies.
Next slide, please.
How is it different? This is an FDA initiated process. We basically reviewed the public data and the professional recommendations. We have determined, having done that, a need for submission of data, and we requested the sponsor submit the application, and we ask the investigators and sponsors to participate in this public discussion.
So that is different than the usual process.
Next slide, please.
As you all are aware, this is a unique situation. Fortunately bioterrorist attacks do not occur on a regular basis, and we are dealing with what is the appropriateness of the IND process for a marketed product with extensive safety record and additional other studies, including significant animal study of inhalational -- typo there -- anthrax in a situation in which it is ethically unacceptable to conduct trials with the organism in humans.
That is the circumstances in which we are addressing this morning.
Next slide, please.
What we will do today is to look at the body of evidence that is available, and Dr. Chikami and Dr. Meyerhoff will spend a lot more time on this with you, in addition to the speakers that we have asked to address this issue, but this slide is a very succinct summary in that we have a large body of clinical safety information. We have animal studies. We have PK/PD data in animals and humans, and in vitro microbiologic data that will be reviewed for you today.
Next slide, please.
Another thing that's different about today, we normally do not make a recommendation. We provide an assessment to the Advisory Committee. Clearly, we thought it rather disingenuous to come to the committee having outlined for you the process in which we have undertaken and not assume that we have a recommendation.
However, we felt this recommendation needs public input and discussion, and so that is the other difference that you will see today.
We will be asking you, if you've seen the questions, you agree with the recommendation, but we will be making a recommendation of what our assessment is.
Next slide, please.
And my last opportunity this morning is to tell you that there have been a number of people at FDA who have put in a tremendous amount of work gathering information, reviewing it, and involve both Anti-Infectives and Special Pathogens Divisions' cooperation with a number of scientific individuals.
And I wish to personally recognize the effort and commitment they have put into this activity.
CHAIRMAN RELLER: Thank you, Dr. Murphy, for that important background information.
Later this morning we're going to have the opportunity to hear about the clinical manifestations of anthrax and its epidemiology presented by Dr. Martin Hugh-Jones; the pathology of inhalational anthrax portrayed by Dr. David Walker; and a detailed discussion of the non-human primate model of inhalational anthrax by Dr. Friedlander.
Before that discussion of the epidemiology/pathophysiology of the disease for which the sponsor is coming forth with their presentation, we will now hear from Bayer their presentation of the relevant information regarding safety and other aspects of ciprofloxacin.
Andrew Verderame will present. He is the Associate Director of Regulatory Affairs for Bayer.
MR. VERDERAME: Thank you, Dr. Reller.
I'm Andy Verderame of Bayer Corporation.
I wish to thank the members of the Advisory Committee, the FDA, and the other invited guests today for their participation in a discussion of a new indication for our fluoroquinolone ciprofloxacin.
The agenda for my remarks is as presented. In the next 20 minutes or so, I'll spend some time reviewing the events that have brought us here today from the Bayer perspective, and because our submission contains no human data for the proposed indication, I will present some indication that provides a strong rationale for the use of ciprofloxacin in the event of an anthrax release.
Now, in February of this year, Bayer submitted labeling supplements for all ciprofloxacin oral and IV formulations to the FDA for an indication of post inhalational exposure prophylaxis of anthrax. We have been told by the FDA that this is the first anti-infective drug application submitted to treat patients from the intentional use of a biological agent.
This slide presents our proposed labeling highlights. The indication is anthrax post inhalational exposure prophylaxis. The recommended dose for adults is 500 milligrams given twice a day as either the tablet or oral suspension. The IV dose is 400 milligrams twice a day.
The recommended pediatric dose is ten to 15 milligrams per kilogram given twice a day in either the oral or IV forms.
Treatment with ciprofloxacin should begin as soon as possible after exposure. Once the susceptibility of the strain has been determined, the most appropriate antibiotic should be administered to complete a total of 60 days' treatment.
These recommendations are taken from those published in the Journal of the American Medical Association by the Working Group on Civilian Biodefense and are similar to those recommended by the Centers for Disease Control.
Ciprofloxacin tablets were approved in 1987, and subsequently the IV and oral suspension products became available in 1990 and 1997, respectively.
The otic and ophthalmic formulations have been out-licensed and are not currently marketed by Bayer.
Ciprofloxacin has been proved to treat a wide variety of indications as listed here. Important to note is that the approvals for many of these indications include the severe category.
Also, many of these indications were approved subsequent to the original NDA approvals of the formulations, and as such, ciprofloxacin's safety and efficacy has been reviewed by FDA many times over the years.
The chain of events which ultimately has led us here today actually began about ten years ago. Bayer supplied over 30 million cipro 500 milligram tablets to the U.S. government prior to and during the Gulf War. It is our understanding that these tablets were provided to the air and ground troops to be used in the event of a biological attack.
We do not know if any tablets were actually used for this purpose.
After the war, Bayer was commended for meeting all production and delivery time lines necessitated by the emergency nature of the time.
Also during this period, the Department of Defense conducted the anthrax testing in Rhesus monkeys, which we included in our submission. My presentation will not include remarks on this topic as Colonel Friedlander, who performed the testing, is here today and will present his data to you shortly.
Fast forward now to 1998. The possible threat of a biological attack in the United States has been raised by the media and others as an issue of public awareness. During this year, the third edition of the Medical Management of Biological Casualties Handbook was issued. Prophylaxis with ciprofloxacin 500 milligrams tablets is prescribed as a preferred treatment.
In 1999, two additional publications on this topic also came to Bayer's attention. The Centers for Disease Control's morbidity and mortality weekly report published recommended treatment guidelines for the post exposure prophylaxis of anthrax. Ciprofloxacin is listed as a treatment of choice.
Later in that year, the Working Group on Civilian Biodefense published their consensus statement in JAMA with the recommendations for the public health measures to be taken following an anthrax attack. Ciprofloxacin is again listed as a preferred agent.
It is from the consensus statements from this working group that the recommended doses and durations of ciprofloxacin therapy are based.
I would also like to mention at this time that Dr. John Bartlett from Johns Hopkins University is here with us today. He was a member of this working group and is available during the morning session until about 11:00 a.m. to answer any questions concerning their recommendations.
Also during 1999, Bayer was asked by government agencies to provide information in the development of the emergency preparedness plans being generated in the event of a bioterrorist attack. These queries, coupled with the published recommendations for ciprofloxacin use for anthrax, prompted Bayer to evaluate our responsibilities and our options to further disseminate this information in the interest of public health through appropriate product labeling.
Now, the summary basis of approvals for penicillin, doxycycline, and all other agents with any product labeling regarding anthrax or Bacillus anthracis were reviewed, but unfortunately they provided no information on the data necessary for those approvals.
So we gathered all information available to us and submitted a briefing document to the FDA to initiate and facilitate discussion with them. A teleconference was held in which FDA advised us that the information presented with a few other requests was sufficient for their review of a supplement and encouraged us to submit this information formally.
Now, because we have proposed that an indication be granted for pediatric patients as well as adults, the committee may be interested that occurring at this same time were discussions between Bayer and the division concerning the conduct of new ciprofloxacin clinical trials in children.
Discussions started in August 1998 and culminated in May 1999 with the issuance of a letter to Bayer requesting that pediatric patients be included in well controlled clinical trials.
Enrollment in two trials is currently underway, and I'll briefly discuss these trials in a few moments.
Finally, in November 1999, Bayer received a call from a representative of the CDC's Bioterrorism Response Group. The representative asked if Bayer was aware of the recommendations for the use of ciprofloxacin in the event of an anthrax release and was pleased when informed that we had already contacted the FDA and were preparing a submission.
And as was mentioned earlier, this submission was formally made on February 29th of this year.
Because we cannot intentionally expose human subjects to the anthrax microorganism and because inhalational anthrax is an extremely rare disease, this submission contains no human data. We rely on the animal data to be presented by Dr. Friedlander and upon what we know about ciprofloxacin.
I would like to discuss now the additional points which lead us to believe that ciprofloxacin therapy would be safe and effective for this indication. I will review certain aspects of ciprofloxacin pharmacokinetics, especially in relation to the MIC of Bacillus anthracis. I will also present additional information concerning the efficacy and safety of our products.
The MIC range for ciprofloxacin for all tested strains of Bacillus anthracis in our submission was 0.03 to 0.06 micrograms per mL. The MIC-90 was also 0.06.
The half-life is approximately four hours, and the protein binding is approximately 30 percent. The absolute bioavailability of the oral formulations is about 70 percent.
Plasma concentrations for adults and pediatrics observed that the dosages recommended by the Working Group and in our proposed labeling are shown here. All C-max and AUC values are fairly comparable, with the one C-max value somewhat striking from the pediatric IV study.
However, the infusions in this study were completed in just 30 minutes. One hour infusion, which is the recommended duration, provides results similar to that observed in adults. The minimum concentrations observed at the end of the 12 hour dosing interval for these studies is approximately 0.2 micrograms per mL, which is still three to fourfold higher than the MIC of the infecting organism.
It has been suggested that for optimal antibiotic effect the ratios of C-max to MIC and AUC to MIC should be at least eight to ten and 125, respectively. The C-max to MIC ratio with ciprofloxacin 500 milligram oral dosing in adults is approximately 50, and the 12 hour AUC to MIC ratio is 228.
There are later speakers who will address the pathology and pathophysiology of anthrax infection. In short though, it is believe that inhaled Bacillus anthracis spores reach the pulmonary alveolar epithelium where they are phagocytosed by pulmonary macrophages. The spores are transported to the local lymphatic system where they are thought to germinate into vegetative Bacillus anthracis.