Development of Fluoroquinolones for

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Wednesday, November 19

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The meeting was held in the Versailles Room 3 and 4 of the Holiday Inn, Bethesda, Maryland, at 8:00 a.m., William Craig, M.D., Chair, presiding.



ERMONA McGOODWIN, Executive Secretary





















Page No.

Call to Order, WILLIAM CRAIG, M.D., Chair 4

Conflict of Interest Statement, ERMONA 7

McGOODWIN, Executive Secretary

Opening Remarks, MURRAY LUMPKIN, M.D., Office 9

Director, ODE IV

Presentation of Certificates, GARY CHIKAMI, M.D. 14

Acting Director, Division of Anti-Infective

Drug Products

Issue: Development of Fluoroquinolones for

Use in Pediatric Patients

Introduction, MARK GOLDBERGER, M.D., M.P.H. 16

Director, Division of Special Pathogens and

Immunologic Drug Products

History of Previous Advisory Committee Meetings 19

on Study and Use of Quinolones in

Pediatric Populations, BRAD LEISSA, M.D.,

Medical Officer

Future Role for Fluoroquinolones in Pediatric 28

Populations (i.e., Increasing Concerns

about Resistance), ROBERT HOPKINS, M.D.,

M.P.H., Medical Officer

CDC Presentation on Streptococcus pneumoniae and 36

Resistance, SCOTT DOWELL, M.D.

Quinolone-Induced Arthropathy in Juvenile 61

Animals: Pre-Clinical Data, AMY ELLIS, Ph.D.,


Relationship of Immature Articular Cartilage to 75

Quinolone Arthropathy, DAVID VAN SICKLE,

D.V.M., Ph.D., FDA Consultant

Fluoroquinolone use in Pediatrics, Epidemiology 98

Review of FDA AERS and Drug Use Data,

CAROLYN McCLOSKEY, M.D., Medical Officer

PRESENT - (Continued):

Page No.

Pediatric Indications for Quinolones: The 121

Ciprofloxacin Experience, DEBORAH CHURCH,

M.D., Deputy Director, Medical Research,

Bayer Corporation

Duration of Follow-Up in Clinical Trials, 135

SCOTT HOPKINS, M.D., Group Director,

Clinical Development, Pfizer, inc.

Rationale for Studying Quinolones in Children, 141

ROGER ECHOLS, M.D., V-P, Infectious

Diseases R&D, Bristol-Myers Squibb

Presentation - JON ABRAMSON, M.D. (AAP), 155

FDA Consultant

Presentation - JOHN BRADLEY, M.D., FDA 160


Presentation - JEROME KLEIN, M.D., FDA 170


Quinolones in Pediatrics: Viewpoint of a 173

Clinical Pharmacologist, PAUL LIETMAN,

M.D., Ph.D., FDA Consultant

Quinolone Adverse Events Experience 180



Committee Discussion, Questions and Vote 189


(8:14 a.m.)

CHAIR CRAIG: Could people please take their seats?

I'd like to welcome you to this meeting of the Anti-Infective Drug Advisory Committee. This is the 62nd meeting. They are going to be changing the board, so fairly soon everybody else will have their microphone, but I think they are picking it up on the documentation of the record for the meeting, so we can still go around and introduce each individual telling who they are and where they are from. And, I guess I'll go ahead and start.

I am William Craig. I am from the University of Wisconsin, and I'm the chair of the Advisory Committee.

So, if we could start here on my right. Use the microphone because it is still at least being picked up -- none of them are now? Say it loud.

DOCTOR VAN SICKLE: Doctor Dave Van Sickle from Perdue University, Department of Basic Medical Sciences.

DOCTOR LIETMAN: I'm Paul Lietman. I'm Director of the Division of Clinical Pharmacology at Johns Hopkins.

DOCTOR DOWELL: Scott Dowell from the Respiratory Diseases Branch at the Centers for Disease Control.

DOCTOR BRADLEY: John Bradley, Children's Hospital San Diego and the University of California San Diego.

DOCTOR ABRAMSON: Jon S. Abramson, Chairman of the Department of Pediatrics at Bauman Gray, and also representing the American Academy of Pediatrics.

DOCTOR KLEIN: Jerome O. Klein, Pediatric Infectious Disease, Boston University School of Medicine.

DOCTOR BIDAULT: Irene Bidault from the Agence du Medicamanet, the National -- and the Pharmacovigilance.

DOCTOR RELLER: Barth Reller, Committee for Infectious Diseases and Clinical Microbiology, Duke University.

CHAIR CRAIG: And, I guess I might inject here that these are all our consultants for this meeting, and now the members.

DOCTOR HENRY: Nancy Henry, Pediatric Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

DOCTOR DANNER: Robert Danner, Critical Care Medicine Department, National Institutes of Health.

DOCTOR AZIMI: Parvin Azimi, Pediatric Infectious Diseases, Children's Hospital, Oakland, California.

MS. McGOODWIN: Ermona McGoodwin, FDA.

MR. RODVOLD: Keith Rodvold, University of Illinois, Consumer Representative on this committee.

DOCTOR NORDEN: Carl Norden, I'm the Head of Infectious Diseases at Cooper Hospital in Camden, New Jersey, at the University of New Jersey Medical School.

DOCTOR PARKER: Don Parker, Professor, Department of Biostatistics and Epidemiology at the University of Oklahoma.

DOCTOR MELISH: Marian Melish, Pediatric Infectious Disease, University of Hawaii School of Medicine.

DOCTOR PARSONNET: Julie Parsonnet, Infectious Diseases and Epidemiology at Stanford University.

DOCTOR GOLDBERGER: Mark Goldberger, Director of the Division of Special Pathogens Immunologic Drug Products, Safe for Drugs, FDA.

DOCTOR LEISSA: Brad Leissa, Medical Team Leader of the Division of Special Pathogens.

DOCTOR HOPKINS: Bob Hopkins, Acting Medical Team Leader of the Division of Special Pathogens.

DOCTOR ELLIS: Amy Ellis, Pharmacologist and Toxicologist of the Division of Anti-Infective Drug Products.

CHAIR CRAIG: Okay, thank you, and, again, I'd especially like to welcome all of our consultants for this meeting.

Ermona McGoodwin will now read the Conflict of Interest Statement.

MS. McGOODWIN: Thanks, Doctor Craig.

The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the meeting to preclude even the appearance of such at this meeting.

Based on the submitted agenda and information provided by the participants the Agency has 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.

In according with Section 208(b)(3) full waivers have been granted to Doctors Craig, Norden, Parsonnet, Azimi, Danner and Rodvold. A copy of these waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.

With respect to FDA's invited guests, there are reported interests with respect to the firms that make fluoroquinolones that -- should be made public to allow the participants to objectively evaluate the comments. Doctor Jon Abramson would like to disclose for the record that he has received honorarium from Bayer and has consulted for Merck. Doctor Jerome Klein is a member of the Pediatric Anti-Infective Advisory Committee and Ortho Consultant to the Scientific Board. Doctor David Van Sickle owns a nominal amount of stock in Merck, he has been an investigator and co-investigator on studies funded by Eli Lily, Bayer and has been a consultant to Eli Lily. Lastly, Doctor John Bradley was a co-investigator on two studies sponsored by Pfizer.

In the event that the discussions involve any other products 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 on.

Thank you.

CHAIR CRAIG: Thank you, Ermona.

Our next speaker is going to be Murray Lumpkin, who is the Office Director of ODE, that will have some opening remarks.


DOCTOR LUMPKIN: Good morning, everybody.

My name is Murray Lumpkin, and what I'm here to say this morning is, first of all, welcome to all of you on behalf of the Center for Drug Evaluation and Research. To the guests we have in the audience today, our consultants, and to the members of the committee we are delighted to have all of you with us today.

I know you have your plates quite full, as you can see from the agenda, on several different diverse, and, I think, very interesting topics. One of the things, though, that I thought would take just a few minutes this morning and try to clarify, particularly, for the committee, is some of the structural and personnel changes that have happened within the Office for Drug Evaluation since the last time you met.

Just to try to keep things from getting a little confusing, as you meet different people, and hear people's titles, I wanted to spend a few minutes to tell you about some of the changes that we've undergone. The first change is the fact that I am not really the Office Director for OED IV, as most of you know. I'm the Deputy Center Director at the Center for Drug Evaluation and Research, but about six weeks ago David Fiegal, who had led the Division of Antiviral Drug Products, and who was then the Office Director for OED IV, was promoted to Deputy Center Director at CBER, at the Center for Biologics. I think this was a great promotion for David. It was one that he truly deserved, and I think he will use his considerable talents in that particular area to look at some very concerning issues for the country, particularly, the safety of the blood supply and the development of vaccines and, particularly, vaccines for various viral diseases.

However, for us within the Center for Drugs it was quite a loss to lose David, and it began a series of dominoes as we started looking for replacements for David, and also looking at how the Office of Drug Evaluation IV was structured.

As many of you know who have followed over the last five years as we have endeavored within the Center for Drugs to meet the performance goals that were established five years ago under the Prescription Drug User Fee Act, one of the management things that Janet and I undertook at that point in time, with the idea of creating more divisions who would be smaller in number and more focused in their work products, and both Janet and I believe that this has worked well over the last five years and has been one of the things that has helped us achieve and actually exceed the performance goals that Congress established for us five years ago.

This also has affected this particular office. For those of you who have been on the committee for a while, who remember the days when I was in the Division of Anti-Infective Drug Products, we had the Division of Anti-Infective Drug Products, and they had this advisory committee to help them, and we also had the Division of Antiviral Drug Products, and they have a committee that looks at their particular drug products.

We now have three divisions within the Office of Drug Evaluation IV that oversee the antimicrobial products. There is the Antiviral Division, there is the Anti-Infective Division, and there is a division now that we call the Division of Special Pathogens and Immunologic Drug Products, and this is the group that you are going to be hearing from first today. It's a group that primarily deals with anti-fungal drug products, anti-microbacterial drug products, various drug products for parasitic diseases, as the name implies, drugs for immunologic diseases, particularly, various immunomodulatory drugs, but also because of the work load implications in trying to spread the work out between the three divisions they also oversee the fluoroquinolones.

The individual who was chosen to be the Division Director for that division is Doctor Mark Goldberger, whom you will be hearing from in just a few minutes, and the person who is his Deputy is Doctor Renata Albrecht, whom you will, I'm sure, be meeting through the day.

The Division of Anti-Infective Drug Products is right now being capably led by an Acting Division Director whose name is Gary Chikami, and you will be hearing from him when you get to some of the other drug products, and his Deputy is Lillian Gavrilovich, who many of you, she has had that position for many, many years. She was the Deputy when I was there, and she is still ably fulfilling that position.

Within the Division of Antiviral Drug Products, as you know also Donna Freeman, who was leading that division from the time that Doctor Fiegal left, she has also retired from government service and that division is now under the leadership of an Acting Director by the name of Deborah Bernkrant.

We have been, for the last several months, in a series of national searches to find a permanent director for the Anti-Infective Division, for the Antiviral Division and for OED IV. Those have been incredibly interesting. We have had a lot of interest expressed in these positions, both internally and externally. There has been a series of search committees for the three jobs. Many people have been brought in and interviewed, and I think we will have announcements for those permanent positions within the next several weeks.

But, at least for today, as you begin your work here on the committee and in the future, I just wanted to make you aware of some of these personnel changes and some of these structural changes, because as our products go we will be bringing products from these three divisions to either of the advisory committees that seem to be the most appropriate advisory committee based on the issue and based on the drug product.

So, if you have any questions about this, you know, please feel free to see me. Please feel free to see any of the leadership individuals whom I've mentioned today, and, again, Bill, I appreciate the time to explain this, I appreciate all of you coming here today, and I wish you tremendous success in a very daunting agenda.

Thanks again.

CHAIR CRAIG: Thank you very much, Murray.

This is the last meeting for the year for the committee in its current grouping, and some individuals will actually be leaving the committee after this meeting, and to present their certificates Gary Chikami will now -- there you are, okay.

DOCTOR CHIKAMI: Thank you, Doctor Craig.

There are actually five members of the Anti-Infectives committee who will be rotating off after four years of very able service, and we certainly appreciate their scientific and clinical input into our deliberations over the years.

I'd like to present them with a letter of appreciation from the Deputy Commissioner of the Food and Drug Administration and also a plaque from Doctor Woodcock, who is the Director of the Center for Drug Evaluation and Research.

Doctor Henry Francis?

CHAIR CRAIG: Not here.

DOCTOR CHIKAMI: Not here, okay.

Doctor Marian Melish.

Doctor Roselyn Rice.

CHAIR CRAIG: Also not here.

DOCTOR CHIKAMI: And, Doctor Parvin Azimi.

A fifth member is also rotating off, and that's Doctor Edwin Thorpe, who couldn't join us for this three-day meeting.


CHAIR CRAIG: Thank you, and, again, I'd also like to join in my appreciation to the members for their service on the committee.

And now, we are here for the issue, which is the development of fluoroquinolones for use in pediatric patients, and the individual that's going to give our introduction to the topic is the Director of the new division, as was just mentioned, the Division of Special Pathogens and Immunologic Drug Products, and that's Mark Goldberger.

DOCTOR GOLDBERGER: Thank you, Doctor Craig.

I'd also like to extend a welcome to the committee. As Doctor Lumpkin indicated, there will not be a new advisory committee created especially for this division, so we anticipate bringing quite a number of products to the Division of Anti-Infective Drug Products, just as we will be to the Division of Antiviral Drug Products.

Doctor Craig indicated the topic that we will be discussing today, that is, the development of fluoroquinolones for pediatric indications. As all of you are probably aware, this is, I think, the third committee meeting that has occurred on this topic. One of the lead-off FDA presentations by Doctor Brad Leissa will, in fact, give a little history of some of the previous committee meetings.

We're interested, obviously, in getting some general advice from you about this question of further development of fluoroquinolones for pediatrics. Depending on the answer we get from that, as to whether this is appropriate, we would like to get from you first some advice on particular indications, where there is currently the greatest amount of interest, and I think the one that is most obvious would be the development of fluoroquinolones for otitis in children, and I think it would be, if the committee feels that further development is something that is appropriate, that's a topic that we would like you to give your advice about.

Beyond that, more generally, we would like, if further development is recommended, or even not, a framework for how we could proceed in assessing specific indications and thinking about how one might proceed in the future.

Going along with the issues that relate, obviously, to activity of the fluoroquinolones in a number of situations, of course, the major indication and the major concern has been safety. We will be presenting at least a couple of pre-clinical presentations talking about the toxicity related to arthropathy in animals, as well as some clinical epidemiologic data that will be presented by a number of people during the morning to outline some of the concerns that exist, and also the amount of data that currently exists about the use of these products in children.

We would expect the discussions to focus on the issue of arthropathy, but they do not necessarily need to be limited to that, and that is up to members of the committee in terms of other concerns about toxicity that you would like to bring up.

We are interested, obviously, in thinking qualitatively. Certainly, when we talk about the issue of arthropathy that potentially includes a number of things, ranging from simple effusion, for instance, of a knee joint, which might rapidly resolve after the conclusion of therapy, to a more permanent disability. We'd like to get a little bit of advice about putting together a hierarchy of these events, in terms of how you would value them in their importance, and going along with that some sense of how you would view them qualitatively, particularly, the issue, perhaps, of severe toxicity that might occur relatively uncommonly. And, again, beyond specific advice, we'd like to get a framework of your thinking about how we might approach safety over time, as different companies present different questions to us.

Before I close, I'd like to thank a number of people who participated in putting together the agenda for this meeting. Many of them, in fact, will be presenting, that would include Brad Leissa to my left, and also Bob Hopkins. I'd also particularly like to thank Doctor Renata Albrecht, the Deputy Director of the Division, who helped with much of the presentation, and in particular also some of the reviewers in the pre-clinical area, most notably Teri Peters, a pharmacologist from the Division of Anti-Infective Drug Products, the supervisory pharmacologist in that division, Doctor Bob Osterberg, and Doctor Amy Ellis, also a pharmacologist in Anti-Infective who will be one of the presenters.

Perhaps, later on this afternoon when we actually get to discussion of the questions, we may want to talk a little more about some of these issues to ensure that, you know, we get the advice that we need on some points, but I think now I'll close in the interest of keeping us relatively on time.

Thank you.

CHAIR CRAIG: Thank you, Mark. In fact, we're even ten minutes ahead, gained a lot of time very quickly there.

Our next speaker then is Brad Leissa, who is going to give us the history of the previous advisory committee meetings on the question of the use of quinolones in pediatric populations.


DOCTOR LEISSA: Good morning. I'm going to try a very difficult task, which is to try to catch everyone up in the next 15 minutes with regards to history of this issue.

As Doctor Goldberger had mentioned, this has been brought up twice to the advisory committee back in 1989 in a closed session, as well as in 1993, the issue about what do we do about quinolones in pediatric populations.

History is interesting because, obviously, it's a continuum and issues that occur and how one responds depends on what are the various factors going on at the time. Last night, of interest when I got home and went through my mail, the most recent issue of
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