FOOD AND DRUG ADMINISTRATION

	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

	MEETING OF THE

	BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

	8:15 a.m.

	Thursday, July 15, 1999

	Versailles Ballrooms I and II
	Holiday Inn
	8120 Wisconsin Avenue
	Bethesda, Maryland  20814

	ATTENDEES

COMMITTEE MEMBERS:

DANIEL R. SALOMON, M.D., Acting Chairman
Associate Professor
Department of Molecular and Experimental
  Medicine - SBR5
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California  92037

GAIL DAPOLITO, Executive Secretary
Scientific Advisors and Consultants Staff
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike
Rockville, Maryland  20852-1448

HUGH AUCHINCLOSS, JR., M.D.
Associate Professor of Surgery
Harvard Medical School
Transplantation Unit
Department of Surgery
Massachusetts General Hospital
GRB504, 55 Fruit Street
Boston, Massachusetts  02144-2696

RICHARD E. CHAMPLIN, M.D.
Professor of Medicine
Division of Medicine
Department of Blood and Marrow Transplantation
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Boulevard, Box 24
Houston, Texas  77030

RICHARD A. GOLDSBY, Ph.D. 
(attending via teleconference call)
Professor of Biology
Department of Biology
Merrill Science Center, Campus Box 2237
Amherst College
Amherst, Massachusetts  01002

	ATTENDEES  (Continued)

COMMITTEE MEMBERS:  (Continued)

CAROLE B. MILLER, M.D.
Associate Professor of Oncology
The Johns Hopkins Oncology Center
600 North Wolfe Street, Room 132
Baltimore, Maryland  21287-8985

W. MICHAEL O'FALLON, Ph.D.
Professor of Biostatistics
Chair, Department of Health Sciences Research
Harwick Building, Room 766-A
Mayo Clinic
Rochester, Minnesota  55905

EDWARD A. SAUSVILLE, M.D., Ph.D.
Associate Director
Developmental Therapeutics Program
Division of Cancer Treatment
National Cancer Institute
6130 Executive Boulevard
Executive Plaza, North Room 843
Bethesda, Maryland  20892

TEMPORARY VOTING MEMBERS:

VIRGINIA C. BROUDY, M.D.
Associate Professor of Medicine
Department of Medicine
Division of Hematology, Room K136
University of Washington School of Medicine
Seattle, Washington  98195

ABBEY S. MEYERS, Consumer Representative
President and Executive Director
National Organization for Rare Disorders
Fairwood Professional Building
Post Office Box 8923
New Fairfield, Connecticut  06812-8923

JULIE M. VOSE, M.D.
Vice Chairman and Professor
Department of Internal Medicine
University of Nebraska Medical Center
983332 Nebraska Medical Center
Omaha, Nebraska  68198-3332

	ATTENDEES  (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

JOSEPH B. BEKISZ
BETTY GOLDMAN, M.S., M.P.H.
PATRICIA KEEGAN, M.D.
AMY S. ROSENBERG, M.D.
WILLIAM SCHWIETERMAN, M.D.
JAY P. SIEGEL, M.D.
KATHRYN E. STEIN, M.D.
KAREN D. WEISS, M.D.
KATHRYN C. ZOON, Ph.D.

ALSO PRESENT:

THOMAS SCHAIBLE, Ph.D.
Senior Director, Immunology Medical Affairs
Centocor, Inc.

	C O N T E N T S

AGENDA ITEM	PAGE

ADMINISTRATIVE REMARKS - by Ms. Gail Dapolito	8

OPEN PUBLIC HEARING
  Dr. Thomas Schaible, Centocor, Inc.	10

TOPIC I - FDA REGULATORY POLICY UPDATE

  Fast Track/Evidence of Effectiveness -
    by Dr. Jay Siegel	27

  Pediatric Rule - by Dr. Karen Weiss	77

TOPIC II - REPORT OF THE XENOTRANSPLANTATION
  SUBCOMMITTEE, JUNE 3-4, 1999 MEETING
    by Dr. Hugh Auchincloss	114

PRESENTATION OF CERTIFICATES
  by Dr. Kathryn Zoon and Dr. Jay Siegel	126

TOPIC III - IMMUNE REACTIONS AGAINST THERAPEUTIC
  AND DIAGNOSTIC BIOLOGICAL PRODUCTS
    FDA Perspective:

      Immunogenicity of Therapeutic Proteins
        by Dr. Kathryn Zoon	130

      Immunogenicity of Monoclonal Antibody
        Products - by Dr. Kathryn Stein	134

      Immunogenicity of Interferons
        by Mr. Joseph Bekisz	153

      Immunogenicity of Other Therapeutic Proteins
        by Dr. Amy Rosenberg	169

      Clinical Perspective -
        by Dr. William Schwieterman	193

      Committee Discussion of Questions Presented	213

	P R O C E E D I N G S
	(8:15 a.m.)
DR. SALOMON:  Good morning, everybody.  I'm going to open the meeting today.  My name is Dan Salomon, and I'm a member of the Scripps Research Institute in La Jolla, California.
I'm going to act as the acting Chair today.  It just seems a little strange to me -- I've already noted that -- with having Dr. Vose to my left who, ever since I've been on the committee, has been the Chairperson and basically been for me a role model for what a Chair should be of this kind of a committee.  I can only be a facsimile of Dr. Vose.  I've asked her to just sort of elbow me from time to time if I'm not doing it right.  But anyway, I apologize.  I really won't be able to do as good a job as she does.
The meeting today will start in a moment, but I thought what we ought to do, just to begin, is go around the table and introduce everyone and everyone just sort of briefly tell us what institution they are from and what their basic clinical or scientific interests are.  If we can start on the left.
DR. O'FALLON:  I'm Michael O'Fallon from the Mayo Clinic.  My expertise is in biostatistics.

DR. CHAMPLIN:  Richard Champlin from the M.D. Anderson Cancer Center and the Chairman of the Blood and Marrow Transplant Department.
DR. SAUSVILLE:  I'm Ed Sausville from the National Cancer Institute and the Developmental Therapeutics Program, and my interest is in the development of new drugs for the treatment of cancer.
DR. VOSE:  Julie Vose from the University of Nebraska Medical Center, and my research interests are in lymphoma and hematologic malignancies, transplantation, and immunotherapy.
DR. SALOMON:  Again, as I said, Dan Salomon, Scripps Research Institute.  My interests are in transplantation, xenotransplantation, and gene therapy.
MS. DAPOLITO:  Gail Dapolito, Executive Secretary for the committee.
I'd also like to announce that Dr. Richard Goldsby from Amherst College is participating on the speaker phone this morning. 
I'd also like to take this opportunity to introduce Ms. Rosanna Harvey, the committee management specialist.  As the committee knows, Rosanna was instrumental in the preparations for today's meetings, and as usual, she'll be around all day to help out with any questions.
Thank you.

DR. BROUDY:  I'm Virginia Broudy from the University of Washington, and my interest is in hematopoietic growth factors. 
MS. MEYERS:  Abbey Meyers, President of the National Organization for Rare Disorders, which is NORD.  I'm a former member of the committee I believe and a consultant today for consumers.
DR. MILLER:  Carole Miller from Johns Hopkins.  My interests are in hematologic malignancies and bone marrow transplant, clinical.
DR. STEIN:  Kathryn Stein, Director of the Division of Monoclonal Antibodies, CBER.
DR. SCHWIETERMAN:  Bill Schwieterman, Chief of the Immunology and Infectious Disease Branch, CBER.
DR. SIEGEL:  Jay Siegel, Office of Therapeutics at CBER.
DR. SALOMON:  Yes.  I'd also like to add that Dr. Hugh Auchincloss from Harvard Medical School will be joining us in a few minutes. 
Next Gail will read into the record the administrative remarks.
MS. DAPOLITO:  This announcement is made part of the record at this meeting of the Biological Response Modifiers Advisory Committee on July 15.  

Pursuant to the authority granted under the committee charter, the Director of the FDA's Center for Biologics Evaluation and Research has appointed Dr. Virginia Broudy, Ms. Abbey Meyers, and Dr. Julie Vose as temporary voting members for the committee discussions.  
Based on the agenda made available and on relevant data reported by participating members and consultants, it has been determined that all financial interests in firms regulated by the Center for Biologics Evaluation and Research that may be affected by the committee's discussions have been considered.  The following participants have been granted waivers, in accordance with 18 U.S.C. 208, which permits them to participate fully in the committee discussions:  Drs. Hugh Auchincloss, Virginia Broudy, Richard Champlin, Carole Miller, and Julie Vose.  Dr. Michael O'Fallon has requested to be recused from the discussion of the report of the Xenotransplantation Subcommittee.
In the event that the discussions involve specific products or firms not on the agenda for which FDA's 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 public record.

Screenings were conducted to prevent any appearance, real or apparent, of conflict of interest in today's committee discussions.  Copies of the waivers addressed in this announcement are available by written request under the Freedom of Information Act. 
With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
DR. SALOMON:  Thank you, Gail.
Are there any other comments from the FDA staff we need to deal with?
(No response.)
DR. SALOMON:  I'm going to, as Chairman, try and stay on time but, in the same way, allow everybody to participate in the discussion as much as possible. 
Obviously, for recording interests, it's going to be important for us, as usual, to make an effort to speak directly into the microphones.  I apologize if we have to remind anybody of that.  I usually forget myself.
Then I'd like to open up the public hearing.  We have one scheduled speaker which is Dr. Thomas Schaible, Senior Director of Immunology and Medical Affairs for Centocor.  Welcome, Dr. Schaible.

DR. SCHAIBLE:  Thank you.  Good morning.  We appreciate the opportunity to share our experience at Centocor regarding immune responses to therapeutic biologics.
This morning I'd like to touch upon a few of the key issues revolving around immune responses and, more specifically, share with you our experience with two of our products, Remicade and ReoPro, and then finish up my presentation with some conclusions based upon that experience.
Now, certainly one of the key issues with biologics is their potential antigenicity, and if antibodies develop against these agents, what is the clinical relevance both in terms of safety, whether there are potential allergic reactions or hypersensitivity that may result from these antibodies, but also in terms of efficacy, is there potential for blocking antibodies that may result in reductions in potency of these agents.
I think as a quick background, it's important to recognize that a number of biologic agents, both recombinant molecules, as well as monoclonal antibodies, do develop antibodies at varying incidences as well as magnitudes.

Now, in terms of our own experience, I'll focus on our two products:  Remicade, which is infliximab, and ReoPro, which is abciximab.  I think it's important to point out some important differences in these products both in terms of the molecules themselves, but also in terms of the diseases in which these agents have been developed.
First of all, with Remicade, Remicade is a whole chimeric IgG.  It has a long serum half-life of approximately 10 days.  It has been developed primarily in the treatment of chronic inflammatory disorders.  Therefore, multiple dose regimens have been a key part of that development, and it has been used both with and without concurrent immunosuppressive agents.
With regard to ReoPro, abciximab, it is a chimeric Fab fragment.  It has a short free serum half-life, less than 10 minutes.  In part, that's due to the fact that it immediately binds to platelets after it's administered intravenously.  It has been developed for treatment of acute coronary syndromes, and as such, it has been given primarily as a single dose, but it's important to recognize that because of recurrence of these types of syndromes, there's clearly a potential for readministration of this agent.
In terms of the development of Remicade in chronic inflammatory diseases, we have extensive clinical trial experience now both in Crohn's disease, which is an inflammatory bowel disease, as well as rheumatoid arthritis, and this experience includes both experience with single-dose regimens, as well as longer-term repeated dosing regimens.
In terms of experience with single-dose regimens, in Crohn's disease, we have observed a 13 percent incidence of human anti-chimeric antibodies, or HACA.  Generally these are of low titer, less than 1 to 80.  The incidence is lower in patients who receive concurrent immunosuppressants such as Immuran, such as 6MP.  This incidence is about two-fold lower in patients receiving concurrent immunosuppressants.
In addition, we have observed some delayed hypersensitivity events, but specifically this has occurred in patients who have had a long interval, that is, 2 to 4 years, between exposures to the agent.
Now, in rheumatoid arthritis, we have a more substantial experience with long-term repeated dose regimens.  In these studies, doses were given at 0, 2, and 6 weeks, and then every 4 or 8 weeks thereafter.  We have studied doses of 1, 3, or 10 milligrams per kilogram, and we have studied these doses both with and without current methotrexate treatment which is the immunomodulator that is currently one of the standards of treatment in RA.
Now, in our phase II experience, we observed that both dose and concurrent methotrexate treatment were important in the incidence of HACA development.  First of all, what we observed was that lower doses of Remicade were associated with higher incidences of HACA.  In addition, if Remicade was given in combination with methotrexate, this also had the effect of reducing the incidence of HACA.
Now, in our phase III program, because of these findings, as well as a number of other reasons, we selected to study doses of 3 and 10 milligrams per kilogram given in combination with methotrexate.  
One of the key issues here is to establish how well these agents are tolerated over time when they are given repeatedly.  I think our experience in our phase III trial, which is called the ATTRACT trial, has been very helpful in getting a better understanding of this.  
Here I'm showing data for infusion reactions.  These are adverse events that have occurred either during the infusion or within 1 hour after the infusion.  And here we show data for the incidence of infusion reactions when Remicade is given every 8 weeks or every 4 weeks.  I think this data show that there is overall a low incidence of infusion reactions in patients over time, slightly above placebo rates, but only by a few percentage points.  And more importantly, there's no trend over time for an increase in infusion reactions.
Now, what have we learned from this experience?  First of all, antibodies do develop against Remicade.  It appears it's in the 10 to 15 percent range.  The incidence can be modified by several factors, including the dose, the frequency of dosing, as well as whether the agent is given in combination with immunosuppressant therapies.
However, the clinical relevance of antibody development is still uncertain.  HACA development is not predictive of subsequent hypersensitivity events, but more importantly, what we are observing is that long-term repeated treatment indicates that one can give these agents with sustained effectiveness, as well as the fact that these drugs are well tolerated given over the longer term.
Now let me focus in on the ReoPro experience.  First of all, I think it's important to point out that the experience here is substantial, that we have done HACA measurements in over 6,000 patients in clinical trials, and this includes the EPIC trial, the CAPTURE trial, and the EPILOG trial, where with initial administration of ReoPro, we have observed an incidence of about 5 to 6 percent for HACA.  Again, these are generally of low titer, less than 1 to 400, and there has been no increase in allergic reactions compared with placebo groups.
Now, in addition, we have undertaken a registry to collect data prospectively in patients who are readministered ReoPro commercially.  This is a phase IV multicenter prospective registry which is being conducted in the U.S.  It has now enrolled 791 patients, and in 579 of these patients, we now have data on HACA both pre and post a readministration of ReoPro.  
The objectives of this trial were, first, to determine the HACA incidence, its titer, and duration, as well as to evaluate safety and efficacy after readministration, and this would focus on adverse events, success of the angioplasty procedure, as well as in vitro assays of ReoPro potency.
Now, looking at the results for HACA incidence, following an initial administration of HACA in this registry, there was a 6.4 percent incidence of positive HACA.  The median titer was 1 to 100.  With readministration of HACA, there was an increase in the incidence of HACA, increasing to 27.1 percent with a modest increase in the median titer, going up to 1 to 400.
In terms of the durability of the HACA response -- that is, how long could it be measured in the serum -- it was generally 4 months or less.
In terms of major safety events in this readministration experience, there have been no deaths associated with adverse events, no allergic or hypersensitivity reactions, and no occurrences of intracranial hemorrhage or retroperitoneal bleeding.
Looking at the success of the angioplasty procedure, we can focus on the two yellow bars which show results for patients who were positive for HACA entering the procedure and those who were negative for HACA entering the procedure.  In both groups, there was a high success of the angioplasty procedure, and there was no difference as to whether a patient was positive or negative for HACA.
Then we have also looked in vitro at assays to measure the potency of ReoPro.  Here we have taken normal donor platelets and added them to sera that is positive for HACA at varying titers.  And if we look at the IC50 in these studies, there's really no apparent decrease in potency looking over a range of titers of HACA.  So, it appears that ReoPro is still able to inhibit platelet aggregation in these assays.
So, what have we learned from the ReoPro experience?  ReoPro is clinically effective when it's readministered.  Readministration has not been associated with allergic or hypersensitivity reactions.  And finally, a positive or a negative HACA titer is not predictive of clinical effectiveness or other clinical events.
Now, putting all of this experience together, these next two slides I think will summarize that experience.  Development of immune responses to therapeutic biologics has raised the concern of increased allergic reactions and/or loss of potency.  However, over the last 10 years, extensive time and effort have been given to developing and analyzing HACA responses and their effects.  We now, with over 8,000 patients in clinical trials and 5 years of post-marketing experience in over 500,000 patients, can conclude that, first of all, a large database of HACA measurements have been established and that antibodies can be detected in a relatively small proportion of patients receiving these agents.
However, the large clinical experience has also demonstrated that the immune response is modifiable by both dosing strategy, as well as concurrent medications.  Readministration can be accomplished safely and without loss of efficacy.  And in terms of the future, the focus should be on continuing pharmacovigilance of retreated patients rather than accumulating additional information on HACA titers.
Thank you for your attention.
DR. SALOMON:  Thank you, Dr. Schaible.
I'd like to request any questions, comments, or discussion from the committee.  Questions.  Yes.
DR. SAUSVILLE:  So, do you have any idea quantitatively, when you said there's a titer of X or Y or Z, what actual amount of antibody you're detecting in here?  Is it micrograms or nanograms per ml?  Has that been calibrated?
DR. SCHAIBLE:  No, it has not been calibrated.  We just haven't done those types of studies.
DR. SALOMON:  Abbey.
MS. MEYERS:  I'm trying to understand what you said in ordinary, plain English.  These products seem to cause a reaction in a certain number of patients.  Right?
DR. SCHAIBLE:  That's correct.
MS. MEYERS:  But you don't know whether that reaction is clinically relevant or not.
DR. SCHAIBLE:  Right.
MS. MEYERS:  For example, if they have antibodies, you don't know whether that means anything.  Right?
DR. SCHAIBLE:  That's correct.  We have developed methods for determining the presence of antibodies, but the clinical relevance of those antibodies I think, based on our experience, is still uncertain, and it may represent the fact that there are a number of different types of antibodies that develop against these agents.
MS. MEYERS:  But it doesn't mean anything if you rechallenge the patient later with the same agent.  Right?  I mean, they seem to respond just as well after they --
DR. SCHAIBLE:  The majority of patients do.  I wouldn't say that there are antibodies that are not clinically relevant.  Certainly there are.  We have seen instances of patients who have been previously exposed to Remicade who then, on a subsequent exposure, very long after that initial exposure, have developed a delayed hypersensitivity event.  So, we have seen instances of that.  I wouldn't want to say that these are totally irrelevant.
MS. MEYERS:  How serious has that been?
DR. SCHAIBLE:  The events are manageable, clearly manageable.  The events that we've experienced with Remicade have all been medically manageable and there have been no long-term sequelae of those events.
I think the issue here is whether these types of assays provide information that is predictive as to when these types of clinical events may occur, and I think our experience to date is that the predictive value of these assays is actually not very good either from a positive sense or a negative sense.
MS. MEYERS:  So, you don't know which patients are going to have this reaction.
DR. SCHAIBLE:  No.  That's very difficult to determine.
MS. MEYERS:  I see.
And the two products you're talking about, one is for Crohn's disease, the other one is for heart problems.
DR. SCHAIBLE:  It's for coronary angioplasty.
MS. MEYERS:  And yet, these reactions or these antibodies seem to appear the same amount in both products.
DR. SCHAIBLE:  Yes.  I think our experience overall is that they're in the 5 to 15 percent range.
MS. MEYERS:  So, is this going to happen with most biological products?
DR. SCHAIBLE:  I'd be interested to hear the committee's view on that one. 
DR. SALOMON:  Yes.  I think, as usual, Abbey has done a great job of putting her finger on the key question.
(Laughter.)
DR. SALOMON:  Jay?
DR. SIEGEL:  Yes.  I have a question.  
You presented the data with in vitro testing I guess of IC50 in patients with high titer.  One of the things that we see with some products -- and I don't know what the data are with your product.  That's basically my question -- is that while there's not neutralizing or inhibitory activity of antibodies, that in patients with high titers of antibodies, the half-life changes considerably.  
And so, the question is do you have pharmacokinetic data?  And if there is a change in half-life, does it correlate, as one might expect, with a change in the time until -- I guess in the case of ReoPro, there are sub-inhibitory levels of antibody on board.
DR. SCHAIBLE:  Well, the experience with those assays so far is that we have experience only up to certain titers.  So, you saw data up to 1 to 3200 titers.  There is very limited experience beyond that because there are much fewer patients who have developed high titer responses.  So, at least over that range of data, we have not seen any inhibition of potency.  I really can't speak to whether, if you were to really boost the titer, that that might ultimately have an effect on potency.
DR. CHAMPLIN:  My question was what fraction of these were neutralizing antibodies.
DR. SCHAIBLE:  Neutralizing in terms of whether they bind to the portion of the drug that is involved in its effectiveness.  Our experience is that most of the ones with Remicade are.  However, with ReoPro, as I've shown you the data, it appears that they're not neutralizing in terms of the anti-aggregation effects in patients in terms of platelet function.
Yes?
DR. SAUSVILLE:  I was simply going to enlarge on, I guess, the point that Jay was getting to.  In other words, this issue is likely going to occur with, quote/unquote, every biologic to one degree or another, but whether or not it's of clinical significance is a dose and nature of molecule type of thing.  And I think it's going to be very difficult.  I mean, it's very good that in your experience you appear to have efficacy and the events appear to be manageable.  But to extrapolate from that experience to any other biologic, I think is going to be really difficult.
DR. SCHAIBLE:  Right.
DR. SAUSVILLE:  I think a key harbinger of potentially having an effect would be either, as you say, the neutralizing question or an obvious change in pharmacology.  I think it's ultimately going to have to be assessed for each product.
DR. SCHAIBLE:  Right.  I would just add that our approach to this also is to gain as much prospective data post-marketing as we can, and that involves designing and implementing registries.  You saw that with the ReoPro readministration registry.  We're also just implementing now one in Crohn's disease because I think in the long term you want to know how these patients are responding clinically, both in terms of how effective the agents are and how well tolerated they are from the clinical perspective.
DR. SALOMON:  Dr. Miller.
DR. MILLER:  On the Remicade, what is your retreatment data?  And the reason for that is with the data you showed here, you continue to have a response in decrease in swollen joints, and I think with many biologics that interfere early on in the blockade, you don't know how long the effector cells from the initial treatment are still affected.  So, I don't think we really know how long you have to treat patients with some of these biologic modulators of the immune system.
So, my question is, since especially in the Remicade it appears to be neutralizing antibodies, number one, you don't know if those doses after the neutralizing antibodies are truly necessary for continued response.  And so the only way you can get that is to get retreatment data on patients who actually had neutralizing antibodies.
DR. SCHAIBLE:  Right.
DR. MILLER:  Do you have that?
DR. SCHAIBLE:  No.  We have limited data on that.
One of the problems also is that with long-term repeated dosing, so long as the agent stays in the blood, it will interfere in the assay for antibodies.  So, in fact, you have to wait a very long time until patients are essentially off the drug before you can get a valid measurement as to whether these antibodies are present or not.  And these trials are ongoing.  So, that's the reason why we have limited data in terms of taking patients who have antibodies and then retreating them at that point.
DR. SALOMON:  Do you have data on immune complex formation, and do you have data on complement activation in any of these patients after retreatment?
DR. SCHAIBLE:  Very little, very little.
DR. SALOMON:  Another issue that concerns me about biologics and repeated administration is going to be whether or not we generate neo-immune responses and generate auto-antibodies, for example, then which later can cause problems.  I don't know that these antibodies are more likely than any other, but overall I think it's an issue with new therapeutics.
DR. SCHAIBLE:  In terms of antinuclear antibodies or anti-double-stranded --
DR. SALOMON:  Have you looked for, for example, anti-platelet antibodies after ReoPro administration?  Let's say 6 months after these patients have been in the trial.  Have any of them developed platelet auto-antibodies, and have you measured bleeding times a year, maybe, after repeated administration?
DR. SCHAIBLE:  No.  I know we definitely haven't measured bleeding times in that time frame.  I don't know if we've look at any anti-platelet antibodies or not.  I'm not aware.  If we have, I'm not aware of it.  Sorry.
DR. SALOMON:  I bring these up just because you were brave to get up.
(Laughter.)
DR. SALOMON:  Clearly this isn't to discuss specifically your product, but I think the results you presented are very apropos obviously to the discussions that will happen this afternoon where we definitely want to grapple directly with what kind of assays should sponsors be developing.  So, I hope you'll forgive --
DR. SCHAIBLE:  It's quite all right.  Thank you.
DR. SALOMON:  Are there any other comments?
MS. MEYERS:  There's some biotech products that have been on the market for a much longer time.  Has anybody spoken to those companies and tried to get this data from them?
DR. SIEGEL:  We'll be presenting some of those data in just a couple hours.
DR. SALOMON:  Yes.  There is an experience to draw from.
Dr. Goldsby, I don't want to exclude you.
DR. GOLDSBY:  I have no questions.
DR. SALOMON:  We're trying out this new technology.  I hope you'll forgive me if it seems a little awkward.
Are there any other comments?
(No response.)
DR. SALOMON:  Well, then I want to thank very much Centocor and Dr. Schaible and his colleagues for this.  I think it was an extremely informative presentation and will again, as I said, be very useful this afternoon.  I hope you're staying around.  You'll be here this afternoon.  Excellent.
At this point, it's also appropriate to ask is there anyone else that would like to present anything to the committee before we close this portion of the committee, the open public portion.
(No response.)
DR. SALOMON:  Then for the minutes, let me note that no one else wants to address the committee, and we are now therefore closing the open public hearing portion. 
We would like to move on to topic I, the FDA Regulatory Policy Update, and for that I'd like to introduce our own Dr. Jay Siegel.
(Laughter.)
DR. SIEGEL:  Thanks.  I also would like express and add my appreciation to Dr. Schaible.  I think, as you'll soon see, those data will be very useful and mesh well with our presentation and planned discussions regarding immunogenicity and policy approaches.
What I'd like to do today and what actually Dr. Weiss and I will do in the next couple of presentations is update and inform the committee regarding some areas of active policy development.  The last 2 to 4 years have been an extremely active period of time for the FDA vis-a-vis development of new policies and new guidances in many areas, in part spurred initially by the anticipation of Congress' development of the Food and Drug Administration Modernization Act of November 1997.  After that act was passed, it mandated substantial additional policy and guidance development.  It has been an active period, and it has impacted a number of areas that this committee and other committees and members of this committee as they sit often on other committees that we visit as well have frequently raised questions on and have shown a great deal of interest in.  
So, we're going to pick out a few of those areas which particularly impact the deliberations of this committee vis-a-vis product approvals in terms of what is the standard for proving efficacy for biologics products, what is the nature and what's new regarding accelerated approval for products for serious and life-threatening diseases, and what are the recommendations and requirements and guidelines regarding doing pediatric studies.  Those of you who have been a member of this committee for a while know that those are issues that come up frequently, and there have been some significant changes for at least clarifications in all of those areas.  I'm going to focus primarily on issues regarding the evidence of efficacy and then Dr. Weiss will be speaking specifically about pediatric indications.
Now, the 1962 drug amendments established a standard of effectiveness which has been applied, at least by the Center for Drugs and, to some extent, by the Center for Biologics over the period since that point in time.  It says that effectiveness must be established by substantial evidence, and it defined substantial evidence to be "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and expertise" -- I omitted a few words there -- "on the basis of which it could be fairly and responsibly concluded by such experts that the drug will have the effects it purports or is represented to have."  
Although it may not show up, I bolded the letter "s" in "investigations."  One of the most important phrases here is "adequate and well-controlled investigations," something that the Centers for Drugs and Biologics look for carefully in studies.  I bolded the letter "s."   As a matter of policy, as well as court decisions, this was taken as a key indication that there needed to be more than one adequate and well-controlled investigation.  There's now substantial legal and policy clarification on that issue which is one of the key issues that I'll be discussing over the next several minutes.
That was from the Food, Drug and Cosmetic Act.  All biologics are, to my knowledge, either biological drugs or biological devices, but biologics are additionally covered by the Public Health Service Act which requires that they be safe, pure, and potent.  There is substantial case record and legal support for the notion that potency means effectiveness, not simply biological activity.
But the linkage to the standard that I just read regarding drugs has, at least till recently, until FDAMA of 1997, been indirect.  It's now more directly linked.
On the basis of these different legal approaches, there was, up until maybe five or six years ago, the widespread notion, with some basis in reality, that there was a requirement.  It turned out that it wasn't an absolute requirement.  But there was essentially a requirement for at least two adequate and well-controlled investigations for drugs and there was a perception, with again some basis in truth, that biologics sometimes required only one efficacy trial.  Indeed, the approach in Biologics was that the number of trials was just one of several indicators of quality and quantity of evidence, and it perhaps wasn't as carefully focused on as it was in the Center for Drugs, although certainly recognized to be important.
But there was concern both within the agency and outside, particularly as biologics began to be applied to and used for a broad variety of indications, many of which are competing against drugs in a similar indication, that there really ought to be some level of harmonization.  Back about six years ago, Dr. Zoon and I and Bob Temple and Janet Woodcock and a few other people began talking and trying to come to a meeting of minds and discovered, in fact, that we had each evolved to a position that was not particularly dissimilar.  
In 1996, the agency began an initiative to clarify, because there were a lot of misunderstandings, regarding what type of data are needed for a supplemental indication, for a new efficacy indication for an already approved drug.  In doing that, we came to realize that that really needed to be broadened.  There wasn't really a different standard, and many of the issues that applied to supplemental indications also applied to first indications.  This evolved into really work on an effectiveness guidance.  It was published in draft in early 1997.  
In late 1997, the Food and Drug Administration Modernization Act -- and I'll quote its passages -- essentially endorsed most of the concepts in that guidance.  That was clearly the message from Congress as we met with Congress on these issues.  The guidance was then, on the basis of public comment, finalized and formalized, and I'll be reviewing it shortly.
The Food and Drug Modernization Act has a section entitled Number of Required Clinical Investigations, and what it says is, specifically in clarifying the intents of the words "adequate and well-controlled investigations," "If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence," substantial evidence being the legal standard.  And the guidance document, again that I will summarize shortly, goes into significant detail to clarify what the agency considers to be appropriate confirmatory evidence in the context of this law.  But it also addresses several other issues.
As I noted earlier, there are historically some different approaches between drugs and biologics.  The Food and Drug Modernization Act of 1997, a section entitled Modernization of Regulation included the following language.  "The HHS Secretary shall take measures to minimize differences in the review and approval of products required to have approved biologics license applications under section 351 of the PHS Act," which is what we grant our biologics license applications, "and products required to have approved NDAs under section 505(b)(1) of the Federal FD&C Act."
A letter of congressional intent clarified the issue, as there was significant confusion, that this was not intended to change in particular different approaches to generics for drugs and for biologics, and it was also clear from discussion that different scientific issues raised by the different classes of products needed to be addressed.  
But one of the issues that this was clearly intended to address is in fact the focus of my talk today, the efficacy standard, and lacking specific scientific reason for differences, clearly the message here is that such differences should be minimized or eliminated.
On the Biologics web site -- Gail, was the efficacy guidance document distributed to the committee?
MS. DAPOLITO:  Yes.
DR. SIEGEL:  It was, okay.  So, the first document you have.  There are a couple other documents I'll talk about which I didn't feel that you'd probably want to weigh down your briefcases with, but are readily available to you or anybody through the Internet.  A whole slew of our guidance documents are at the site.  The address is noted on this slide.  The Center for Drugs has a site as well with extensive FDA guidance documents, some of which you might find interesting.  These two documents are indeed on both sites as they and an increasing number of policy guidances apply equally to both centers.
The guidance that I'm going to focus most of this talk on, as I've said several times -- and I'll get to it soon -- is the guidance for industry on providing clinical evidence of efficacy for human drug and biological products.  
I'll note here, although not specifically discuss, an additional guidance that we put out that really addresses how this general guidance applies specifically in the case of cancer treatment.  It's entirely consistent, but it's a specific application in terms of more detail in the setting of oncology as to what the agency would and would not or might and might not consider adequate evidence of efficacy for cancer treatment uses.
The introduction to the guidance gives as the reason for the guidance -- and it's one of several reasons, but certainly a critical reason -- that from an historical basis, there's been an evolution of clinical development so that the types of data generated and the types of indications sought are now not what they were in 1962, for example, when the clarification on effectiveness for drugs legal standard was set.
There are narrower, more closely related indications which occurs as we understand diseases better and we understand different subsets of patients and diseases.  We're beginning to understand more of the genetics of diseases, and we have, in many cases, more finely focused agents that may fit better in certain stages or subsets of diseases.  We have many agents that have very related similar uses in different populations, in different combinations, alone or in combination, in different doses.
Also there has been a trend from having collections of relatively smaller trials typically done at a single center to having more rigorously designed and analyzed multicenter trials, and all of these have impacted the thinking about effectiveness and particularly about numbers of clinical trials. 
Now, a key focus of this document and of FDA policy is the need for independent substantiation of clinical data, and this underlies the issue of how many clinical trials might be needed and the question of -- I'm forgetting what the word was, but the question in FDAMA -- the legal standard -- I don't want to misquote that.  Hold on a second -- of confirmatory evidence, of one trial and confirmatory evidence.
This makes quite clear that what the agency is interested in is not replication, something that had been frequently used to describe the drug standard of more than one clinical trial.  It's usually not wise to do the exact same trial twice.  And what the agency is really looking for is evidence that substantiates the evidence that might be present in a single trial and often may come from a related trial but one that differs in ways that the document discusses.
Some of the reasons for substantiation are the possibility of systematic bias in a single study, the possibility, reflected by the p values, that the positive results might result from chance alone, issues regarding lack of generalizability if the study is done in a single trial with a single regimen and entry criteria and so forth.  There are often many unanswered questions about generalizability and rarely, but sometimes present, concerns about fraud.
The general default and the focus of this document -- the general default position of the agency is that the most common and usually best way to provide independent substantiation is to have two or more adequate and well-controlled trials, each demonstrating efficacy.
However, there are many, many exceptions to that general default position.  The document starts by listing some areas in which no new efficacy trial may be required for a new indication.  One is the area Dr. Weiss will be speaking about in more detail:  pediatric use where pharmacokinetic data, together with safety data relevant to use in children may well bridge the gap from adult use to pediatric use if enough is known about the pathophysiology of the disease and the pharmacology of the drug.
New formulations and strengths of a drug, if there are data showing bioequivalence and pharmacokinetic linking to older formulations and strengths, may well not require additional trials.  
Even new doses or regimens.  If there's a very well understood pharmacokinetic and pharmacodynamic relationship, someone can predict efficacy of those new regimens. 
This is a somewhat old slide.  I'm not sure of the status of it now, but what internally in the agency has been called the "animal rule," which recognizes that there are some clinical settings in which clinical trials are impossible.  This refers not to the many settings where we hear, well, we can't really do that trial for this, that, or the other reason, but specifically most commonly to settings such as preventative or therapeutic treatment for, say, a disease caused by a bioterrorism vector where that disease does not commonly occur outside of that setting and it would be very hard to do a clinical trial demonstrating effectiveness.  One, with animal studies, together with certain pharmacological studies, say, inducing immune responses, for example, might be able to approve a product despite the lack of the clinical investigations requirement of the law.
The effectiveness standard document then clarifies and has for each of these bullets a paragraph or a few paragraphs -- clarifies the types of independent substantiation that the agency might find acceptable other than a second study when there's a single study establishing effectiveness of a trial.  And these include:  evidence that different doses, regimens, or dosage forms of the product are also effective; evidence that the product is also effective in other phases of the disease; evidence that the product is effective in other populations; the issue of combination or monotherapy.  A single trial showing that the drug is effective as a monotherapy supplemented by a single trial showing that it's effective in a certain combination, those two trials may substantiate each other or either might substantiate the first.  
Effectiveness in a closely related disease.  As I pointed out, disease categories and indications are often being more and more narrowly defined, but if we know a product works in one disease and there's a very closely related disease or even -- as it says diseases with the same purpose of therapy -- a disease that's physiologically more different like infections in different organs in the case of an antibiotic, single studies in two different organs might suffice.
And evidence of different clinical endpoints might each support the acceptability of a claim in the other so that if you have one trial showing a drug effect, say, exercise tolerance, and another showing that it affects, say, mortality, although neither finding what's replicated in the other trial, there may well be a setting where both findings are considered supportable.  Again, the standards by which this sort of inference will be acceptable are somewhat explained in somewhat more detail in the document.
The next area is an area perhaps of importance particularly to biologics, although it applies to all agents:  independent substantiation of a single study by pharmacological or pathophysiological endpoints.
Now, the general tenor of this section is that it's almost always the case that there's a rationale for why a drug works and that it has relevant pharmacology.  And it's not the intent that the agency will take the fact that it has any physiological effect that seems relevant as substantiating the evidence of efficacy, but it defines parameters where that might be the case.  When the pathophysiology of the disease and the mechanism of action of the drug are very well understood, but the pharmacological effect is not a validated surrogate or an acceptable endpoint for accelerated approval.  There are some pharmacological effects which in their own right are already accepted, and this is a non-issue.  If you lower blood pressure in hypertension, that's considered an accepted surrogate for approval.  
In the case of accelerated approval, as I'll talk about a little bit later, a surrogate need not be fully validated, but needs to be reasonably likely to predict clinical benefit to be acceptable for marketing approval.
The linkage needs to be not just theoretical but based on prior therapeutic experience or well understood pathophysiology.  So, there needs to be a pretty strong database to support the notion that this physiological effect will correlate with efficacy.  An example given is replacement therapy.  I think there's a specific example of a clotting factor replacement.  If the disease is known to be clearly due to a deficiency and there are data demonstrating both replacement of that deficiency and restoration of physiological activity, that those sort of data may well supplement a single efficacy trial and establishment of effectiveness.
There's a cautionary note of single trials with compounds with relevant pharmacological activity, such as suppressing arrhythmias or inotropic agents, which of course you may well know.  In both those cases, we've observed trials where drugs were effective anti-arrhythmics or effective inotropes but, when studied in greater detail, were found to increase mortality in cardiovascular disease.
The next section of the document talks about when a single study may suffice.  Generally, this will be applied to situations where there's a mortality or an irreversible morbidity effect or prevention of serious illness.  And those are often situations where, in fact, it's practically or ethically unfeasible to confirm single studies, if those studies are quite compelling or convincing.  In most other cases, the default position is that a single study would not suffice. 
The single study should have generally some of the following characteristics.  These are the characteristics that are looked at to determine its adequacy.  Being large and multicentered, having internal consistency within the study, factorialization with internal confirmation.  
Factorial studies are designs which allow more than one comparison.  So, you may have a placebo versus drug A by which you can look at efficacy of A, and then you might have drug B arm versus A plus B, another comparison of separate patients within the same trial, relevant to the efficacy of drug A.  This pattern is in increasing usage and provides additional internal confirmation or has a potential to provide that. 
Effects on multiple endpoints within the study that are not closely related to each other, and findings in a study that are statistically very persuasive.  Here too, there's a caution about considering the totality of the data, noting cases where a single trial showed efficacy but other pieces of data suggested that that may not be a definitive finding, and future trials showed, in fact, that it could not be replicated.
The next section of the document, after dealing with the quantity, if you will, the number of trials needed, talks about quality of evidence and quality assurance because the standard pharmaceutical approach has been submitting detailed amounts of all data collected in a trial, together with careful monitoring and checking, 100 percent checking, of the validity of each data point.  But not all trials are conducted that way, and there have been many questions about use of other types of data in the regulatory process.  This document provides guidance in that regard:  the first of two-part design, the use of literature reports, the use of study reprints, if you will.  The second section is about the use of studies that have not been quality assured in the typical manner.
It provides guidance that I think will be more useful or mostly useful to sponsors seeking approval as to what sorts of information they might seek to obtain that would be useful in improving the value of an article which was not done perhaps under their sponsorship and for which they do not have a full data set but they have reprints.  This includes availability of the clinical trial protocol and its amendments, the existence and availability of a prospective analytic plan, randomization codes and entry dates, full accounting for all subjects, a record of critical data by subject, and information particularly if safety is an issue, which it isn't always an issue because often these are drugs that have already been approved with a large safety database, information on deaths, serious adverse events, and dropouts.
The areas in which use of literature reports alone are most likely to be acceptable to the agency are those which have multiple independent studies, detailed reports, objective endpoints subject, therefore, to problems of bias, robust results by prespecified analyses, and which were conducted in organizations with established standard operating procedures and a history of implementing those procedures for clinical trial development in an effective manner.
Then the issue of studies with non-standard QA, which means quality assurance that deviates from the typical industry approach of checking each data point, visiting all sites before, during, and after the trial, and providing a reasonably high level assurance of accuracy of the data submitted.  A large number of trials in recent years have been conducted by multicenter groups, by NIH, other organizations, which take different approaches, large, simple trials, many other types of trials which often are quite acceptable to the agency in terms of the quality of data.  
And the guidance provided here is that the critical factors are that there have been or be a prospective plan for quality assurance, relatively simple procedures in the trial which minimized the likelihood that they are not followed correctly, availability of primary data in the trial so that the quality can be checked when questions arise, primary data like medical records, and that the trial have been conducted by a group with established procedures and a history of implementing them regarding quality assurance.
I'd like to take just a little bit of time, although it received more prominent billing in my title, to talk about the fast track policy.
A lot of the fast track policy really has to do with how the agency will interact with sponsors seeking to develop products for serious and life-threatening illnesses which have the potential to address unmet medical needs and really come into play largely in the developmental phase and address issues like the types of meetings and guidance that the agency will support.  I'm not going to go into too much detail on that, but I am going to focus on the fast track policy to the extent that it provides some clarification regarding the effectiveness standard.
The Food and Drug Administration Act of 1997 again instructed the agency to develop guidelines regarding how we deal with products for serious and life-threatening illnesses and also presented some new authorities and some new approaches to older authorities.  This provision is implemented in another document, which I've not distributed but again is available on the web site cited, entitled Guidance for Industry:  Fast Track Drug Development Programs - Designation, Development, and Application Review.
Now, a lot of what this document does and a lot of its purpose and a lot of Congress' and industry's purpose in asking for it was really to consolidate and clarify programs already in existence.  And I wouldn't underestimate the benefit and value of that.  It turns out that the affected public, including pharmaceutical sponsors, I think had relatively limited understanding of a collection of policies that have evolved over the last 10 years, in many cases in response to issues raised by patient communities, HIV, cancer, and other serious and life-threatening diseases.
But those documents were found in many places, some of them rather obscure and hard to find, preambles to regs that few people could locate.  So, really one of the critical issues of this guidance is to put everything in one place.  It's a road map to what the agency will do regarding treatments for serious or life-threatening conditions with the potential to address unmet medical needs.
It has some new provisions in it, some new approaches.  One is designation of such products or more appropriately product development programs, products together with indications and planned development programs to achieve those indications essentially prior to filing the IND or at the time of filing of the IND so that while the agency has always had priority designation for review of NDAs and BLAs, or at least for many years has, this now provides this sort of designation early on with impetus for the agency to provide additional support to development of those products that receive this designation.
I think an important issue is new clarifications in this document about what the agency means by a serious of life-threatening condition and particularly what the agency means by treating a serious or life-threatening condition.  I won't go into detail on this point, but it talks about differences between treating the condition, treating manifestations of the condition.  It addresses issues such as treating the side effects of drugs used in a serious or life-threatening condition, such as the CSFs that we see from time to time in this committee.  It addresses of what this means vis-a-vis diagnostic agents and preventative agents.  It provides substantial clarification and clear and, I believe, highly appropriate standards for what makes a product a priority, what are the critical features for broad varieties of products.
Similarly, it provides clarifications regarding what the agency means by potential to address an unmet medical need, what it means to have potential, what exactly is an unmet medical need in this context.  The agency still has ongoing work to further develop standards regarding how we determine what we call an unmet medical need or what we mean by the standard used elsewhere of beyond existing therapies.
Now, the part of this document that has the most relevance to the efficacy and to issues that might come before this committee, in addition to defining what's eligible, are other provisions that also pertain to the accelerated approval regulations, something that has come up from time to time in a variety of committees, often the question, well, would this product be eligible for accelerated approval as opposed to the more traditional mechanisms of approval.  In addition to defining the criteria related to seriousness and so forth, this document also provides -- and I'll summarize briefly -- some clarifications regarding a provision in the accelerated approval regulations regarding accelerated approval based on clinical endpoints other than survival or morbidity.  Accelerated approval is generally thought to apply to surrogate endpoints, and there was considerable congressional interest and inquiry into the implications of the application of accelerated approval to clinical endpoints.
There's also a new provision in this document, probably a fairly important one, but not one that I'll go into detail with this committee, which allows for a company to submit an incomplete application under certain circumstances when some portions of the application are complete.  Perhaps the clinical data are complete, but validation of certain aspects of manufacturing are yet complete.
To talk about what's new in the accelerated approval regulations, it's probably worth giving a brief overview of the accelerated approval regulations, something again that comes up from time to time in our deliberations.
It applies to serious or life-threatening illnesses.  Another standard for its implementation is not the wording in FDAMA, "potential to address unmet medical need," but is a closely related wording, "meaningful therapeutic benefit to patients over existing treatment."
Importantly, it has a standard of adequate and well-controlled clinical trials, the same evidentiary standard that I was just talking about at some length.  So, the nature of the evidence proving the point, if you will, is not different, and the quality of the evidence and the standard for the evidence is not different.  This is an important point.  
There was some confusion as this issue was under discussion.  Would this mean, for example, that now p values of .1 are okay if it's a serious illness?  The answer to that question per this regulation and the implementation of FDAMA from the agency is, no, that is not the intent.  The evidentiary standard remains the same except that it can apply to a different sort of endpoint, not simply a clinical endpoint, but the accelerated approval regulation has noted that it may also apply to the use of a surrogate endpoint that is reasonably likely to predict clinical benefit, reasonably likely being a standard substantially different from validated to predict clinical benefit.  And it talks about that being based on pathophysiological, pharmacological, and other types of data.
And the regulation also has this provision which again had been under-utilized, essentially unutilized, until recently and which we've attempted to improve and increase the utilization of through clarification in the guidance document, the use of clinical endpoints other than survival or irreversible morbidity.  And I'll give a little more detail on that in just a moment.
Then I think as many of you are aware, the regulation carries sections about requiring post-approval studies to confirm the effect on the clinical endpoint or ultimate outcome in the disease, the potential for certain restrictions on the use of the compound, mechanisms for withdrawal of those compounds which fail to confirm efficacy or in which there's a failure of due diligence in pursuit of the data to confirm efficacy, certain restrictions on the promotion of such compounds, and some other issues that I won't go into detail on.
I think this is my final slide, which is good because I'm not holding up here. 
The guidance document, as I said, on fast track, for which I've given you the reference, provides some clarification in some detail and this highlights a few of the issues, regarding what is intended or meant by accelerated approval with clinical endpoints.  This has been a somewhat confusing issue because clinical endpoints have always been acceptable for traditional approval, whereas accelerated approval allowed surrogate endpoints to be acceptable in certain circumstances.  But the agency's intent is that there are circumstances in which clinical endpoints are not and have not been in the past acceptable for approval and that this is a broadening of approaches of potential routes to approval that are clarified here.
The first one I've listed here is effects on lesser symptoms which do not per se outweigh risks but are expected to lead to a favorable effect on ultimate outcome.  So, this in a sense is a surrogate.  It's a clinical endpoint that is functioning as a surrogate for other more important endpoints.  
I can't speak to specific cases where I know this will be the case, but for example, you might imagine a serious disease, a type of cancer or infectious disease, characterized, say, by night sweats or weight loss where one might believe that a drug which had a profound effect on those phenomena was reasonably likely to have a profound effect on ultimate outcome because its mechanism of action was such that it wasn't directly preventing sweating, it was really treating the tumor.  And one might be able to use those endpoints that are reasonably likely to predict, again not endorsing a particular endpoint, but that's the general notion, that clinical endpoints can also be used as surrogates for other more important clinical endpoints based on the same standards as non-clinical surrogates have been used under the accelerated approval regulations.
Short-term benefit in chronic conditions where short-term benefit per se does not outweigh risk and durability is expected but uncertain.  Now, in most chronic diseases, the agency is going to want some evidence of some durability of benefit for chronic use and they will want some durability of safety data as well.
There have been cases where drugs have shown remarkable benefit over the period of, say, a year or so where the nature of the disease and the process and of the treatment and of the side effects are such that if that were to wear off before three or four or five years, it might well be that there isn't a favorable risk/benefit situation.  And this makes clear that rather than require three to five years of data, the agency also has an option under certain circumstances to accept one year with the presumption that efficacy will persist but with the stringent requirements of the accelerated approval regulation to require that the persistence of efficacy be, in fact, proved in the post-marketing period.
A third example would be a drug with substantial benefits that in their own right might be efficacy data suitable for approval, but where there exists significant but limited concern regarding adverse events and ultimate outcomes.  So, we've seen cases of, say, cancer interventions which might have significant impact on important symptomatology, important complications of cancer, some of the agents used to prevent the toxicities of cancer therapy, but where there are variable levels of concern as to the impact of those agents and even the possibility of potentially harmful impact on ultimate outcome on cancer growth.  
And this makes clear that we see a third potential approach to data in those cases where the concerns are high enough that the agent may actually have an adverse effect on the cancer.  We would likely require that to be studied in the pre-marketing period.  
Where the concerns are very low and highly remote, we may well just do a standard approval with some post-marketing collection of data to ensure it's not the case.  
Where the concerns are low but not so remote, we might do an accelerated approval with the stronger post-marketing commitment and potential for withdrawal depending on the ultimate outcome.
So, we believe that this regulation will give the agency and, to some extent, its advisory committees more flexibility in how we look at the appropriateness of data, its adequacy for approval -- it's not a regulation.  I misspoke.  This guidance will clarify ways in which the regulation might be used to accomplish those ends while still ensuring that products are safe and effective and come to market in a timely manner.
And with that, I'll close.  Should I take questions now if there are any, or wait till after Dr. Weiss?
DR. SALOMON:  I think we have a little extra time, Jay, so if there are some specific questions.  Yes, Dr. Broudy.
DR. BROUDY:  I'd just like to make the point that we have been de facto using this process in this committee's deliberations for the five years that I've been on this committee.  If you think about the approval of G‑CSF or GM-CSF or a number of the biological agents, the stem cell selection devices, we have not shown that these decrease, for example, infectious death during hospitalization after leukemia induction chemotherapy or decreased death from breast cancer, for example, but we've used a surrogate endpoint such as day of neutrophil recovery.  So, in fact, we've been using these guidelines in our deliberations for a number of years, and I don't see anything that's truly new about this that differs from what we've been doing over the past five years unless you have some other points you'd like to make.
DR. SIEGEL:  Well, in fact, the initial approvals of those agents and some of their indications were accompanied by data demonstrating the decreased hospitalization and decreased antibiotic usage and decreased episodes of febrile neutropenia which is an endpoint which is hybrid, if you will, between a lab value and a clinical event, febrile neutropenia.  And we, in fact, discussed with this committee in 1994 and 1995 which of those endpoints to use when.  So, I just want to, as a record of fact, indicate that to some extent or varying degrees we're dealing with endpoints for some products that have already been validated.
Having said that, I would have to agree entirely with your comments.  For the most part, both this issue of evidence of effective and these issues of acceptability of different types of endpoints clarify rather than change approaches the agency has been using.  
There are some subtle changes, and in fact I think that one of the things that they accomplish is to provide consistency within the agency so that there have been different approaches at use within the agency.  It's my belief and our belief that the approaches that we've harmonized on are largely the approaches that have been utilized by my office and this committee.  So, we may be seeing less change than certain other areas, but we're providing additional and I think important clarification to our reviewers, to sponsors, to the committee. 
There are some things that are more specifically new here.  I tried to highlight those and some options that are new. 
DR. SALOMON:  Dr. Auchincloss?
DR. AUCHINCLOSS:  Jay, can you just clarify for me what's the difference or the relationship between these various guidances which include the fast track guidance and the accelerated approval reg?
DR. SIEGEL:  Are you asking what's the difference between regs and guidances in general or how they relate to each other?
DR. AUCHINCLOSS:  Is the regulation the basis for the guidance or are they separate things?
DR. SIEGEL:  Yes.  A regulation is something that's legally enforceable and that is a way that a government agency implements its legal mandate.  A guidance document is used as a way to provide guidance as to, amongst other things, how best to be in conformance with regulations.  Guidance documents clearly and always are a proposed approach.  However, alternative approaches, if justified, as ways of meeting a regulatory standard or regulation, can be also be deemed and found to be acceptable. 
So, in the specific case, therefore, of the specific question you're asking, the accelerated approval regulation and other regulations implemented under the Food and Drug Administration Modernization Act, the Food, Drug and Cosmetic Act, and the Public Health Service Act establish the standards for efficacy, the standards by which we can approve products, and in the case of accelerated approval regulation, the standard for accelerated approval.
However, we found, for example, with that guidance that there was a lot of confusion and sometimes inconsistency as to what was serious and life-threatening.  There was some general public thought that that really only meant AIDS or only AIDS and cancer, for example.  There was some confusion as to what the use of a clinical endpoint for accelerated approval would be when a clinical endpoint should get regular approval.  So, a guidance document is an important document that provides clarification and guidance but doesn't have that sort of regulatory impact.
DR. SALOMON:  Dr. Champlin?
DR. CHAMPLIN:  The guidelines that you've proposed are largely directed to making sure there's a high level of confidence that a product is, in fact, safe and effective for its approval.  
My concern is, as the process becomes increasingly onerous and expensive, particularly small market or orphan indications then don't seem to be economically feasible for companies and corporations to develop.  As the understanding of medicine advances, we are increasingly splitting disease states into smaller and smaller entities defined by their pathophysiologic mechanisms.  So, you're increasingly developing these sort of small potential indications for therapeutic intervention.
So, the bottom line is that the guidelines should ideally be a balance that would favor and enhance and encourage the development of new and effective treatments.  Right now, at least, there's a perception that the guidelines or at least the regulatory process is an expensive and onerous one that only justifies development of a $100 million drug.  So, somehow we have to come to, again, a balance of those opposing considerations.
DR. SIEGEL:  I would only comment that your phrase "as the standards become more onerous, we run into these problems," that these documents to a large part and the act itself to a large part represent making standards less onerous.  I'm not specifically addressing whether or not they're too onerous, which is the point that you're raising, as I think you have legitimate concerns that, of course, also need to be balanced against the importance of having adequate safety and efficacy data.  
But it should be noted that this evidence of effective document, for example, represents a significant move from, in many parts of the agency, routinely requiring more than one clinical trial to a clarification that there are many cases in which one clinical trial will suffice and, in the case of fast track, to providing clarification regarding a broadening of the types of endpoints that might be acceptable for approval and types of approaches.
On the issue of orphan indications, of course, I haven't addressed those, but there are in place a substantial amount of laws and policies to try to assist and facilitate development of products for orphan indications.  Interestingly, many of the products that this committee sees have been developed under orphan drug provisions, which is not to say necessarily that what we have is currently adequate or that there might not be other ways to improve the process, but just to note that there are a lot of relevant provisions.
DR. SALOMON:  Dr. Sausville?
DR. SAUSVILLE:  I have a question or a comment and it relates to this use of surrogates and clinical endpoints.  How does the agency impute value to different types of surrogates?  Because I think it's one thing to say that you're going to use surrogate markers or clinical endpoints.  But I think there's a lot of confusion certainly among sponsors in terms of when they come to us and talk about the strategies they might conceivably use for an investigational agent, and there may actually be confusion in the clinical community as to what surrogates to use because ultimately not all surrogates are created equal I guess.  So, I'd be interested in your thinking on that.
Also the comment would be I'm concerned that tying the, quote/unquote, effects on lesser symptoms to some expected ultimate outcome could potentially not address clinical needs.  And to pursue your example, let's say that you had a drug that was really good for night sweats but didn't actually treat the underlying cancer.  I imagine most people who were in the unfortunate position of being afflicted with that problem would rather not be sweating even if their survival was not affected.  How would you address that?
DR. SIEGEL:  Fair enough.  Let me address both parts of those questions.
I think the first part is a critical question of our times.  The Food and Drug Administration Modernization Act of 1997, in fact, instructed not the FDA but the Department of Health and Human Services to address the issue of utility of surrogate endpoints, and in part as a result of that legislation, but also other perceived needs, as you're quite aware, there have been two NIH/FDA co-sponsored conferences, one this past April on biomarkers and surrogate endpoints in clinical diseases, one I guess it was October or November on issues regarding statistical and clinical approaches to the validation of surrogates. 
I wouldn't really be able to answer your question as to how exactly we determine acceptability of an endpoint, because it's too complex and dependent on the specifics of a given case, except to say that we believe the best time and way to do that is prior to the conduct of the definitive clinical trials.  We're quite open in these settings to meeting with sponsors and encourage that to discuss the acceptability of the surrogate.  
And we also believe that there's a role for advisory committees on critical questions that arise in that area, and it would be our intent and practice to invite either individual members of advisory committees with appropriate expertise to discussions with the sponsor or, in some cases, to come to an advisory committee, as we've done in a number of cases in the past specifically to talk about acceptability of different endpoints in different diseases.
DR. SALOMON:  Yes.  In fact, I wanted to interject.  I think that that's probably one of several of the major roles expert advisory committees such as this one play.  I have to say over the last seven, eight years that I've been participating in various ways with these committees, we've had just that, meetings where specifically we dealt in a number of different areas with the surrogate endpoints.  Because your point is well taken, not all surrogate endpoints are the same. 
What's more concerning to me is sometimes our best clinical judgment on the value of the surrogate endpoint halfway through a trial suddenly becomes very clear that that surrogate endpoint has a lot less meaning than it had when we originally made our projections.
DR. SIEGEL:  Yes.  The question is also a very important one.  You asked about the clinical endpoints.  It's a little clearer, I hope, in the document than I presented.  But on that case, for example, of night sweats -- and this is the confusion because clinical endpoints are in fact acceptable for approval in their own right. 
What the issue boils down to is what is the collection of benefits that you're going to weigh against risks.  So, if you had, say, an entirely safe agent that prevented night sweats and did nothing else, that would be an approvable agent.  
Now, if you had a cancer therapy that caused, say, profound neutropenia and intestinal ulceration, and your evidence of efficacy was based largely on night sweats, but you could establish that that impact on night sweats was reasonably likely to predict favorable impact on an ultimate outcome of survival or other more important -- well, the benefit on night sweats per se might not weigh adequately against the risks of the drug, but the night sweats might be taken as a surrogate for a greater benefit that we might consider under accelerated approval.  So, that's the difference.  In fact, that sort of setting is not infrequently seen.  And in that regard, then the night sweats become more like a surrogate because in their own right they wouldn't merit approval because of the toxicity of the drug.
DR. SALOMON:  Jay, one of the things you didn't mention -- and I didn't have a chance to review the document -- is where do the results of international trials come in in this approval process.  It has been an issue in the past and I know the FDA has a position on it. 
DR. SIEGEL:  Oh, yes.  Through the ICH process, the International Conference on Harmonization, we've been quite involved, and I personally have been very involved, in international negotiations regarding a variety of issues of international standards, including specifically the acceptability of foreign data.
The current position is that foreign clinical trials that are adequately and well-controlled and conducted under good clinical practices can provide a substantial part of the data in an application, in some cases, the entirety of the application, with the provisos that there are often specific concerns regarding the fact that concomitant therapy may differ, that diagnostic methods may differ in regions of the world so that different stages of disease may be treated or assessed differently and other factors.
And so, what this guidance document, the ICH E5 guidance on ethnic factors and the acceptability of foreign data, does is define sets of intrinsic factors, genetic factors such as liver, metabolic enzymes, and extrinsic factors such as diet and medical practice issues that might impact drug efficacy and provides guidance as to how those factors should be assessed and where they may then call for a strategy of bridging data so that in some cases foreign data in their own case might suffice.  In some cases, foreign data with certain bridging data to show that they are applicable in the U.S. or the home region will suffice.  In some other cases, trials may be required in the U.S.  But that does not exist as a regulatory standard, and we are quite open to the use of foreign data.
DR. SALOMON:  Dr. Auchincloss.
DR. AUCHINCLOSS:  Jay, just a clarification about how I should be listening to this presentation and Karen's in just a moment.  I found the update on FDA policy very helpful to me, but I'm not sure what you want of us, the committee.  I don't see questions for us.  Is there some input that you want us to be thinking about?
DR. SIEGEL:  This was done as an update not seeking input, which isn't to say that input isn't -- you know --
(Laughter.)
DR. AUCHINCLOSS:  No, no.  I understand.
DR. SIEGEL:  -- isn't welcome.  
(Laughter.)
DR. SIEGEL:  It's just to say, no, I'm not specifically seeking input.
DR. AUCHINCLOSS:  Not encouraged.
(Laughter.)
DR. SALOMON:  Dr. Miller.
DR. MILLER:  Do you have any data on how this has been implemented, the percentage of drugs that have applied for fast track or biologics that have applied for fast track and have been granted a fast track?  And are there any drugs that have gone through the fast track process?  I don't think we've had any biologics that have actually been approved. 
DR. SIEGEL:  Well, Betty, do you have those data?  Betty Goldman, who is my Associate Director for Policy, kind of chaired the FDA's policy implementing fast track guidance and may have some information on that.
MS. GOLDMAN:  I don't have the numbers with me.  I'd say a couple of months ago, I think at the end of April, approximately 80 applications for fast track in both CDER and CBER, Center for Drugs and Center for Biologics.  I think about a third had not been designated, were actually turned down for designation, and we've had a couple go through the rolling review, the incomplete application process.
MS. MEYERS:  Two-thirds then have been designated as fast track?
MS. GOLDMAN:  Of those that have applied.  Of course, it is completely up to the sponsors whether to apply or not.  We don't solicit the applications.  Of those that applied, I would say approximately two-thirds have been granted.
MS. MEYERS:  About two-thirds have been.  Yes, it seems to me, because I track new drug approvals every month, that there are an awful lot of me-too drugs that are being designated as high priority.  For instance, the new class of arthritis drugs, for example, even though there are three or four of them, have all been high priority, and I just don't understand it.
DR. SIEGEL:  Yes.  Let me clarify a few things.  First of all, we're talking about a number of different things here.  Fast track designation is something that usually occurs not at the approval or priority stage, but is something that occurs in most cases relatively early in development and is something that kicks in then additional meetings and support in terms of planning the development of a drug even before it has gone into humans. 
And the reason some get rejected is largely because the plan for the development may not really address the issues that fast track was intended to address.  Will this product truly be studied for its potential to treat something serious and will it be studied for its potential to address unmet medical needs?  And we specifically exclude me-too type drugs or even drugs that at the end you won't know if they're me-too or not or if they offer something new from that designation.  So, the policy is intended to limit to those drugs whose developmental program will really establish an important role for the drug or establish whether that exists.
As to the approval issue, I can't speak specifically -- I guess you're referring to the Cox II drugs.  Those are over in the Center for Drugs.  It is the intent of the priority designation for review as implemented in Biologics and I believe also in Drugs, although they have a somewhat different standard there, that that not be applied to me-too drugs.  
There is another guidance document -- you'll find it on the same web site -- as to how each of the centers applies its standard of priority designation.  It came out sometime last year.  The language is in there regarding the requirement that the drug offer something new and different.  
If it's your perception that you don't understand why that's applied or you believe it may have been applied incorrectly, you might want to inquire.  Robert DeLap is the office director I know, a good friend of mine, who is responsible for the arthritis drugs and will probably be able to provide some guidance as to that issue.
MS. MEYERS:  If three companies come to you with the same drug and they all ask for priority review, even though it's the same drug, you might grant priority review to all three --
DR. SIEGEL:  Well, what's the same and what's different is a very complex issue.  This committee actually -- I think it was to this committee that we brought two drugs actually, Simulect and Zenapax, which were two drugs for organ transplantation, antibodies to the IL-2 receptor.  Or at least we brought one of them.  Do you remember?  Did we bring both of them?  We brought one of them, yes.  And that came in at around the same time.  These are complex.
The simple answer is that if there's a drug approved for an indication and another drug has not shown that it does anything beyond being an alternative that is not a priority.  And in fact, there are specific examples of cases that I can think of in house now where we've made that very clear where one drug got approved as a priority; a few months later, the other drug comes in and is not a priority. 
Now, if a drug comes in at a time when a competitor drug is under review, well, there's still an open question as to whether that drug is even going to be approved, and so in fact, it may well get priority designation.
And then we face the question, well, if we're halfway through the review, do we change the designation and what does it mean to change the designation in the middle of the review if we've already proceeded on a priority time line.  And we don't really have a clear answer to that question, and often we don't change it, though.
MS. MEYERS:  Is it a significant strain on the FDA staff that two-thirds of your biologics are designated as priority drugs?
DR. SIEGEL:  I think it's more than two-thirds, and the answer is yes.  It's a tremendous strain.
DR. SCHWIETERMAN:  I think it's an excellent question.  I think it's important to keep in mind that the fast track approvals depend not simply on whether the agent is similar to the other agents but, as Jay was pointing out, the indication.  So, you can have actually a class of drugs, all of which work relatively similarly with respect to their physiological mechanisms, but the sponsor is pursuing different aspects of that disease.  
One of the virtues, frankly, of fast track is that it encourages sponsors to seek out new ways.  An example:  if you give an anti-TNF for the treatment of signs and symptoms of Crohn's disease but then you have another company that comes out with maybe another agent and they seek it for steroid sparing of that same disease, they would get fast track designation even though they have almost virtually the same agent, these sorts of things.
I think that that was one of the intentions of the fast track document.  I think that that we think that that's actually a good thing because it gets sponsors to -- and of course, we make them address that particular concern. 
So, maybe that helps clarify some of your questions.
MS. MEYERS:  In other words, it's encouraging innovation?
DR. SIEGEL:  It's encouraging getting better and additional and more important clinical data in the sense that a drug of the same class, if there's already a drug approved that has a certain symptomatic indication and a competitor with a drug that is similar and might have a similar use but claims to show a survival advantage or some other -- our tendency would be to give that a priority in part because it might be a superior drug.  But even if we think that the other drug might also have that effect, it does in fact encourage sponsors to do trials which provide important and useful clinical information, such as impact of a drug on survival.
DR. STEIN:  I don't want to prolong the discussion, but I want to answer Dr. Miller's question about fast track approvals for biologics.  Actually the agency's first fast track approval was a biologic.  It's Herceptin, a monoclonal antibody to the HER-2/neu receptor, and that was approved in September of 1998.
DR. SIEGEL:  Yes.  That was the first approval of a product with designation.  Right.  
MS. GOLDMAN:  I just want to clarify that two-thirds of the products that have applied for fast track designation received it.  They're usually very on in development, often before they've done any clinical trials whatsoever.  So, it's based on animal preclinical information or whatever.  So, just as most drugs don't actually make it through to an NDA or BLA application to begin with, they have a long way to go in showing they continue to meet the potential to address an unmet medical need.  That two-thirds shouldn't be linked to the two-thirds then going to priority review later on.
DR. SIEGEL:  I clearly made a mistake in devoting only three or four slides to fast track and only focusing on effectiveness because I think I may have created more confusion than I clarified.
But just as an issue of background so you'll understand it, the fast track is an aggregation, if you will, of a large number of policies that have to do with serious and life-threatening illnesses.  So, there's early designation at the IND phase.  This is something that's new.  That triggers whole bunches of meetings and support and so forth, some of which already exist and defined under subpart (e) regulations promulgated 10 years ago.  The program incorporates but does not automatically trigger the potential to use the accelerated approval regulation for approval based on a surrogate.  It incorporates and probably does essentially trigger the priority review mechanism.  If you're a fast track drug and you proved what you intended to prove, you should meet the standards for priority review.  And it enables and the fast track designation is required for but is not the sole requirement for the ability to submit incomplete portions of an application.  And there are other things involved as well.
So, when we talk about fast track, we're talking about a whole collection of policies, all described in one guidance as to efforts the agency is making to facilitate development of treatments for serious and life-threatening illnesses that add to the therapeutic armamentarium in significant ways.  But priority designation, accelerated approval, IND fast track designation are amongst those programs.  So, sometimes people have referred to those as fast track.  There's a little bit of terminology confusion, but that's basically the nature of what fast track is.
DR. SALOMON:  Two more comments.  Dr. Sausville?
DR. SAUSVILLE:  Maybe the program is too young, but what fraction of agents that either have been approved or are in the process of being approved by fast track that lose that designation owing to clarification of things in development?  
I mean, everyone would praise moving forward with things rapidly.  On the other hand, one doesn't want to create the impression that there are ways of getting around or parallel tracks or different tracks or depending on how you couch things, that you might be able to go this route as opposed to others.
DR. SIEGEL:  Well, there's no question that over the course of the development of a drug what was an unmet medical need may no longer be an unmet medical need, and what appeared to be the potential to address that need -- the drug may no longer show that potential.
It's too early to say how often that will happen.  And the agency has provided some but not complete clarification as to whether and when it will actually withdraw fast track designation, something that has yet to happen.  But what would clearly happen is if those things didn't exist, as you went through development, if you no longer appeared to kick in the criteria necessary for, say, accelerated approval based on a surrogate because there was already an approved treatment for that indication or if you didn't kick in the criteria for a rolling application or a priority review, you might not get that even though you had initially received fast track designation.  Whether or not you would get a letter of de-designation is something that's not yet clear. 
DR. SAUSVILLE:  I just think that the criteria for such a letter and the process used to make that determination needs to be pretty clear to people so that they're aware.
DR. SIEGEL:  There are proposals out there.  We're receiving public comment on it.  Obviously, there are significant implications that are of some concern to sponsors as to what it means to get a letter that says you've been de-designated and so forth.
(Laughter.)
DR. SAUSVILLE:  You're done.
(Laughter.)
DR. SIEGEL:  And we're aware of that and working on that issue.
DR. SALOMON:  Dr. Vose?
DR. VOSE:  I just had one short comment I want to make.  I want to kind of put a plug in for having the appropriate clinical and scientific expertise on the committee to try and deal with not only the biologic aspects but also the aspects of the specific disease that we're dealing with and also to have those people or other people involved in a lot of these early meetings that you're having because I think they put a neutral perspective on.  They're not involved with the drug and they're not involved with the FDA, but the expert can be helpful as far as the overall picture in helping with some of those, kind of standing up for the patients and what's needed in that disease entity.  And I think the ones at least I've been involved with have been kind of helpful in that situation, and trying to get involved very early I think is very important.
DR. SIEGEL:  Well, thank you.  I think we should be doing more of that.  I think that would be wise. 
For the sake of the new members of the committee who may not have experienced this, it's hard obviously and it's impossible on this committee to retain all the types of clinical expertise pertinent to the products that we might face.  And so, we may well take a treatment for, say, arthritis or Crohn's disease or cardiovascular disease to a different advisory committee that has more of that appropriate expertise.
Nonetheless, we find that there are certain common themes that arise with our products such as immunogenicity that we're going to discuss today so that we have a very common practice of asking members of this committee -- Dr. Vose, I know you've done this on several occasions -- to sit as members and panelists on other committees when we take a product.  We will invariably ask at least one and often several members with the most relevant expertise on this committee to sit with the Oncological Drugs Committee or the Rheumatoid Arthritis Committee or whatever it might be to discuss our products.  We very much appreciate that contribution because there is a broad mix of types of issues that comes up and we struggle within the rules we operate under to bring together the right expertise so we can get the best advice on any given product.
DR. SALOMON:  Thank you very much.  It was very informative.
The next speaker is Dr. Karen Weiss, and she's going to address the pediatric rule.
DR. WEISS:  Good morning, everybody.  I am trusting that all the questions that you asked Dr. Siegel means that there are going to be fewer for me, especially because everybody is going to want to go to the break. 
But it is a pleasure to be here this morning to provide you with an update on what has been happening in the area of pediatric regulations.  This has been a very active, dynamic area in the agency in the last few years.  Our former Commissioner, who was a pediatrician from Hopkins before he came to the agency, had certainly a very great interest in pursuing and promoting adequate studies in pediatrics.  Also the American Academy of Pediatrics has been a tireless advocate in this area.  And it has culminated in a number of important developments in the last few years that I'm going to go over.
First of all, this is just some general principles that are actually set forth in one of the ICH documents.  It's actually E7 which is a guidance document on Studies in Support of Special Populations:  Geriatrics.  But it's very applicable to what I'm going to what I'm going to be saying about pediatrics, as well other groups.  And those principles are:  Drugs should be studied in all age groups for which they will have significant utility, and that patients entering clinical studies should be reasonably representative of the population that will be later treated by the drug.  
I think those are good principles, and I don't think that was really apparent a couple decades ago.  There seemed to be a systematic exclusion of particularly important groups such as pediatrics, such as geriatrics, such as women of childbearing potential, and over the last 20 years, there has been a shift towards more inclusion and representative of these important groups and others as well.
In order to come to the present regulations for pediatrics, I thought it would be helpful to first go through a very brief history of what has been happening in the world of pediatric regulations, and it's fairly short and fairly brief.  It's 1979, 1994, and now 1998.
In 1979, that particular regulation -- and I have the citation in the Federal Register for you on all these three -- the purpose of that was to establish a pediatric use section of the labeling.  Prior to that time, there was no requirement in our labeling regulations that there be any mention, acknowledgement, whatever of pediatric use of a particular drug/biologic that would be approved.  So, this established it for the first time.
I will go over these all in a little bit more detail.
In 1994, it was to try to clarify certain situations, similar to the effectiveness standard that Jay Siegel mentioned earlier, where one could perhaps extrapolate efficacy from trials in adults down to pediatric patients. 
And then 1998, which is going to be bigger focus of my presentation. 
So, 1979, in the regulation what was set forth, the goal of which to try to ensure that labeling of approved products would regularly contain adequate information about prescription drugs in pediatric populations.  As I said, it established for the first time the particular section in the labeling called the pediatric use section that was supposed to be filled out with correct information about pediatric use.  
The regulation further went on to say that the basis for the information in the pediatric use section of our labeling should be substantial evidence, the same standard that we have, from adequate and well-controlled studies in the pediatric population unless that requirement was waived.  
The problem was that this regulation in 1979 did not have the effect it was intended to have.  There was a pediatric use section of the labeling that was routinely put into our labels, but it really did not contain particularly useful information about pediatric use.  And the reason why is because there was a mistaken impression that the only way to get pediatric claims, pediatric use sections into the label was to conduct adequate and well-controlled studies in the pediatric population, pretty much what the regulations said.  And there was that waiver clause, and the waiver was intended when other information could suffice.  
However, the particular conditions for when a waiver should be requested was not very clear.  I don't know if there were any cases where anybody actually asked for a waiver, and I don't think the agency really had a particularly good idea of what conditions it would follow, what criteria to basically grant a waiver.
And so the default position is what we generally had had, which was that prescription drugs continue to lack information on pediatric use.  That section of the regulations that was required to be filled out basically contained the standard clause which anybody who is in pediatrics who has ever looked at labeling to try to prescribe a particular drug for a pediatric patient would see the particular statement that would say safety and effectiveness below the age of X have not been established, whether it's 6, 2, 12, 16.  Whatever age they had, there was always this particular default position that was available on the labeling which was not particularly helpful because in practice, again anybody who had been in pediatrics would know, you really couldn't use the label to help you, to guide you in terms of prescribing a particular medication for pediatrics.  You didn't really know what dose to use.  People would just take the dose that was recommended for use in adults and kind of do some calculation by whatever voodoo they knew about and come up with a dose for a pediatric patient or they'd take the tablets and they'd cut them in little pieces and it was never quite standard.  It was very much a problem.
So, along came 1994, something that was referred to commonly as the 1994 rule.  That one said, gee, 1979 really wasn't very helpful.  It didn't get the desired effect.  There really needs to be more encouragement of pediatric studies.  There is certainly a lot of resistance to putting pediatric patients on clinical trials, which you can understand.  There are issues about consent, some of the ethics.  If you're going to be doing a placebo-controlled trial, is that really something you really want to do in a pediatric patient who really doesn't understand particularly the potentially painful procedures if you have to do blood drawing, when you have pediatric patients on trials who may not really understand.  So, that was really I think probably the bulk of the reason not to put pediatric patients on trials.
Now, where I and many other people come from, which is the pediatric oncology side of things, that was clearly not the case.  Pediatric patients were routinely put onto clinical studies.  But I think for the vast majority of many of the other products, that really was not the case.
So, in 1994, the final regulations that were proposed in 1992 and finalized in 1994 stated that there are times when you don't really have to do the complete randomized controlled trials that everybody thinks one needs to have.  In fact, there may be cases where one could extrapolate efficacy from adult populations from adult data, from adequate and well-controlled trials in adult studies, and those cases would be when there is substantial evidence can include studies conducted in adults "when the agency concludes that the course of the disease and the drug's effects are sufficiently similar to permit extrapolation."  In those types of cases, generally pharmacokinetic and additional safety data would be required.  It said "where needed."  
And you could understand that, for instance, if you were extrapolating efficacy down from adult studies to adolescents, you may not need a lot of additional information on pharmacokinetics, but if you were going to try to extrapolate efficacy from adults down to the same condition in a neonate, you might very, very well need a lot of good pharmacokinetic data to understand the dosing because the metabolic pathways may be very, very different.
As this committee probably knows very well, since 1994 -- and actually it's about the time when this committee first formulated -- we have been asking this committee this very question.  With many, many products that we have taken to this committee, data were based on adequate and well-controlled trials in adults, oftentimes with some smaller amount of data, primarily pharmacokinetics, in pediatric patients.  And we almost routinely ask this particular committee, can we extrapolate efficacy?  Is the disease course similar enough that we can actually do away with the controlled clinical trials in pediatrics and extrapolate efficacy from adults so that we can actually put this into the labeling?  
And that has been a source of a lot of discussions.  I know Ms. Meyers was instrumental in a lot of those discussions, a lot of other people here on this very topic.  I think it has been very good.  It's a very difficult issue to determine, whether or not you can extrapolate efficacy, and there are cases when it's probably very easy to do and other cases where it's much more difficult.
The 1994 rule basically called upon sponsors of these licensed products or approved drugs to go back and review existing data because there was the feeling that there may already be substantial use in the community of these approved products and that in fact it wouldn't be terribly onerous.  Our manufacturers could go back and gather what data had already been done in pediatrics, submit those data to the agency, and there would be a number of supplements coming in that would fulfill this particular requirement to add the appropriate information onto the labeling.
Now, the rule specifically did not require sponsors to go forth and conduct studies either for already marketed products or for new products coming on to the market.  It specifically said that our sponsors should not propose labeling if they do not believe that the disease and the drug effects are similar or if pediatric use not otherwise adequately supported.  So, there was no specific requirement to do studies.
The 1994 regulation was very helpful, though, because it forced all of us to really focus more on pediatrics and to think more about it, to regularly discuss pediatric studies and pediatric use with our sponsors who are coming through in development and again to bring it up to committees like this committee on a routine basis.  So, it did accomplish some things. 
However, in the years after this regulation issued, there was growing concern by advocacy groups, a number of other groups that this particular regulation just did not go far enough, that there just wasn't enough data being collected, there were just not enough studies being done.  In fact, when one went back and reviewed the approvals, primarily on the drug side, because that's where it's really much more of an issue, and did surveys from 1991 on through 1997 where applications were coming to the agency for an indication that had potential usefulness in pediatrics, only at best 30 percent or so of those actually contained pediatric information.  So, even though it was better than nothing, it still had a long way to go and it wasn't as complete as it should be.
So, in 1997, in response to this growing concern that 1994 regulations just were not adequate, the agency proposed regulations in 1997.  These became finalized in December of 1998.  The title of this regulation is called Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients.  It's a requirement.  It's the first time now that we are actually requiring these data to be generated.  This regulation became effective six months after the date it was finalized; so April 1st of 1999 it became effective.
However, even though it became effective April 1st, any new application coming before the agency from April 1st for actually the next couple years probably will not have the data in hand at the time the application is submitted because, of course, it takes time to generate clinical data.  It may take even more time to generate data in pediatric patients.  Therefore, it's not going to be until 20 months after the effective date of the rule, which basically means December of 2000, when those data will have to be in hand.  Obviously, we'll take it sooner if those data are available sooner, but it's not going to be until December of 2000 that those have to come in.
Let me just step back just a second and just say that in 1997 when this regulation was first proposed, it created quite a bit of controversy.  There was a big dichotomy, if you will, of opinion with the proposed regulation.  There were on one hand the advocacy groups who said this regulation doesn't go far enough.  It really needs to be much more compelling, much more straightforward in telling sponsors that they have to get these data.  There should be no exceptions, et cetera.  And on the other hand, there were industry representatives, not all of course, who basically felt that the regulation had gone too far and that, in fact, FDA was overstepping its bounds.  It was going to create all sorts of problems.  Pediatric patients would be put on studies before it was safe to put them on studies.  It was going to delay approval of therapies for adults.  These were all things that were voiced as concerns.  And so, there's quite a dichotomy of opinion about the 1997 proposal.
However, despite the fact that there was this big dichotomy, one was able to, I think, try to come up with some reasonable compromises, and the regulation was finalized in 1998.  And so, highlights of this 1998 regulation are as follows.
There's the presumption that manufacturers will assess drugs and biologics in pediatric patients, and that assessment should be available during development so that at the time the application is submitted to the agency, those data will be in hand, and if not at the time the application is submitted, sometime soon thereafter.  What we're talking about are new indications for sure, but even other things, new dosage forms, which isn't so much an issue in biologics.  The majority of our products are parenterally administered.  But in drugs there are tablets, liquids, suspensions, sustained release, all those different types of formulations, and if something new comes along that might have potential usefulness in pediatric patients, that would need to be studied, a new route of administration, et cetera.  So, all new aspects of a particular product, whether it's a brand new application or a new indication, et cetera, or new variation, the presumption is going to be that those data will be in hand for pediatric patients and that new drug biologics will contain adequate labeling, as I said, at the time of approval or very soon thereafter.
The agency does have the authority to go back and require studies on already marketed products, and I'll mention that standard or that criteria in a minute.
Specifically what is not applicable in this regulation are orphan drug products, the idea being that there should be an incentive to get things on the market for orphan indications and that this regulation was not going to go further and require -- you can imagine if it's an orphan indication for an adult, it's probably going to be even much more orphan for a pediatric population.  So, orphan products are excluded from this particular regulation.
So, what are the conditions where the agency will require studies in pediatric patients?  One is when it's likely to be commonly used in the pediatric population.  
What does "commonly used" mean?  With the proposed regulation, we were taking the criteria that are used for orphan drugs, which is if it affects 200,000 or less, it's an orphan indication.  However, the pediatric population doesn't make up the entire universe of the population.  It's only a fraction of it.  And so, there were some manipulations that went around and some mathematics, and what came out in the final regulation was commonly used would be if it was greater than 50,000 in the overall pediatric population or 15,000 in any particular subgroup.  And I'll mention a little bit later on about the different age groups of pediatrics to give you an idea.  So, that was the numbers that were proposed.  
So, that's one, if it's commonly used.
The second is if it provides a meaningful therapeutic benefit, MTB, to pediatric patients over existing therapies.  It's somewhat similar to what Dr. Siegel already proposed or mentioned with fast track and accelerated approval, et cetera, a somewhat similar concept.  So, it could be used in a very small number of patients but still provide a meaningful therapeutic benefit.
And I put this down because this was well highlighted in the pediatric regulations, and it's not mentioned many other places.  In some classes of some diseases, there is really a need for alternative therapies even if it has not been demonstrated to show a particular advantage.  But you can imagine in AIDS and cancer there's rapid development of resistance, and those are particular diseases where one might not have to show that it can only be used in people for third line, fourth line, fifth line therapy, but it's a particular class where it would be important to have available therapies and alternatives for patients.  So, those would also be considered to be drugs or biologics that would offer a meaningful therapeutic benefit.
And then for marketed products, a similar standard, it's commonly used or offers a meaningful therapeutic benefit, and -- it's an "and" -- absence of labeling could pose significant risk.  It's felt that this particular requirement to go back and require studies on marketed products would not be used, imposed very often, maybe a few times a year.  It's going to be a little bit difficult I think to determine whether or not absence of labeling could pose a significant risk, but that would be the criteria that would be used.
Types of studies that the agency will require is very variable.  Just like in 1994, the agency said there are times when one may not need to do full-fledged, randomized efficacy trials, sometimes PK studies, safety studies may suffice, the same goes in 1998, a range of particular types of trial designs are available and can be appropriate depending on the situation.  It can range anywhere from smaller studies of just some PK again to randomized controlled efficacy trials. 
The particular age ranges that should be studied is going to depend on what ages are affected by the particular disease.  In 1994, the regulations basically set forth four different age ranges of pediatric patients:  neonates, infants, children, and adolescents.  This is why I try not to talk about this proposal as being children, but pediatric patients because children refers to a particular group age 2 to 12, even though they're all children.  In particular, these adolescent groups are.
But anyway, in the 1998 regulations, we didn't specify particular age ranges with these particular cutoff dates because we realize it's somewhat arbitrary and there may be physiological differences why other particular age groups should be studied as opposed to these definitely prescribed ones.
Most importantly, the kinds of data and studies that will be required will be only for the indication that is being claimed.  If something is about to be approved or already approved for an adult indication and there's substantial off-label use in pediatrics for a different indication, the agency does not have the authority.  It will not be able to ask for studies in that off-label indication.  So, it's only for the indication being sought.
When to conduct studies is a very open question and one that has been the subject and will continue to be the subject of great debate because one doesn't want to go into pediatric patients too soon.  However, one doesn't want to have the default that we've had over the last couple decades, which is to be too late and in fact to not do these things at all.  
So, it's going to depend on the seriousness of the disease, whatever preliminary data are available in adults, if appropriate.  There are some settings where adult data are not appropriate and not necessary to have and these new products go right into pediatric populations, but that isn't always the case.
And availability of other therapies for the particular condition.  In general, the regulation says this I think quite clearly.  One would think about going earlier into pediatric patients if you're talking about a very serious disease where there are very few or no alternative therapies, perhaps later for things that are considered to be me-too type of products.  In some cases, one might not even want to go into pediatric populations until there's substantial post-marketing safety experience that's obtained in adults.  It's really going to depend on the particular situation.
Now, the regulation says that pediatric data will be available unless that requirement is waived or deferred.  So, when do we waive the requirement?  And it can be waived for the entire pediatric population or for some populations like it can be required for adolescents and children but not infants and neonates for instance.  So, it would be waived if it's not an advance, unlikely to be used, or ineffective in those particular populations, studies are impractical, too small.  The population is geographically dispersed and it's just absolutely impossible to conduct a trial.  
And then this last one, which has also been the subject of quite a bit of controversy, again not for us in biologics because we don't deal much with formulations.  We don't have to think much about taking a tablet or a sustained release or a capsule and figuring out how to make a liquid formulation that's palatable.  Palatable, the big thing, of course.  If anybody has ever tried to get a liquid down the throat of a child, it's easier to do it for your dog than it is for your child.
(Laughter.)
DR. WEISS:  So, the inability to develop the pediatric formulation.  So, I don't probably have all the appreciation for all the chemistry that goes into formulations, but when this initial proposal came out, one of the controversies was the advocacy groups said that should never be a reason to waive the requirement.  They should just be required to develop a formulation, no ifs, ands, and buts.  And others on the other side saying this is extremely difficult, extremely expensive, and sometimes just not feasible to do.  So, if the company has, in good faith, attempted and failed to develop a pediatric formulation, they will be waived of the requirement.
Deferral.  It's not a waiver, but deferring the studies until sometime later on can be available where the adult safety or efficacy data are needed to be collected before appropriate studies in pediatric patients.  Of course, then the pediatric studies will be delayed.
If the product is ready for approval in adults but the pediatric studies are underway and have not yet completed, the agency has said over and over again that we would not delay approval of an important therapy that's ready to go out there for adults while waiting for the pediatric studies to be completed.  
However, if there is a deferral, one would have to reach agreements -- we would all reach agreements -- regarding the timing of the pediatric data, when we would expect it to come in to the agency.  And the regulation says that the pediatric studies of sponsors is going to be required to update the agency on the progress of the pediatric studies in their annual reports to the licensing applications.
One of the good aspects of this 1998 regulation, just like in 1994, was that it's forcing all of us to focus in on pediatric development early on in the development process of the particular product.  The regulation specifically calls for early discussions with the agency on the need for pediatric studies and the timing of pediatric studies and the type of pediatric studies that will be required.
Specifically, if we haven't had these discussions and determined earlier on by the end of phase II development -- and actually it will be phase I for a serious or life-threatening disease, but certainly by the end of phase II for the ordinary types of products, most of which we don't have in biologics -- we tend to have the serious, life-threatening kind -- we're supposed to inform sponsors about whether or not the need to have pediatric data and when we think it would need to come in, et cetera.  When we have meetings with our sponsors at the end of phase II to discuss the phase III trials and the entire development plan, the sponsors are supposed to submit in their meeting packets their proposals and their plans for pediatric studies at that particular time, if not before.  And that is specifically called for in the regulations.
This is called my carrots and sticks approach.  What are the incentives to doing these pediatric studies?  Because there are some.  The main one is exclusivity, which was actually finalized under the Food and Drug Administration Modernization Act of 1997.  The agency will also and has waived user fees for supplemental applications that come in for pediatric use.
What are the penalties for sponsors who do not comply with the 1998 regulations?  Well, there can be an injunctive action.  The product can be considered to be misbranded, and one could go to court and the federal courts can require these sponsors to do the studies and submit data or they will suffer contempt and fines and other types of adverse outcomes. 
The agency will specifically, though, not withdraw approval.  It's not like the accelerated approval that's conditional upon doing the required phase IV studies to confirm the surrogate.  In this case, it would not be feasible or possible to withdraw an approval if it has already been shown to be safe and effective in adults.  So, there isn't really that particular stick that is available in the accelerated approval regulations.
Now, exclusivity has been a very important tool towards getting pediatric studies.  Exclusivity, like I said, was finalized when FDAMA was signed into law in November of 1997, and it is a very large incentive for manufacturers.  It calls for tacking on an additional six months of exclusivity whether it's orphan drug exclusivity or six months of additional marketing protection under the patent protection for any drug that qualifies.  
There are specific procedures that have to be followed for a particular product to qualify for exclusivity, and there's a guidance document that the agency issued called Qualifying for Pediatric Exclusivity under 505A of the FD&C Act.  I'm putting this there because in the next slide you'll see why -- well, actually before you do that, let me just make this point.
If the companies perform the required studies to be eligible for exclusivity and those studies are done and they're inconclusive or they actually fail to show that there is benefit in pediatric patients, they will still get the exclusivity.  They don't have to have a positive outcome in those studies.  They just have to do those studies according to the specifications set forth by the agency and they will get this additional six months of exclusivity.
Now, there are some important differences between the rule and between the exclusivity provisions of FDAMA.  The rule is mandatory.  The exclusivity is voluntary.  Any company can request it.  They can ask for it.  The agency can have discussions with those companies who are thinking about doing studies to get exclusivity, but they don't have to do it.  As a matter of fact, they can think it out and say, we thought about it and we're just not going to do the studies, and that's their prerogative.  But it's not the case under the rule.
Under the rule, the studies that have to be done are only for the drug and indication being sought.  One is not going to require things that are not in that particular marketing application, other indications where there may be utility but are not being pursued by the company.
Under FDAMA, it's the active moiety that is under question.  Again, this is not so much an issue for biological products but for drugs when there are sustained release and suspensions and inhalations and suppositories, all types of things.  They all have the active moiety.  When the sponsor does studies, as part of the exclusivity, the required studies, they will get exclusivity for all the active moieties, all formulations of this particular product.  So, even if some of the formulations are not used in pediatrics because they've done their necessary studies on those formulations that are felt to be useful in pediatrics, they get exclusivity on the whole shebang.  And so, that's why there's a very large incentive.
Now, the other important difference is here.  The rule applies to all drugs and biologics.  Under FDAMA, it only applies to products that are under 505 of the FD&C Act.  Biologicals are under the authority of the Public Health Service Act.  The bottom line is that almost all biologics are not eligible for exclusivity.  For our products, we don't have this great incentive that's actually been extremely successful with my colleagues in the Center for Drugs for getting the studies.  When I say extremely successful, in all the years from 1994 on, there have been very small numbers of applications that contain appropriate studies in pediatrics.  But since FDAMA went into effect, there has been well over 100 applications -- excuse me -- not marketing applications, but well over 100 requests from the agency -- it's very complicated and I'm screwing it up royally.  
There has been a lot of interest in doing the pediatric studies to get the exclusivity and there's a lot of development and a lot of studies underway.  FDAMA was only signed into law in 1997.  A few of those have now gone on to have the pediatric data to be submitted and have gotten their exclusivity, but there are many, many others that are under development.  The studies are underway. 
And there's a real incentive because for some of these products, exclusivity is about to expire, and if it expires you don't get it added back on again.  If it expires, you've kind of lost the ball game.  So, it's very important to get these studies in and the data submitted to the agency before exclusivity expires.
There has been some interest, by the way, of some people on the legal side to try to see whether or not these provisions can now be extended to biological products, but thus far biologics do not have to deal with the exclusivity issue.
The very last slide I had is on a pediatric advisory committee.  Our regulations calls for the development of a pediatric advisory committee to tackle important questions about pediatric studies.  And that has been done now.  There is a pediatric advisory committee that is a subcommittee of the Anti-Infective Advisory Committee.  That subcommittee is made up of expertise from a number of different advisory committees.  
I tried very, very hard to get somebody from the BRM Advisory Committee added to this committee, but it was very difficult because of the timing.  There were not many options in terms of when the first meeting of the pediatric subcommittee could be held, and there are people who are SGEs who can be used for the pediatric advisory committee like Malcom Brenner, Joanne Kurtzberg, people with relevant pediatric expertise in some of the types of therapies that we have.
This committee is supposed draw on expertise, like I said, from existing advisory committees.  It's going to include people with ethics backgrounds, clinical pharmacology backgrounds, an industry representative.  And they are supposed to tackle a range of important pressing issues in the area of pediatric development.  The idea, though, is that a disease specific application for pediatrics would go to the right committee.  If it's for an asthma drug, it would go to the Pulmonary Advisory Committee, for instance.  If it's an oncology drug, it would go to ODAC.  But this committee would tackle issues on a much broader basis. 
That's my final slide.  I also just wanted to mention that in addition to all the things that I mentioned, there are a number of other activities that are going on with respect to pediatrics.  There's a pediatric pharmacokinetics guidance document that was issued as a proposal in the end of this year, and comments are being incorporated and a final document should issue.  
There is a big effort going on in international harmonization.  I'm a member of that delegation.  We're going to be meeting again in Washington in October of this year to hopefully finalize an international guidance on pediatric studies.  It's very interesting because we're trying to harmonize with Japan and Europe, and there's a big difference, particularly among the Japanese, with respect to putting pediatric patients on clinical studies and their views.  So, it has been a very good learning process and hopefully it will be a very useful document as well. 
So, with that, I'll be happy to take any questions the committee might have.  Thank you for your attention.
DR. SALOMON:  Thank you, Karen.
I just wanted to make a point for those of you who are following time there was a policy to allow the time to expand just a little bit having to do with just efficiencies a little later so that people shouldn't be over-concerned that we're a few minutes late.  So, there is time for some discussion here.
MS. MEYERS:  If biologics are exempt from the pediatric rule, does that mean that FDA doesn't really have the right to say you want all the new biologics --
DR. WEISS:  Excuse me.  Abbey, biologics are not exempt from the pediatric rule.  They're exempt from the exclusivity provisions.  Biologicals have to comply with the provisions of the 1998 rule, meaning that they have to conduct studies in pediatric patients.  If it's likely to be used or offers a therapeutic benefit, they have to have those data either at the time of the approval or it could be deferred to some time later on.  But they have to comply.
MS. MEYERS:  I'd just like to comment that it's a very interesting phenomenon because it's about 20 years now that we've been advocating to do something about the pediatric uses of drugs.  Our organization has worked for it.  We're just so happy to see that something was finally being done about it.  
All of the excuses that the industry used all of those years about it not being ethical and being too expensive and all of these things that could be well documented, every one of them didn't even complain on the day that FDAMA passed because they knew that they were going to get six more months and essentially a patent extension.  And for some of these drugs, actually a half a billion dollars in six months, a billion dollars, or $2 billion for six months.
Now, when the regulations were issued -- and it just confirms the same principle as the Orphan Drug Act which is:  build it and they will come.  Tell them they're going to make money and they're going to do it.  Suddenly it's very ethical to do these types of studies.  
Now, this has just caused a big problem in the consumer community in two ways, first, the healthy consumers and then of course the sick consumers.  But the healthy consumers who are drowning under the cost of drugs, particularly the elderly, are just waiting for these patents to expire so they can buy a generic.  And this has put off generics for six more months buying some drugs that are huge, big sellers, I mean, ulcer drugs, et cetera.
Then FDA said if you get this pediatric exclusivity, you're going to get it on a form of your drugs.  So, somebody came along and did some exclusivity trial.  I forget if it was Advil or Tylenol, some unbelievable drug.  I think they did it on the liquid formulation of pediatrics, and they got six more months of exclusivity on a pill that all these other people need, and they have caused a tremendous uproar because that means they have to pay an inflated price for six more months.  That's major in their minds.
So, I wonder, if you're going to do a pediatric study and you get exclusivity on the liquid form on something like aspirin, you shouldn't get it on all aspirin.  You should get it just on that liquid form.  So, I don't know what led FDA to come to the decision that you were going to do this which is going to cost United States consumers multi-billions of dollars every year.
The second issue is exempting the orphan drugs, and I don't understand why that was done, especially without consultation with the orphan disease community.  We are American citizens.  FDA is a consumer protection agency.  When we get orphan drugs on the market, we want them to be as safe and effective as any other drug.  We don't want you to say let's make an exception for orphans and put out dangerous drugs or drugs that don't work.
But you've done this here with exempting the pediatric requirement for orphan drugs even though a huge number of orphan drugs are cancer drugs that get approved for cancer, and once they're out there, they used on every type of cancer and we have no pediatric data.
So, I'm a little bit upset about that.  Can you respond?
(Laughter.)
DR. WEISS:  I think you have raised good points.  I don't know if there are any avenues at this point with this regulation being finalized to address them.  Exclusivity -- I can't really talk a lot on it.  I don't know what the thinking was and what the negotiations were that were going on.  Given the fact that biological products were not eligible for the exclusivity, I haven't paid as much attention to all of the legislative history with it.
I suspect, though -- and I don't know if anybody from industry who is in the audience knows or can comment on that -- that I'm sure that as part of the negotiations under FDAMA, you're right, people probably looked at the incentives and said, we need a whopping big incentive and this is what we need.  
So, most people here in this room were probably not involved in those discussions.  So, I really can't specifically comment on that.
With respect to the orphans -- and it's too bad that somebody from Orphan Drugs is not here -- we're actually going to be meeting and have some more discussions about this issue about exempting orphans for pediatrics because I think there is some concern, just what you raised.  I don't know what's going to happen with that, but I think there needs to be some more discussion.
I can tell you from personal experience with even some of our particular products that you have orphan indications that have been studied for adults.  We haven't had problems thus far with talking to our sponsors and saying, you know, yes, you actually could be exempt and are exempt, but you really need to get these data and it's the right thing to do.  And we have not met with obstacles in terms of people not doing the studies.
In pediatrics, I think for oncology from my personal experience in the field -- I don't know, Ed, maybe you can comment more.  People who have spoken a lot in this area have actually felt that many of the studies for cancer have actually come through first in pediatrics.  I mean, there are differences of opinions about that, but I think most of us on the cancer side are really happy with the fact that there are these big, cooperative groups ongoing and a lot of effort in studies of pediatric cancer drugs.
DR. VOSE:  I just want to say I haven't had such good luck in trying to get sponsors to use that clause of FDAMA because the last three lymphoma drugs, like diffuse sparse cell lymphoma drugs which does affect the pediatric population, I've tried to just get them to do studies down to 13, and they won't even do adolescents.  So, I think I can't say I've had very good luck at all with that.
DR. SAUSVILLE:  If I could continue with the discussion.  I was actually very concerned that if you look at the Federal Register list, forgetting orphans, but just the diseases that waivers are automatically granted to, 12 out of the 20 categories are cancer.  So, one could imagine a scenario where, to elaborate on the point made, that you go for an indication in, say, pancreatic cancer and then clearly the pediatric patients might then not be addressed because the indication gives you an automatic waiver.  So, I think this issue needs to be thought through, and I agree that sponsors, sometimes where the perceived market is in an adult population, might not actually be very motivated, as it were, to pursue the pediatric --
DR. VOSE:  But even in lymphoma where it does affect pediatrics, they weren't willing to.
DR. SAUSVILLE:  So, that would only augur more unfavorably for drugs that might have a perceived larger market share -- 
DR. WEISS:  I can tell you the exclusivity has a sunset clause of 2002, and in 2001, there's supposed to be a report to Congress about this to see how good it's working.
Part of the controversy, when we finalized 1998 regulations, on particularly, I think, part of the industry's side was, hey, we have these incentives now.  We don't need a mandatory, forced-down-our-throat type of regulation.  We're going to do it because we have the incentives.  So, I think a big part of this report to Congress is going to see how well the incentives have worked and whether or not that will continue.
DR. SALOMON:  Dr. Miller?
DR. MILLER:  I have just a clarification.  If you have the rule and it applies under the rule, can they still get the incentives?  Why do you give incentives if it's something that's already a rule?
DR. WEISS:  It's felt that the rule was still going to be necessary because, for instance, biologics are not eligible, certain antibiotics and things that are off patent would not be eligible.  There may be things that there would be the exclusivity, but maybe studies would have to be done in neonates.  Neonates in particular have been real therapeutic orphans, the feeling is, in terms of actually having clinical trials conducted in those populations.  So, the feeling, as outlined in the preamble of the regulation, was that despite the fact that we have the exclusivity, there was still going to be a large number of gaps and that the regulations, if you will, might help fill in those gaps where the information was not being collected.
DR. MILLER:  That wasn't my question.  My question was, once you have the rule, are they still eligible for the exclusivity?  Once you make a rule, you don't have to give carrots and sticks anymore.
DR. WEISS:  Because you do it.
Well, the idea, though, is that if the sponsors meet the provisions of exclusivity, they will get the exclusivity.  It's a little bit confusing and every time I think I understand it and I reread it again, I realize that it's still quite confusing.  But the idea is to actually allow everybody the opportunity first to have exclusivity and then to apply in those situations the rule when they have not gone forth with the exclusivity.  
The exclusivity is probably more for existing products, for the marketed products, because the rule really isn't really go back and do much for the marketed products.
DR. MILLER:  Right, but why do new products --
DR. SALOMON:  One way would be, if you're thinking about the negotiation process that led up to the rule, whether we agree or not, it's going to cost the sponsors money to do these trials and submit them to the FDA and go through all the different changes to comply with the rule.  It doesn't surprise me very much that in negotiating the final wording of the rule, that this got incorporated for a large number of drugs already out there.
DR. SIEGEL:  Well, now, it should be noted -- please correct me if I'm wrong.  Dr. Weiss understands this a lot better than I and that may be why I'm more able to understand the confusion.
(Laughter.)
DR. SIEGEL:  Exclusivity is a law.  So, you could question whether or not Congress did the right thing and they're going to revisit it in a couple of years.  But to the extent that the company does something that meets the criteria in the law, they will get exclusivity.
Now, the agency in promulgating the rule recognizes that that law does not cover all the things that are needed and that financial incentives may not get all the things that are needed, so additionally provides for some requirements, not all of which necessarily have all the teeth that it might take to enforce it or all the carrots that it might take to enforce it, but that's how we come to this combination of approaches.
DR. SALOMON:  The concern I'd like to express is when you start applying this rule that you go overboard with it.  I was just on a site visit for a series of trials sponsored by the NIH, and I know it's not the FDA, but it's pertinent in that they put in the description of the RFA that it should be done in children too, which was to me the NIH's interpretation of the pediatric rule, for a complicated trial involving stem cell transplantation in patients with autoimmune disease.  And it was completely ridiculous to be doing this in kids, and it was entirely experimental.  But the people applying for the grants were being compliant with what had been put out in a federal document describing the RFA. 
So, my only point is that I think there's got to be an expert committee, and the FDA really needs to pay attention when the pediatric rule is necessary to be applied.  Otherwise, the other side of the coin here is you're going to force a lot of children to undergo experimental therapies.  It's inappropriate.
DR. WEISS:  I think there has to be a balance.  It's not an easy call to make.  But we're finding the same thing that you just outlined, Dr. Salomon, that we're in the position sometimes of saying to our companies, back off.  I think I'd like to have more safety data or I'd like to see how this performs in some of the adult settings first before I want you to go into pediatric patients.  So, it's a little bit of the shoe on the other foot from what we've had experience in in the past.  
Because there is the rule out there and everybody knows they're required to have these studies, but for something that's a me-too type of therapy, you might want to wait because you know that post-marketing you might see adverse events that haven't been determined or elicited in a smaller database pre-marketing.
DR. SCHWIETERMAN:  Dr. Salomon, I'd just like to add I think you raise a very good point.  It's another useful role of the many useful roles that I think these committees have.  In fact, this very issue has come up and I think we're very likely to bring it to a committee, probably the Arthritis Advisory Committee, supplemented with members of this committee, to discuss that because I think you're absolutely right.
MS. MEYERS:  It's an example of why politicians shouldn't do things involving medicine when they don't understand medicine.
(Laughter.)
DR. SALOMON:  They thought they were doing the right thing I'm sure and that's usual.
I was in a debate in Switzerland.  The guy was a politician; he was a senator.  And he said to me, when politicians have questions, they have to act.  And my only response was that I hoped that reasoning never got across the ocean.
(Laughter.)
DR. SALOMON:  Anyway, with that, unless there's anyone else with a really pressing comment, I'd like to thank everyone for the first part of the morning and take a 10-minute break and then we'll get started again.
(Recess.)
DR. SALOMON:  So, as we restart this session this morning, I'd like to introduce Dr. Hugh Auchincloss who's going to present the report of the Xenotransplantation Subcommittee which he chairs.  Dr. Auchincloss.
DR. AUCHINCLOSS:  So, what I'm doing is I'm bringing to you a report of a subcommittee of the Biological Response Modifiers Advisory Committee.  That subcommittee is the Xeno Subcommittee, or Xenotransplantation Subcommittee.
I should point out to you that Abbey Meyers was present as a member of that committee and your chairman, Dan Salomon, was a member of that committee.
And just to tell you about the report, following the meeting, I prepared a summary statement of what I thought had transpired.  That was circulated to all members of the committee and, in fact, many of the visitors as well for some clarifications and extra points which were added.  Then that report was approved by the subcommittee members, at least by a majority of them, and everybody who was a member of the committee had an opportunity to send in some additional comments.  We have one additional comment from Leroy Walters which is included with the document that you received, and I think Dan Salomon himself may want to make some additional comments as well.
Because you have had the document and had a chance to read it, I'm not going to read it in full.  What I want to do is give you the three-minute version and then answer questions, as much as you'd like, again for clarification.
There were essentially three areas for discussion.  The first was the FDA came to us and said, we have a lot of data that has been presented to us by various potential sponsors relative to the question of PERV infection of potential human recipients or in fact human recipients of animal tissues.  Can you help us to evaluate the data?
We looked at a large amount of data that, in sum, indicated that there was no evidence at this time that any human or non-human primate recipient of the xenograft had demonstrated evidence of an infection with porcine endogenous retrovirus.  So, that was the conclusion that the data suggested.
The question then became in the face of a large amount of negative data, how valuable, how reliable is that data, particularly in a situation where you don't have a positive control?  And so, a substantial amount of discussion took place in which experts who were members of the subcommittee suggested kinds of assays and improvements in assays that should be sought over time that would give us increased confidence that negative data was as reassuring as it seems on the surface to be and that those kinds of recommendations are included in my summary document.  So, that was question number one.
Question number two had to do with what I've termed a concept of relative risk.  In effect what the FDA said to us is we've set up a definition of xenotransplantation which is reasonably comprehensive, and it means that we've got a lot of regulating to do.  Can you point out some areas in xenotransplantation that are so unrisky that we might be able to be a little bit less stringent?  That's probably not the right word, but where the review process could perhaps be streamlined in some fashion.  
I would say that the subcommittee probably had trouble with that concept.  If the potential benefits of xenotransplantation were like this, our judgment about the real level of risk was something very small like this.  To try and make gradations of risk within this narrow band of very small risks didn't seem to us a particularly useful concept at this time.  That isn't to say that there aren't some forms of xenotransplantation that are more risky than others, but that the difference between them in the grand scale was too small.
I'm not sure that we have fully grappled with this larger issue.  There may, in fact, be forms of, quote, xenotransplantation that are encompassed by the definition in which the same types of review process and the application of the guidelines suggested by the FDA might not be fully required.  One example was that contact between human cells and those from invertebrate animal sources probably would not require the same degree of scrutiny, but even that point I think the subcommittee members ended up saying we're not terribly expert in that particular issue.
The third question that came to us was the FDA basically said we have a number of potential sponsors of solid organ xenotransplantation trials who are beginning to indicate that they are thinking about initiating clinical trials.  What they're asking us and, therefore, what we're asking you is, what do you expect to see in the way of preclinical data that would be thought of as reasonable as a basis for initiating clinical trials? 
There there was again a great deal of discussion, and I don't mean to suggest that there was any unanimity.  
First of all, let me make a point that I think is very important for clarification.  There are trials of clinical xenotransplantation being conducted at this time under supervision by the FDA that involve cellular transplants.  So, this conversation that we were having about preclinical data and how good should it be applied only to solid organ transplantation, effectively pig hearts, kidneys, or livers, and it really came down to kidneys or hearts that we were talking about.
In general, what the committee ended up saying was that data from non-human primate experiments is probably the best data that you're going to get.  It's an important set of data that you need.  It has some limitations, but it probably is the right model to be working with, and that frankly the results that we would expect to see in a non-human primate model should be pretty darned good and should be in the realm of what you would expect to see in human recipients before initiating clinical trials.
Again, I will not try to go through the wide range of opinions that were expressed by committee members -- and there were, indeed, a range of opinions -- because that's not so important to air here.  It's in the document.  I think the important thing was to air for the FDA and for the potential sponsors here's the kind of range of feeling that you will encounter when you come back to us with real proposals for clinical trials when you have a subcommittee or a committee of experts, somewhat like us, listening to your proposals.
So, Mr. Chairman, I think I'll stop there and basically respond to questions, and I believe you may want to make some additional comments as well.
DR. SALOMON:  Thank you, Hugh.
Essentially, as presented, I would think that was a very fair representation of what happened at the committee.  I think some of the interesting things that are challenges in these things came up during the committee discussions that I just wanted to add here.
One issue has been an assumption that cellular transplantation of xeno-derived tissue, specifically pig extracorporeal circulation, pig liver, extracorporeal circulation on whole livers and cells, use of fetal pig cells in mesencephalon transplants, that these which are now approved and ongoing clinical trials somehow represent less risk of transmission of porcine endogenous retroviral infections than the next major step that xenotransplantation will take, and that is of actual whole organ transplantation or eyelid transplantation.  
Based on a general approach, taking that as a starting assumption, there was then a lot of discussion about what was the quality of data in an animal model that would be required to justify clinical trials.  I would say that there are many of us in the field that, number one, don't necessarily accept this starting assumption, that we think that the risk of transmission of this endogenous retrovirus is as great with cellular transplants as it is with organ transplants or, I think as Dr. Auchincloss also did a very nice job, we can get into arguments that then come down to very small, incremental risks very difficult to quantify.
Should we move forward to clinical trials then became a major focus of the latter half of the subcommittee's discussion.  And it is true that in that subcommittee, the majority felt that we were not ready to move forward into clinical trials of organ transplants.  I just would like to point out in closing that there is a minority of that subcommittee, which obviously I represent, that does not agree with that position, and it would be a long discussion about the details of why.  I think Dr. Auchincloss has not gone into the details, and so I won't either.  But I think it's just important for the record that majority/minority -- does it really represent majority or the minority of the transplant community?  I'm certainly not in a position to speak to that today, but I think that overall I've already noted to Dr. Auchincloss privately that I think he did a very fair job in the report itself, showing that there was discussion.  I just wanted to highlight that there are some differences in opinion that will have to get sorted out over the next few years.
DR. SIEGEL:  I'd just like to rephrase the summary of the second point in a somewhat different language.
DR. AUCHINCLOSS:  Thank you.  I think it needs it.
DR. SIEGEL:  I didn't want to offend you.  I'm glad you welcome me to do that. 
The issue that we raised is really less one of graduation of risk and are there some things that are so low risk, but just that what we're seeing, particularly in the area of cellular therapies, is a broad spectrum of products with a broad spectrum of types of risks.  What we sought and, I think as Dr. Auchincloss acknowledges, began to receive in a process that undoubtedly will continue is guidance as to which of those factors are likely to make a difference and what sorts of differences they're likely to make, not to say that there are necessarily high or low risk factors, but that, for example, exposure of cells or use of an animal cell line may require different types of controls from use of fresh animal tissue.  
Certainly the many controls in our guidance document regarding veterinary care and feed records of source animals may be less critical regarding cell lines, and the committee indicated that, versus other controls that can be done in terms of studying cell lines for presence of adventitious issues.
And similarly issues such as vertebrate versus nonvertebrate species raising different issues that may for certain controls that we've recommended because of concerns about certain pathogens, be they, say, trions or retroviruses or herpesviruses, may well apply differently to different species.
We also discussed other issues such as duration of exposure, dose of exposure, use of barriers ex vivo and in vivo exposure around which I think the committee largely said, as summarized, that, well, in general there's not enough about any one of those to make a general comment that one could significantly lower guards or significant concerns on the basis of those issues.
DR. AUCHINCLOSS:  Thanks, Jay.  As soon as I used the word "stringency," I knew that I was in trouble because that clearly is not the point of this.  It was not a matter of lower degrees of stringency, it was a matter of are there different kinds of controls that should be in place.
Abbey, you were there also.  Would you like to any other -- 
MS. MEYERS:  Would you believe I have nothing to say?
(Laughter.)
DR. SALOMON:  No.  No, I don't actually.
(Laughter.)
DR. SALOMON:  That's why I'm looking at you incredulously here.
(Laughter.)
MS. MEYERS:  Actually I thought it was a terrific report.  It really was.  It was very accurate and very unbiased, and I thought it was terrific.
DR. SALOMON:  As I already said, I endorse that.  I also think it was fair.  Dr. Auchincloss and I routinely disagree.  We expect that from each other, and there has been a long record of that, collegially I hope.
With that, I'd like to call this committee to a vote on accepting the subcommittee report by Dr. Auchincloss.
DR. MILLER:  Second.
DR. SALOMON:  Second?
We have a vote.  Do we go around?  Okay.
Dr. Auchincloss, do you accept your own report?
(Laughter.)
DR. AUCHINCLOSS:  Yes.
DR. O'FALLON:  Yes.
DR. CHAMPLIN:  Yes.
DR. SAUSVILLE:  Yes.
DR. VOSE:  Yes.
DR. SALOMON:  Yes.
DR. BROUDY:  Yes.
MS. MEYERS:  Yes.
DR. MILLER:  Yes.
DR. SALOMON:  Dr. Goldsby?
DR. GOLDSBY:  Yes.
DR. SALOMON:  Yes.  Was that yes, Dr. Goldsby, or yes, you accept the report?
(No response.)
DR. SALOMON:  Well, as a triumph of technology, we'll accept that as a yes from Dr. Goldsby.
(Laughter.)
DR. SALOMON:  Then with that, I would say unanimously we've accepted the report.  Thank you very much, Dr. Auchincloss, for all the work.
DR. SIEGEL:  Not to interrupt that concept, which is what I wanted to add to, that I know for myself and many others in the agency that the written summary -- and I think for everyone at the meeting -- that we saw of that discussion that came from Dr. Auchincloss was one of the best summaries of an advisory committee meeting or, in fact, of any meeting that I've ever seen.  And what's more it issued within a day or two of the meeting.  I was totally flabbergasted, and I think that we really owe a great debt because those written summaries, as well as transcripts, are important reference documents for us to make sure that we can do our best to follow the advice of the committee.
DR. SALOMON:  I don't believe it's in my purview to vote a special commendation to Dr. Auchincloss ‑‑
(Laughter.)
DR. SALOMON:  -- at this point, but perhaps at the break you can inform me if I have that power.  But if I did, I would confirm it now from the chair.
Well, then the next thing that we're going to do is invite Dr. Zoon and Dr. Siegel to submit the presentation of certificates for retiring members.
DR. ZOON:  Well, this is one of the few pleasurable events we have at our advisory committee.
(Laughter.)
DR. ZOON:  And it's one that we look forward to which is special recognition and special thanks for those serving on our committee and the time and dedication that they have spent working on important public health issues.
I would just like to say that while this is a new tradition of giving certificates from the Center to our advisory committee, I think that it's one that has long reflected our appreciation for the hard work and the devotion that many of you do and we recognize for very little.  
We thank all the ongoing committee members and hope they keep staying with us, but also special thanks to those who have served.
I'm going to let Jay say a few words before we present the certificates to the departing members, but one, this has been a committee that has a very special place certainly for me.  I was there when this committee was first formed, and it's very impressive to see the evolution of this committee and the importance of this committee and the subcommittees that were created especially as we just finished discussing on the xenotransplantation issues.
So, I want to thank all of you very sincerely and special recognition for those who are leaving the committee today.
I'll ask Dr. Siegel to say a few words.
DR. SIEGEL:  I suspect that the politically correct thing to do would be to allow my boss to do this job, but she graciously consented to let me participate as well because I do feel extremely strongly about the value that your services and advice and contributions over the year have added to the process.  I wanted an opportunity to formally acknowledge that in a manner as I have hopefully done, although I'm sure inadequately to the way I feel, in many informal discussions and conversations. 
I would also like to say that in fact while often contentious and stressful, I almost always enjoy advisory committee meetings.  I think there is a lot of pleasurable experiences.  They're certainly, at the very least, intellectually challenging and stimulating.  I look forward to them.  There's always anxiety as to whether we'll get ready in time, but they are always interesting experiences.  As I've commented on many occasions, it beats working.
(Laughter.)
DR. SIEGEL:  So, we haven't exactly planned out the way we'll do this, but let me just say a couple of quick comments then about the individuals who are leaving the committee.
Abbey Meyers who has been our consumer representative, I think maybe the first one on this committee, and a tireless advocate always on behalf of good issues and good causes, somebody who, like most of our best committee members, has not been reluctant to speak her mind, not been reluctant to ask for explanations or information when needed, and to give opinions when needed, and whose input has been tremendously valuable.
Virginia Broudy, who has always been a sound voice of good scientific judgment and advice, of reason, a builder of consensus, somebody who has I think never made a comment that I wished hadn't been made --
(Laughter.)
DR. SIEGEL:  -- which occasionally happens, not that I'm the final arbiter of what are good comments or bad ones.
DR. ZOON:  You better stop there.
(Laughter.)
DR. SIEGEL:  What I mean to say has always made comments that have been extremely helpful and useful to the committee and to the agency.
And Julie Vose, who has worked several years as our Chair and before that as a member who was selected as Chair based in significant part on her performance as a member and who has as Chair I think -- Dan Salomon's comments are correct.  She's a wonderful role model for a Chair and has done an outstanding job of keeping the committee focused, of ensuring that we get the advice we need, and providing sound answers to questions, both her own answers and summaries of the consensus expressed by other committee members.
So, we have wonderful new people joining the committee.  I look forward to their contributions, but I must say that this also represents a significant loss.  We will, in fact, be asking each and every one of you from time to time to come back as consultants to continue to share your expertise with us.  And thank you.
DR. ZOON:  I just want to say once you've been on an FDA committee, you're never off.
(Laughter.)
DR. ZOON:  It's tradition.
Abbey, could you please come up?  Abbey, thank you very much.  We have a plaque and a letter of appreciation.
(Applause.)
DR. ZOON:  Virginia?  Thank you very much for all your service.
(Applause.)
DR. ZOON:  And certainly but not least, Julie, thank you.  It has been a pleasure.
(Applause.)
DR. SALOMON:  Miraculously we're basically five minutes off time, which is I guess good.
Well, then what I'd like to do is begin the third topic of today's meeting entitled Immune Reactions Against Therapeutic and Diagnostic Biological Products.  This will be introduced by Dr. Zoon in a talk entitled Immunogenicity of Therapeutic Proteins.
DR. ZOON:  This is an area that has a great deal of history and one which we would like to bring to this committee, one, to acquaint you with the issues and, second, to get your advice on a number of particular matters.  This deals with the immunogenicity of therapeutic proteins.
To start, why is immunogenicity an important property?  And it's important because it distinguishes many biological products for most small drug molecules.  As macro-molecules, often even those that have great similarity to naturally present proteins in the body, they present themselves in such a way to be immunogenic, and the consequences of this are something that we would like to share with you today as a result of our experience of at least a decade and a half on recombinant and DNA-derived proteins and monoclonals.  
But I think it's clear, as we look at this data, even from these new molecules that are currently used for therapy and diagnosis, that this is not an issue that was just a result of the biotechnology era.  Many of the issues that we have seen actually occurred in the pre-biotech era, going back to the earliest days of the 1900s looking at equine antitoxins and the fact that antibodies were raised against these causing serum sickness.
Initially other products, plasma-derived products, such as Factor VIII for hemophilia, was also an issue where antibodies were raised against these macromolecules, and in fact with natural Factor VIII derived from plasma, up to 30 percent of individuals treated had antibodies raised against this particular product.  Of those, about 18 percent had clinical significance and patients were actually changed to porcine immunoglobulin, to porcine Factor VIII.  
So, I think there is a history even with naturally derived products that we have in the experience from the past and ones again such as we've seen not only with Factor VIII but also with insulin where the presence of these antibodies could actually abrogate the biological response or clinical effectiveness of those particular molecules.  In addition, they could have adverse event consequences, such as immune complexes being formed that might have some clinical adverse events.
So, in the age of biotechnology and particularly early days of not only products such as insulin and growth hormone that we had experience with, but also products that you'll hear about in greater depth this morning, such as interferon and some of the monoclonal antibodies, have raised important clinical issues both from the efficacy issues surrounding the presence of the antibodies and their ability to neutralize the biological activity as well as some of the adverse events.
We actually have for you today a summary of all the major products that CBER regulates with respect to these.  Some of these products will be looked at in greater depth, and hopefully this will set the stage for the issues that we would like you to address.
While we're looking at a number of these particular areas, I would just like to say that this particular topic of the relevance of immunogenicity and immunotoxicity has been a question that has been raised and has waxed and waned in importance I would say over the past 15 to 20 years.  I think our experience of late, although the issues come and go, has raised a new particular attention to this, and I would like to particularly alert this committee that it's something that we have always been concerned about.  Although some of those concerns might have been theoretical in the past, our experience to date now has enough in our database to suggest that this is something we need to pay greater attention to.
Really the purpose of the presentations today will be to provide you an overview of the data that we have available, to serve as a basis for the discussion of issues in product development related to immunogenicity, and to provide background material for what I believe are important future discussions related to these products.
Clearly the issues to be discussed will include factors which contribute to immunogenicity, how these antibodies are measured and some of the important factors surrounding both the timing of measurement of the antibodies, as well as the methods themselves, the immune response data on a number of therapeutic products, and also their clinical implications.
The agenda for this morning will cover presentations related to antibodies by Dr. Kathryn Stein, a presentation on interferons by Joseph Bekisz, and a presentation on all the rest of the products by Amy Rosenberg.  I think it's very important to put this in the context of the whole, and while we have a great deal of experience with antibodies and interferon, some of the issues Amy is going to raise in her presentation actually raise a number of serious concerns.  And then it will finish up with a short presentation by Dr. Bill Schwieterman regarding the clinical issues.
We'll then go on and have the committee discuss the implications of these data looking specifically at assays, some of the preclinical models and development issues we'd like to see, some of the clinical development issues that we might want to look at, as well as product labeling and claims.
I think this will be a very fruitful discussion.  I myself am very interested in following this issue and working with the committee on this topic.  So, thank you very much.
Now, I'll ask Dr. Stein, if Dr. Salomon agrees.
DR. SALOMON:  Thank you, Dr. Zoon.
DR. STEIN:  Thank you very much and good morning to members of the committee and the audience.
This morning I'm going to discuss the immunogenicity of monoclonal antibody products.
Over the years, we've seen an evolution of monoclonal antibody products from entirely murine to entirely human antibodies.  In the evolution of these products, we've seen various combinations, including chimeric antibodies in which the variable region of the antibody is from the original murine source and the constant regions are from a human source, and more recently humanized antibodies in which only the complementarity determining regions, shown here as the purple stripes, responsible for the antibody specificity are derived from the original murine antibody and the rest of the molecule is human.  And then there are a variety of sources of human antibody, although to date we have less experience with fully human antibodies in the clinic than we do with chimeric or humanized antibodies.
Among the other products we regulate are bi-specific antibodies where half molecules of two different specificities are combined to form an entire antibody that sees two antigens, various fragments, recombinant fragments, or naturally derived Fab or Fab prime fragments.
This is a three-dimensional structure of an antibody molecule showing the two heavy chains in blue and red and the two light chains.  It shows that the antibody combining site is formed by the union of the hypervariable regions or complementarity-determining regions derived from both the heavy chain and the light chain.  This region confers the specificity of each antibody clone and thus each antibody has a unique site related to its specificity that has the potential to form an antigenic determinant.
Thus, antibodies are inherently immunogenic and each monoclonal antibody has the potential to be immunogenic.  These antibodies are unique.  They must be evaluated individually, and comparisons across antibody products for immunogenicity can be quite problematic.
The types of antibodies and the jargon associated with that are human anti-mouse antibodies, human anti-chimeric antibodies, and human anti-humanized, or anti-human antibody. 
Such antibodies can inhibit function, for example, anti-idiotypes that see the antigen combining site.  They can alter the bioavailability, either antibodies to the idiotype or to the Fc region.  They can also cause adverse events, again, both types of antibodies.
What contributes to the immunogenicity of antibody molecules?  Impurities can contribute, those derived from the cell substrate or media components that co-purify with the antibody.  They can be directly immunogenic.  They can act as an adjuvant.  There could also be product-related impurities such as fragments and aggregates that are more immunogenic than the intact molecule.
Modified antibodies such as conjugates of drugs, toxins, chelators, or antibody fusion products can have added immunogenicity due to the added substance, can create new antigenic determinants at the conjugation or fusion site, and antibody fragments, for example, Fab or Fab prime fragments, can expose new antigenic determinants.
Antibodies used as ancillary products, which may not be readily obvious in the final product, can also contribute immunogenicity.  For example, antibodies used to deplete cells either in solution or immobilized on some device can either leach off the device or remain bound to cells and be immunogenic, and antibodies used in affinity chromatography can leach off in the purification process of the final product.  We try to control for these as best we can, but in the case, for example, of cell depletion antibodies, there may be undetectable amounts of antibodies bound to a cell that later turn out to have been immunogenic.
The measurement of immunogenicity of antibodies is very critical, and it has a number of parameters and influences.  First, the detection assay.  The sensitivity and specificity of the assay is important and this will differ from product to product.  Again as I mentioned, comparison of immunogenicity across products can be very problematic because the sensitivity and specificity of the assay is not always known and it may differ widely from product to product.
For antibodies, there are HAMA, HACA, and HAHA antibodies that can be formed against, in the case of HAMA, species-specific antibodies for murine antibodies, antibodies to the class and subclass of the product, antibodies to polymorphic determinants in the constant region, the allotypic determinants, and as I mentioned, antibodies to the idiotype.  I would stress here again that all antibodies have idiotypic determinants and even fully human antibodies can be expected to have some immunogenicity related to the idiotypic determinant.
The measurement of antibodies to products are influenced by the timing of sample collection.  I think as you heard this morning from Centocor, the presence of circulating product itself may inhibit the assay that's used, and therefore measurements taken with high levels of circulating product may not be meaningful.  Many of the sponsors who are measuring HAMA, HACA, or HAHA antibodies use a sandwich type of assay where the product is immobilized on a plate, the product is labeled as a detection system, and they use the patient's serum to cross-link if antibodies to the product are present.  These type of assays can be very highly inhibited by the presence of circulating product and complexes.
There are also many clinical factors which influence the immunogenicity of antibodies.  For example, the patient population, the genetic background.  As I mentioned, constant regions of antibodies have allotypic determinants, and depending on the patient's genetic makeup, they may or may not make antibodies to the allotype.  This is a particular issue in the case of patients with rheumatoid arthritis who have preexisting rheumatoid factors which are IgM antibodies directed against IgG constant region determinants.  Autoimmune diseases where patients may be prone to make antibodies to a greater extent than patients without autoimmune diseases.
Preexisting antibodies not only of the rheumatoid factor but, for example, for antibody conjugates where a bacterial toxin may be coupled to an antibody, for example, diphtheria toxin.  Patients may have and usually will have preexisting antibodies to diphtheria toxin, and those will be on board prior to treatment.
Intercurrent illnesses that disrupt the distribution of proteins, for example, kidney and liver disease, may contribute to the immunogenicity of a product and disruption of the blood/brain barrier may affect immunogenicity as well and the consequences of antibody formation.
Concomitant medications are an important consideration.  Chemotherapy will suppress the ability of a patient to make antibodies, and immunosuppressant drugs even when given with products, as you'll see with OKT3, can have effects or not have effects.  A highly immunogenic antibody such as OKT3 is still immunogenic in the face of immunosuppressive therapy; whereas, you heard this morning from Centocor, their antibody product given with methotrexate had lower immunogenicity than without methotrexate.
Generally, immunogenicity increases with dose and frequency of administration, but there may be exceptions.  And we've seen some indications of high dose tolerance; that is, very large amounts of antibodies and given for a long period of time may be less immunogenic than lower doses.  We heard some of that from Centocor as well about different doses of their product.  Their talk this morning really set the stage for this discussion.
The route of administration is also a potential contributor toward immunogenicity.  In general, subcutaneous routes are more immunogenic than intramuscular or intravenous, but we don't have a lot of solid data on that.
What are the consequences of antibody formation?  First of all, they can limit the usefulness of preclinical animal studies.  Even in non-human primates and even including chimps, human or humanized antibodies can be immunogenic.  So, starting with the most closely related species to humans, you can still have problems related to the immunogenicity, and that will limit the interpretation of PK bioavailability and also will confound the safety data.
Antibodies can affect the bioavailability of a product both by increasing and decreasing.  For example, an Fab product, for which an antibody is present, will effectively be increased in size.  A whole antibody directed against the Fab will increase the size of the Fab and therefore increase its bioavailability.  Antibodies can also decrease the availability of an antibody by increasing the clearance.
There can also be changes in the initial volume of distribution at the first time point due to removal of complexes from the circulation, and so the timing of sampling is very important.
Antibodies can cause loss of effectiveness neutralizing antibodies, in particular anti-idiotypic antibodies.  However, antibodies to the constant region where an effector function is important for the function, for example, ADCC, could also have effects on the effectiveness of the antibody.
We are, of course, concerned about adverse events that are related to antibody formation:  injection site reactions, systemic reactions which range from mild to life-threatening anaphylaxis.
If you have antibodies on board, it can limit the utility of another monoclonal antibody of the same species.
It also has the potential to interfere with monoclonal based diagnostic tests.  This is particularly true for murine antibodies where many diagnostic tests, particularly for cancer antigens, are murine monoclonal antibody based.
I'd now like to turn to the reported data that we have on immune responses to murine chimeric and humanized monoclonal antibodies and again would like to caution that comparisons across products are fraught with problems.  So, what we're going to look at is the data reported for a given product with the assay used by the company during their clinical trials.  I've separated them by species or by type of antibody.
So, the first is murine monoclonal antibodies.  You may not be able to read all this, but these are the licensed products going from OKT3, which is the first licensed murine monoclonal, which is an anti-CD3.  It's an IgG2a kappa and it's a whole molecule.
Another whole molecule, the other whole murine antibody, is Oncoscint, which is an antibody to TAG 72.  This is an IgG1 kappa.
Both of these antibodies have shown antibody formation in a high proportion of patients, over 80 percent in the case of OKT3 which is given over multiple days in the presence of immunosuppressive drugs and Oncoscint which is given once and has been reported to be immunogenic in 55 percent of patients.
The other murine antibodies are Fab prime fragments or Fab fragments, and the reported immunogenicity ranges from less than 1 percent for CEA-scan to 6 percent for Verluma.
Now, in general and as expected, murine antibodies are much more highly immunogenic than either chimeric or humanized, and I think you'll see on the next two slides that there's really very little difference in immunogenicity between the chimeric and the humanized antibodies in contrast to the whole antibodies that you see of the murine species.
Now, what you'll see on the next slides is that most of those antibodies are in fact whole antibodies and given multiple times for therapeutic as opposed to diagnostic reasons.  They show immunogenicity in the low range comparable to the one-time use of murine Fab fragments.
These are the chimeric antibodies:  ReoPro, which you heard about earlier this morning; Rituxan, Simulect, and Remicade, which you also heard about.  They're IgG1 kappa antibodies.  ReoPro is an Fab fragment.  The others are whole antibodies.  The reported immunogenicity ranges from less 1 percent to 13 percent.
Humanized antibodies.  We have three licensed products.  Zenapax, which is an anti-IL-2 receptor.  This is an IgG1 kappa.  Synagis, an anti-RSV, an IgG1 kappa, and Herceptin, an antibody to the HER-2/neu receptor.  This is also an IgG1 kappa.  The immunogenicity reported for these antibodies ranges from less than .1 percent to 8 percent.  These antibodies -- the 8 percent directed at the Zenapax antibody -- are anti-idiotypic antibodies, as might be expected for a humanized antibody.
We've also seen some unusual reactions.  You heard some reference made to Remicade earlier.  In a small group of patients who were treated 2 to 4 years after their initial treatment with Remicade, 10 of 40 patients had delayed reactions 3 to 12 days following readministration.  These were serious reactions consisting of myalgia, rash, fever, polyarthralgia and some other symptoms in a smaller number of patients.  This may be an unusual situation because of the long interval, but it's something that we must consider in evaluation of other products and what happens with a patient who has been untreated for a long period of time. 
DR. CHAMPLIN:  (Inaudible.)
DR. STEIN:  Yes.
MS. MEYERS:  What did you say?
DR. CHAMPLIN:  I just asked if it was a serum sickness-like syndrome with antibodies to the antibody.
DR. STEIN:  Yes.  The answer is yes.
We also saw some reactions with Enbrel which is not a monoclonal antibody intact entirely, but it's a soluble TNF receptor fused to the constant region, the Fc region of an antibody.  For this product, some recall injection site reactions were seen consisting primarily of redness at the site of a previous injection in 15 of 213 patients studied in a controlled trial.  This was most prevalent during the first or second months of treatment, but not subsequent months.
So, what are the issues that we have to deal with?  I have these listed as issues for the future, but they're really ongoing issues with regard to the potential for immunogenicity of antibodies.
We're seeing more and more therapeutic antibodies.  In fact, most of the antibodies we see now in clinical trials are for treatment, and many of those are for treatment of chronic diseases.  As I mentioned, even fully humanized antibodies may be expected to be immunogenic in the idiotypic region, and so this is an issue that we need to be concerned about and to gather more data.
We have made an effort in the Division of Monoclonal Antibodies and other divisions in the Office of Therapeutics to encourage sponsors -- and I guess throughout the Center -- to remove all animal and human-derived, blood-derived products from their process of manufacturing.  Although we don't have any specific data to date that any immunogenicity is directly attributable to approaching contaminant from media or cell substrate proteins, we think this is an issue that must be kept in mind not only for immunogenicity considerations, but also transmission of infectious agents that may be associated with these products.
Finally, we do have new methods of production of antibodies including phage display libraries.  With this technology, we can expect to see new combinations of heavy and light chains or new idiotypes that are not found in the repertoire due to the way this technology is employed.  There are many rounds of antigen selection from these phage display antibodies, and any combination of heavy and light chains that happens to bind antigen might be selected even though it might not normally be expressed in the repertoire.
Finally on this list, we are seeing production of antibodies in plants which is a relatively new technology.  Plants, as I'm sure you're aware, have unusual sugars.  We don't know whether this is going to have an effect on the immunogenicity of antibodies, but it may very well and this is something that we need to pay attention to.
I think I'm going to stop there.
DR. SALOMON:  When we discussed how we were going to present this, the idea was that if anyone had a specific question of the speaker, so specifically on what Dr. Stein has just presented, that we'll go ahead and take a couple questions with the idea of not generating discussion, but mainly making sure that everyone, when it was fresh in our minds, was clear on what had been presented and save discussion issues.  So, let me open it for that.
Dr. Auchincloss.
DR. AUCHINCLOSS:  Well, this issue of comparing products -- and let me just give you one example from your two slides, and you can tell me whether they're real differences or not.  Under the chimeric monoclonal antibodies, you have Simulect anti-IL-2 receptor with evidence of less than 1 percent frequency of antibody responses.  And then under humanized monoclonal antibodies, you had Zenapax with an 8 percent incidence.  
Do you believe that those differences are real?  Do you have an explanation for why in that case the humanized antibody to the same receptor should have such a high rate of antibody, or do you think it's just assay differences?  Or how do we explain that?
DR. STEIN:  Well, let me answer the last part first which is because it's an anti-idiotypic antibody, theoretically a human idiotype or a humanized idiotype could be more or less immunogenic.  It really depends on the primary sequence of the CDRs.  We know that there are many species conserved residues in those regions, and so I don't think it's possible to predict that humanized antibodies or even fully human antibodies will be necessarily less immunogenic than chimeric ones.  
I think if you look at the numbers across those two slides, I don't think we can say that any of those are significantly different from others.  We don't have the data comparing these products side by side in a single laboratory, and as I mentioned, because antibodies are unique and you have to have the specific product to measure anti-idiotypic antibodies, it's really impossible to compare.  
So, I would say that comparing all the products -- the only thing that we can say is that whole antibody of a murine origin is far more immunogenic than chimeric or humanized antibodies.  I think beyond that, it would be a real stretch to say that there were any significant differences.
Also to go further and just allude a little bit to the discussion coming up later, we would not allow comparisons in advertising of those types of differences.
DR. AUCHINCLOSS:  Well, I know that's where you're going, and so that's what I'm trying to figure out here.  You do not believe that there's a difference between less than 1 percent and 8 percent frequency.
DR. STEIN:  I think we don't have the data to know that.
DR. SALOMON:  Dr. O'Fallon?
DR. O'FALLON:  My question pertains to your statement that specificity and sensitivity are important.  Specificity and sensitivity could relate directly to the question that Hugh just asked.  If the specificity of two different assays is different, you're going to have quite different results and the difference between 8 percent and 1 percent could be due completely to specificity.  
So, you must have hundreds of different assays here.  Do you have data about the sensitivity and specificity of these assays?  I don't need an answer, but I think in our discussion that's going to be a very important concept that has to be discussed.
DR. STEIN:  The assay for HAMA, HACA, or HAHA is something that is reviewed by the product reviewer for each product.  We encourage as sensitive an assay as possible with appropriate specificities; that is, not only should the assay be able to detect class and subclass specific antibodies, but the assay should be able to detect anti-idiotypic antibodies.  Beyond that, we just don't have comparative data, and again because idiotypic assays would have to be unique to the product, it may be impossible.
We could develop standards of some sort that would translate back to micrograms per ml of antibodies, and that may be something that should be done.  We just don't have that kind of comparative data.  But all of these differences in specificity and sensitivity could contribute to differences in the results.
DR. SALOMON:  Dr. Broudy?
DR. BROUDY:  I think one very important point is not just what percent have HACA or HAMA, but what is the effect of the HACA or HAMA on the biological effect of the therapeutic antibody product.  That comes up, for example, very well in Factor VIII where 30 percent have antibodies and a small percent have antibodies that are neutralizing and then the patient has tremendous bleeding problems due to their anti-Factor VIII antibodies.  So, in addition to just the percent that have the HACA or HAMA, we'd like to know how does that impact the therapeutic efficacy of the infused antibody product.  And that must be known, for example, for OKT3.
DR. STEIN:  For OKT3, there was a report in 1991 which surveyed all of the studies where titers in excess of 1 to 1,000 were associated with loss of effectiveness.  But I think in many of the other cases, we don't know that a particular adverse event or loss of effectiveness is associated with these antibodies, and I think that's a problem that we have to face.  And even for some of these antibodies, I think it's fair to say we don't know the exact mechanism of action, so we don't have very good assays to measure that. 
DR. SALOMON:  Dr. Vose?
DR. VOSE:  I just want to say I think that's a very important point, that we shouldn't automatically assume that these antibodies dictate and therefore describe that the patient won't have a benefit, and that for each individual specificity, we need to really try to take that into consideration, so that we shouldn't just try and put that in every antibody.
DR. STEIN:  Right.  I think particularly for new products, but for those existing products, it's very important to know what the antibody status of the patient is.  I think in many instances for imaging agents, we've seen loss of the ability to image a patient a second time even though the product may be indicated for single use.  If a patient is re-imaged and has a HAMA titer, you may lose the ability to image with that antibody.  So, there are some instances where we may have a better idea of the effects than others, but in most cases we don't really know to what to attribute this.
DR. SAUSVILLE:  And with that specific example, also to follow on on Dr. Vose's comment, the dose of administered material becomes variable because a given titer might have more import if you're giving a very small amount of the labeled product as opposed to milligrams and milligrams of a therapeutic product.  So, I think that's a factor also.
DR. STEIN:  It certainly is.
DR. SALOMON:  Again, I think these are all great discussion points.  We will return to these really and try and focus on them to answer the FDA's questions. 
I'd like to also put on the table for later discussion the whole idea of showing that there's an antibody against a biologic is one thing, but we haven't talked about showing what that antibody is against since these preparations are often contaminated by fragments of the proteins, aggregates of the proteins.  These may, indeed, be more immunogenic than the intact properly natured form of the protein itself.  I think the implications of that and where we think about where we should look at specificity and how that applies on what the sponsor does in terms of production control I think is another unique element of the biologics.  I hope we'll return to that one as well.
DR. STEIN:  One thing that I didn't mention today and primarily because it's a large issue in and of itself, but proteins undergo post-translational modifications.  You lose amino groups, so there's deamidation.  There are oxidations of methionines.  There's decarboxylation and there are a variety of other modifications that could contribute to immunogenicity.  And that's a three-day symposium I think, so I didn't get into that.  But one should be aware that these are other possible causes of immunogenicity.
DR. SALOMON:  Well, we've got a rich number of topics to discuss later.  Thank you very much.
I'd like to introduce Joseph Bekisz to discuss the immunogenicity of interferons.
DR. BEKISZ:  Good afternoon.  I'm going to be discussing the immunogenicity of interferons.  I am going to discuss some important issues associated with the formation and detection of anti-interferon antibodies, give an overview of the eight CBER licensed interferons, and discuss a few ongoing issues.  But I will begin with some background information on the three types of interferons.
To begin with, interferon alpha.  Its actions are antiviral, antiproliferative, and immunomodulatory.  There can either be 165 or 166 amino acids.  This is because in some interferon alpha subtypes there is an extra amino acid at position 44.  There are two disulfide bonds, one between positions 1 and 98 or 99, depending upon the size of the subtype, and between positions 29 and 138 which has been found to be essential for biological activity.
Interferon alpha is unique in that it consists of a family of at least 13 subtypes encoded for by 13 functional interferon alpha genes which show 70 percent homology.  It contains one potential N-linked glycosylation site and there are 30 percent homology in amino acid structure to interferon beta.
Interferon beta.  Again its actions are antiviral, antiproliferative, and immunomodulatory.  There's only one interferon beta gene.  The molecule has 166 amino acids with one glycosylation site.  We see one disulfide bond between amino acid positions 31 and 141, and this has been found to be necessary for biological activity.  Its sources are fibroblasts and some epithelial cells.
Interferon gamma again has the same actions as interferons alpha and beta, but its antiviral and antiproliferative activities are less than that in interferon alpha and beta.  Interferon gamma is involved in virtually all immune and inflammatory responses, for example, activation growth and differentiation of T- and B-cells.  It has 143 amino acids with no disulfide bonds and two glycosylation sites.  There is no or very little homology with interferon alpha and beta.
It should be mentioned in discussing interferon alpha, beta, and gamma that interferon alpha and beta show the same receptor, whereas interferon gamma has its own receptor.
Types of interferon antibodies.  There are binding antibodies which have been found to be IgM and IgG, and for detection of these particular antibodies, we see at least two different in vitro assays, an ELISA, which is an enzyme linked assay, and an IRMA, which is an immunoradiometric assay.  
In neutralizing antibodies, they are usually IgG and they are directed against the biologically active or antiviral site of the interferon molecule.  They are detected by a cytopathic effect assay.  Interferon has the ability to protect cells against viral challenge.  If there is a neutralizing antibody in patient's sera and it's mixed with the interferon, that activity is neutralized.
With respect to preexisting antibodies, these are not usually seen or seen at very low titers in healthy individuals, but they are seen in some cancer patients and in some patients with viral diseases, specifically in HIV patients.
The important issues which should be considered in discussing antibody formation and detection are route of administration, patient population, dosing regimen, cumulative dose, and dosing duration, the disease in question, the product characteristics, and the assay methodology used to detect both binding and neutralizing antibodies.
The route of administration.  As Dr. Stein mentioned, it's also seen with interferons that seroconversion is more frequent with patients who receive interferon by the subcutaneous route compared to patients who receive IV infusion.
With respect to patient population, there doesn't appear to be any correlation between sex and age.  There has been a suggestion that there is a correlation to ethnic origin, but the important point, obviously, here is immune status.  If a patient is immunosuppressed, that is something that obviously must be considered when analyzing the numbers that we see.
The dosing regimen and cumulative dose, duration of treatment.  In this particular study, what is seen, and what has been reported elsewhere, is that the higher cumulative dose is associated with a lower neutralizing antibody formation.  Here in the first treatment, the cumulative dose is between 504 million and 524 million units which translates to 2.5 milligrams.  The percent neutralizing activity is 13 percent.  The cumulative dose in the second two treatments are exactly the same.  There is a slight difference in neutralizing antibody activity which may or may not be associated with the different regimen.  There is not a great deal of data out there, but the one thing that has been purported by a number of individuals is that there was a correlation between the cumulative dose and the percent neutralizing antibody formation.
The disease itself.  As you will see in a later slides, there are a number of indications for interferon ranging from hairy cell leukemia, hepatitis C, Kaposi's sarcoma.  In general, the higher antibody titers are seen in patients with infectious diseases compared to cancer patients.  This may have something to do with the fact that in a number of instances cancer patients are immunosuppressed to begin with, but direct comparisons are difficult due to the number of variables that we're discussing here:  patient population, dosing regimen, and so forth.
With respect to product characteristics, in mouse models anyway, oxidation my increase immunogenicity.  The reason for this has been purported to be that oxidation leads to aggregation of the interferon resulting in interferon interferon aggregates or, depending upon the formulation of the interferon, if there's HSA present, leading to interferon HSA aggregates as well.
It has also been noted that contamination with certain altered forms may enhance immunogenicity.  By altered forms, I'm referring to acetylated forms of interferon, and there are some altered forms of interferon which only contain -- like for example, an interferon alpha which has two disulfide bonds, an altered form might be an interferon which has only one disulfide bridge.  Both have been shown to increase immunogenicity.
The assay methodology that's used.  The frequency of antibody detection is higher with the immunoassay compared to the neutralization assay.  This is because the immunoassay, whether it be an ELISA or IRMA or radioimmune assay, will detect both neutralizing antibodies and binding antibodies.  The way things are done normally in a test, the patient's sera is screened using an in vitro assay like ELISA.  If there are positives, then the patient's sera is put into a neutralization assay to determine the amount of neutralizing antibody that has been formed.
The next four slides are eight licensed interferons.  The first two on this slide are both recombinant interferon alpha.  Intron-A is interferon alpha 2b.  Roferon is interferon alpha 2a.  They are both recombinant, as I said, made in E. coli.  They differ only by one amino acid.  The indications for Intron range from hairy cell leukemia, where 0 percent neutralizing antibody response is reported, to 13 percent for chronic hepatitis C.  There are three different routes of administration for Intron, IM, SC, and IV, and only IM is used for Roferon.
Continuing with the interferon alphas, the first two, Alferon and Wellferon, are both natural products.  One is leukocyte interferon and one is lymphoblastoid.  Their indications are condyloma acuminata and chronic hepatitis C.  There is no neutralizing antibody response for the leukocyte interferon.  For Wellferon, which has just been recently licensed, a 6.7 percent neutralizing antibody response is reported.  For Infergen, which is consensus interferon, which is indicated for chronic hepatitis and given subQ, there is no neutralizing antibody data for this, only binding antibody data, which is reported as being 15 percent.
The beta interferons, Betaseron and Avonex, interferon beta 1b and interferon beta 1a, both are indicated for the treatment of multiple sclerosis.  The difference here that you see is in route of administration.  One is given subcutaneously.  One is given IM.  But there is a difference in neutralizing antibody response, with Betaseron giving 45 percent and Avonex 15 percent neutralizing antibody response.
Actimmune, the only licensed interferon gamma 1b, is indicated for the treatment of chronic granulomatous disease given subQ, and there is no antibody response here.
With respect to ongoing issues, treatment in the face of antibodies, obviously by definition, neutralizing antibodies neutralize the activity of interferon.  Binding antibodies may affect or be associated with the bioavailability of the interferon.  So, it's an issue that must be addressed.  
In most studies that are done, there's a predetermined time that the patients on the study are going to be given interferon.  They determined at the end of the study or through the study how much, if any, binding and/or neutralizing antibodies are formed.  
One point of interest is a study that was done by Dr. Ron Styce and colleague at NCI a few years ago.  He decided to take a look at the antibody response in patients who were on interferon therapy for a long term.  He found that of 35 patients tested, 16 when they went into the study, patients were given interferon up to 2 weeks before entering the study.  After that time, they were tested on a weekly basis for both binding and neutralizing antibodies.  16 patients did not develop any antibody at all, and they remained so.  9 developed non-neutralizing antibody and lost it over a period of 14.5 months, and 10 patients who developed neutralizing antibody, 3 became negative, 5 developed non-neutralizing antibody, and 2 retained their neutralizing antibody.  This is something that is very interesting because it was something that was not really looked into before.  Patients were on a study for a particular length of time.  It was decided how much antibody they were making, and that was it.
One other thing that was determined in this particular study is that the neutralizing antibodies that were formed were specific for the antibody that was given, which in this case was recombinant interferon alpha 2a, which leads into the next point.
I would like to discuss this recombinant interferon alpha followed by natural interferon alpha.  
Patients who became nonresponders after treatment with recombinant interferon alpha -- it has been found that when they were given a second course of natural interferon alpha, they became responders.  This was also a study done with interferon alpha 2a and the natural interferon that was used was leukocyte interferon.
I think, given all the variables that have been mentioned, it's obvious that standardization of assay methods is something that must strongly be considered.  Obviously there are certain things here that we can control.  One of the things that we can control is an assay method.  Ever since antibodies to interferon was first described in 1981, the numbers in studies have varied tremendously, and people have been looking for a gold standard to use for assays both for binding antibodies and neutralizing antibodies for some time.  This is something that's difficult, but it's something that really must be considered because, for example, even in a neutralization assay, all else being held constant, if the cell line in the cell/virus combination that's used in the assay is changed, the numbers can be affected dramatically.
The last issue is pegylated interferon.  This is interferon with a polyethylene glycol moiety, chemical modification.  It has been shown that addition of this moiety will increase the circulating half-life by two fold of the interferon in the system.  It's also been suggested that this will decrease the immunogenicity of the interferon.
This particular area of study of anti-interferon antibodies has been going on, like I said, since they were first described.  It's something that's continuing.  But I believe, to reiterate, that standardization is something that we really must look into further because the numbers that you saw -- it is a difficult thing to compare basically between the interferon alphas when we don't have a standardized assay method to consider.
I think I'll stop there.  Thank you.
DR. SALOMON:  Thank you.
I actually wanted to start by asking one question.  You've already somewhat addressed it just in that last slide.  When you get neutralizing antibodies against a biologic, one of the concerns I have is if in some patients we're giving a biologic that also is a natural product, we're just giving more.  The interferon is actually a pretty good example, but there are others, of course, like the colony stimulating factors, GM-CSF, G-CSF, et cetera, erythropoietin. 
So, in the case in which you're getting neutralizing anti-interferon antibodies, has anyone looked to see whether or not that is also neutralizing natural occurring interferon?  Now, your last slide you did kind of give one piece of that answer.  Right?
DR. BEKISZ:  It has been shown that recombinant interferon alpha 2a and 2b in neutralization assays cross-react, but there is no cross-reactivity with natural interferon alphas in anything I've seen.  This even comes from our laboratory.  We've done it ourselves and seen no cross-reactivity with natural interferon alpha.
DR. SALOMON:  Yes, Dr. Broudy.
DR. BROUDY:  I think the point that our Chairman was just making is a very important point because particularly in the area of the colony stimulating factors, for example, thrombopoietin in which you give an exogenous agent and then you get an exogenous agent which cross-reacts with the native thrombopoietin, then the patient's platelet counts drop.  So, this is one of the other dangers, is not just that you will lose the biological activity of your administered product, but you then may drop out temporarily or long term the activity of your native protein.  I guess that's one of the major concerns that I have for this.
DR. SALOMON:  Dr. Zoon.
DR. ZOON:  Just to follow up what Mr. Bekisz said, in our studies, looking at human lymphoblastoid interferon, we have done a study where we had obtained serum from the patients that were antibody positive after being treated with interferon alpha 2a or alpha 2b.  What we looked at is the binding to the different interferon subtypes.  As Mr. Bekisz said, there are over 13 functional genes, and we've been able to isolate 21 components of interferon alpha from a natural preparation.
If you look at the cross-reactivity of the antibody raised against the recombinant interferon against each of the subtypes using a binding assay, you will find that there's a differential binding to the different alpha subtypes, and depending on the patient's serum, you won't see the same pattern each time they bind.  So, whatever the response is, it doesn't appear to be to a particular epitope on the interferon.  In fact, when you look at the cross-reactivity, it seems to be somewhat patient-specific.
DR. SALOMON:  But the data you have, Kathy, I guess could be interpreted saying that, indeed, you are getting antibodies that are cross-reactive with natural forms of the molecule.
DR. ZOON:  Yes.
DR. SALOMON:  And it could be different from patient to patient, but that won't do the patient any good.  Right?
DR. ZOON:  Right.  Joe was primarily speaking about neutralizing activity, where I was talking about binding to ELISA plates.  It is very difficult to see neutralization, especially if you're only doing a subfraction of a larger whole, even if some of them reacted.  There may be some that neutralize some of the natural.  It's just the sensitivity of that assay probably isn't enough to pick it up.
DR. BROUDY:  Just one other question.  You presented the data on the 35 patients that were treated with interferon and then followed sequentially.
DR. BEKISZ:  Yes.
DR. BROUDY:  And in many of them, their neutralizing antibodies went away or became non-neutralizing antibodies.  But I guess I'd just like to make the point that what would you expect to happen if you rechallenge the patient then with the interferon.  Would you like to comment on that?  Or perhaps should I address this comment to you?
DR. SIEGEL:  Those studies were in the face of continuing treatment.
DR. BROUDY:  Oh, these were getting ongoing treatment.  Oh, I thought you treated them and then watched what -- because I guess I would have expected that the titers would then go up again.
DR. SIEGEL:  They went down.
DR. BEKISZ:  Oh, I'm sorry.  I mustn't have been clear.  No, this was an ongoing treatment.
DR. SIEGEL:  But another aspect of that question that we don't have a lot of data bearing is what might happen if you interrupted and restarted treatment.  There are some data that might suggest -- and this is involved in one of the questions -- that interruption and restarting treatment may raise concerns, or intermittent treatment may be more immunogenic than continuous chronic treatment.
DR. SALOMON:  Dr. Champlin?
DR. CHAMPLIN:  I was just going to comment that in a system with a lot of redundancy like interferons, if you neutralize one of your 14 interferons, you probably won't lose much, as opposed to a thrombopoietin where it's a single gain system, and you lose that and you have a major problem. 
DR. SALOMON:  I had one question and that was what's an IRMA, an immunoradiometric assay.
DR. BEKISZ:  Immunoradiometric assay.
DR. SALOMON:  Yes.  What is that?
DR. BEKISZ:  It is, to the best of my knowledge, the antigen is -- like for example, in an ELISA, you would coat the plate with your antigen.  You come back with the patient's sera, and instead of an ELISA where you would have an antigen to human IgG or human IgM, which is bound to an ELISA, this is tagged.  This is hot with radionuclide, and it's just read that way.
DR. SALOMON:  Oh, okay.  I had this idea that it was like adding antibody to a cell culture and looking at a CTL effect.
DR. ZOON:  It's radiolabeled NK-2 monoclonal antibody. 
I just want to make one other point.  There's very little literature available in looking at the impact of neutralizing antibodies on patient treatment.  There is one study by Peter von Wushoff where he was treating CML patients with interferon alpha 2b.  The patients that developed high titer neutralizing antibodies had an abrogation of the biological response so that they didn't respond.  When he switched them to natural interferon, they responded again.  Thus again, while there might be some cross-reactivity with some of the natural forms, at least the ones that weren't neutralized were still able to maintain the biological response.
DR. SALOMON:  I think that's a very good start to this afternoon's session.  Just so the committee knows, I guess there's a balcony area, as usual, reserved down in the cafeteria downstairs or the restaurant downstairs.  We'll be back at 1:30 for resuming the session.  Thank you.
(Whereupon, at 12:41 p.m., the committee was recessed, to reconvene at 1:30 p.m., this same day.)

	AFTERNOON SESSION
	(1:45 p.m.)
DR. SALOMON:  Well, welcome back, everybody, from lunch.  What I'd like to do is start again. 
I remind everybody we're doing topic III, Immune Reactions Against Therapeutic and Diagnostic Biological Products.  I think we've got the discussion off to a pretty good start.  Let's see if we can continue that momentum.
Dr. Rosenberg is our next speaker, and the title of her talk is Immunogenicity of Other Therapeutic Proteins which, as promised by Dr. Zoon, is all other proteins. 
(Laughter.)
DR. ROSENBERG:  Good afternoon, everyone.  I've been asked, as you've heard, to present the spectrum of immunogenicity of other therapeutic proteins. 
I encourage people to move to the front because of the encyclopedic nature of this presentation.  Some of the slides are rather small.
So, before I begin this talk, I just want to introduce some caveats.  I'm not going to talk about immune responses to cell and gene therapies.  This will be a separate topic taken up in greater detail in subsequent presentations. 
The other caveat is that with all of these discussions of immunogenicity, immunogenicity is really defined exclusively by detection of circulating antibody.  And the sensitivity of such assays may be low. 
So, with regard to the spectrum of immune responses to biological therapeutics, it ranges basically from no apparent immune response, again limited by the sensitivity of assays -- I, unfortunately, don't have a lot of information on assay sensitivity -- to generation of antibodies which are binding but not neutralizing, to generation of antibodies which are in fact neutralizing and, in fact, to generation of neutralizing antibodies that cross-react on the endogenous factor.  The discussion just before lunch actually anticipated many of the issues that I'll discuss.
The detection of antibodies that cross-react on the endogenous factor is primarily determined by either detecting by a direct analysis taking the natural product and looking for binding in vitro or by effects in vivo, that is, the symptoms of a factor deficiency, of the cell loss, et cetera.
The non-antigen-specific immune type of responses that, for instance, we saw with stem cell factor and was presented in great detail will not be covered today.
So, factors that may impact on the detection of immunogenicity:  basically the type and sensitivity of the assay.  So, for instance, assessment of serum antibody, which is what is almost universally performed, is not necessarily as sensitive as an ELISPOT or a plaque-type forming assay.  In some studies from our Center, the ELISPOT assay was shown to be 200-fold more sensitive in detecting antibodies than a serum assessment.
One questions whether assessment of T helper cell activity may be of use and will it be more sensitive while retaining specificity.  I think that with regard to that, because T-cells are necessary in inducing immune responses, in inducing antibody responses, one may actually be able to detect by, for instance, cytokine release assays the activation of T-cells.  So, in this regard, although T‑cells and B-cells here shown by an APC here with surface immunoglobulin, basically collaboration is required between T-cells and B-cells to produce at least an IgG response.
However, T-cells and B-cells see very different portions or parts of a biological therapeutic, and this has very interesting implications for their contributions to an immune response.  So, the surface immunoglobulin receptor on B-cells can see portions of the native protein, so portions of the intact biological agent.  Whereas, T-cells, as shown by the green peptide fragment that's encased within the MHC molecule here, only see peptide fragments of the biological therapeutic; so that whereas B-cells are then theoretically able to neutralize the activity of a therapeutic protein either by direct binding through its surface immunoglobulin or through the generation of antibodies, T-cells, which see the peptide fragments are not able to do so.
However, an interesting implication of the specificity and the recognition requirements for T-cells is that T-cells may actually participate further in generation of immune responses by destroying cells that take up the biological therapeutic and process and present peptides in association with cell MHC.  I think this hasn't been looked for, and I think it is of interest.  So, whether this occurs by receptor mediated endocytosis of a cytokine molecule or just by other mechanisms, cells that are targeted by a biological therapeutic may be susceptible to destruction by T-cells.
With regard to the second point, the detection of cross-reactivity on endogenous factor, by looking for effects in vivo, I think it was mentioned here that this in large part depends on the extent to which the biological activity mediated by that factor is mediated by other endogenous factors.  So, in the case of interferon alphas where you have maybe 21 species, the loss of 1 is not going to necessarily be detected by just looking in vivo.  In the case of other molecules, which are either primary or solely responsible for maintenance of a cellular level, the loss of that will be picked up very rapidly by assessment of activity in vivo.
So, many factors that impact on immunogenicity have been discussed and I won't repeat them.  Clearly in the products I'm going to show you, the immunologic status of the patient population is something which appears to be critical, at least in some cases. 
A factor that hasn't been mentioned or has been briefly touched on is that of the immunomodulatory properties of the agent.  So, agents that are in general immunostimulatory may actually up-regulate immune responses to themselves; whereas, those that are down-regulatory may actually be able to down-modulate an immune response to itself.  This is something that I think you'll see in the subsequent discussion.
So, I'll start with thrombolytics.  Thrombolytics are of particular interest with regard to immunogenicity because of their very widespread use in immunocompetent populations:  acute myocardial infarction, deep vein thrombosis, et cetera. 
So, with regard to this, we have three products.  The top line is urokinase, which is a natural human product produced by a human kidney cell line.  In this case, no antibodies have been reported.  
Again, the format I show here involves the production cell and, of course, the production cell is important because of glycosylation patterns, whether the antibodies were seen in preclinical models, whether binding antibody was appreciated, whether neutralizing antibody was observed, and whether you see cross-reactivity on the native protein, and as a further measure of immunogenicity, looking for allergic reactions which may indicate hypersensitivity or IgE mediated phenomena.
So, urokinase, no binding antibodies have been reported, and allergic reactions are rare.  
Similarly for tPA, which is a recombinant human product produced in CHO cells, a mammalian cell line.  So, the glycosylation pattern should approximate that of primates.  Antibodies were seen in animals, but the frequency of binding antibodies in a large number of patients was very low.  It's .18 percent.  And no neutralizing activity was observed.
One thing I should point in addition is that although binding antibodies may not be detected in a neutralizing assay, neutralizing assays usually involve the inhibition of proliferation of a factor-dependent cell line by dilutions of patient sera.  At least in theory, in vivo binding antibodies may have the capacity to eliminate your biological therapeutic by Fc receptor mediated uptake and destruction in the reticuloendothelial system.
So, for tPA basically we don't see a high level of immune responses generated.  Allergic reactions were rare.
The third thrombolytic is streptokinase, and that's a bacterial product produced in group C strep.  In this case, there are variable levels of anti-streptokinase antibodies present in individuals as a result of a recent strep infection.  So, in this case there are a lot of allergic reactions that have been noticed on infusion, 1 to 4 percent, and some anaphylactic and anaphylactoid responses.  The manufacturer cautions against readministration within a period of 5 days to 12 months of either administration of streptokinase or the development of a strep infection.
So, in terms of the licensed hematopoietic growth factors, we have erythropoietin, G-CSF, and GM-CSF.  The immunogenicity issue was of increasing importance with regard to these products because both erythropoietin and G‑CSF are increasingly being used off label in healthy human populations.  So, I think it's critical for us to be able to look and see precisely what studies have been done in normal volunteers.  In fact, with regard to G-CSF, there were two recent NIH/FDA joint conferences that were concerned with the effects of this agent in normal volunteers in the setting of allogeneic bone marrow transplantation or peripheral stem cell transplantation.
So, the first one, erythropoietin.  It's recombinant human.  It's produced in CHO cells.  Antibodies were observed in preclinical animal models.  However, no antibodies were reported in either binding or neutralizing assays, and allergic reactions are rare.
G-CSF, produced in E. coli and therefore not glycosylated, unlike the human homologue, nonetheless was also not reported to elicit antibodies, and allergic reactions were rare.
GM-CSF, which is a recombinant human product produced in yeast and used in the treatment of AML and bone marrow transplantation, elicited antibodies, about 2 percent, and these antibodies were neutralizing.  Whether they cross-reacted on native protein, the endogenous protein, is unknown because clearly the activity on granulocytes could be compensated for by G-CSF, the activity on monocytes could be compensated for by M-CSF.  I would have to go back and check whether direct binding activity was observed.  In addition, allergic reactions were reported.
Now, GM-CSF has a lot of immunomodulatory activity as well which is worth considering in that it is a very potent activator of dendritic cells, which are the professional antigen presenting cells in vivo.  Whether this is a factor in the elicitation of antibodies to this is not known.  Also, the glycosylation patterns mediated by yeast are quite distinct from that of mammalians, and whether that's a contributory factor is also unknown.
We come now to the investigational hematopoietic growth factors, and what I've shown here are three of the thrombopoietic growth factors:  the dual cmpl receptor agonist and IL-3 receptor agonist, the peg-MGDF, and the recombinant TPO product.  These are all recombinant products.  The first two are produced in E. coli, the last one produced in CHO cells.
Of great interest with these molecules, as has already been mentioned, is their immunogenicity so that antibody was observed in preclinical animal models and non-human primates.  Unlike most of the situations we see, where the animal response is restricted to the xeno components, the reactivity here actually cross-reacted on the endogenous TPO of these animals.  This is probably due to the fact that there is very high sequence homology among all species.  It's over 80 percent in the business end of the molecule in mice to man and higher in non-human primates.  So, this was surprising.
These agents were used to treat oncology patients and in one study a group of normal volunteers.  They were all injected subcutaneous.
Of interest here, on the screening antibody or the binding antibody was that this was found to be a highly sensitive assay, and it was positive in some subjects prior to administration of the agent.  This was the case for actually more than one of these studies.  So, it either indicates that the screening antibody assay is highly insensitive, or it indicates that in fact in either normal or oncology patients there is a certain percentage of persons who have extant antibodies to TPO.  The implications of that are rather interesting to consider but not the subject for a conversation here.
With regard to the neutralizing antibody in the first trial with the dual cmpl IL-3 receptor agonist, there was a report of neutralizing antibody.  This was, however, reported as weakly positive.  Neutralizing antibodies were observed in the oncology patients in the peg-MGDF study and were present at higher levels in the normal volunteers, so about threefold higher in the normal volunteers than in the oncology patients.  In the full-length TPO molecule, there was also a report of a neutralizing antibody which was read as potentially neutralizing in that it was of low titer, it was transient, and actually is considered partially neutralizing.
Again of great interest is the fact that clinical findings of thrombocytopenia were observed in many of these studies, and the thrombocytopenia was not of necessarily short duration.  No allergic reactions were seen to these products. 
So, I believe this is the worst nightmare scenario where you generate an antibody response that is fully capable of cross-reacting on the endogenous factor.  It was picked up because of the loss of platelets.  And what these data really do indicate is that TPO is the primary, if not sole, agent that's responsible for levels of platelets.  One would have expected that if IL-11, for instance, were important in regulating levels of platelets, that that would have compensated, but it did not.
Turning to licensed interleukins, we have two, IL-2 and IL-11, both recombinant human products produced in E. coli.  Both elicited antibodies in preclinical models.  Both used in an oncology setting.  The fascinating aspect here is with IL-2.  Binding or screening antibodies were observed in an extremely high percentage, 66 to 74 percent of patients in the renal cell carcinoma and melanoma trials.  In those particular trials, none of those antibodies proved to be neutralizing.  
In a different study, 1 out of 106 patients manifested a neutralizing antibody which did cross-react on native protein.  Apparently there were no perceived effects on this patient in vivo.  
Again, IL-2 is one of many factors which can regulate T-cells.  IL-4, IL-10, IL-15, for instance, perhaps compensate in this regard.
In addition, allergic reactions have been reported, and of greater interest is the fact that administration of IL-2 in some cases led to the exacerbation or the initiation of autoimmune or inflammatory disorders, and hypersensitivity responses were also seen in combination with other agents.  I think this speaks to the high percentage of antibodies here and the initiation of autoimmune disease speaks to the immunomodulatory properties of this molecule.
In contrast, IL-11, which is basically a down-modulatory cytokine in immune responses, there were antibodies that were picked up in the binding assay, 1 percent, but none of them were neutralizing.  Just some minor local allergic responses were seen.
So, I think here it may be an example where the immunomodulatory properties of these cytokines figure into the immune response against a therapeutic protein.
Looking at the earlier investigational interleukins, I have limited data here.  However, with regard to IL-1 alpha, a pro-inflammatory cytokine, no neutralizing antibodies were reported, nor for IL-3 or the IL-3/GM-CSF fusion protein.
With regard to the more recent trials using interleukins that figure very prominently in T-cell activation, we see some surprises here.  So, IL-4, which is the prototypic B-cell stimulating factor which also stimulates T-cells, has been tested.  It's a recombinant human product that's made in E. coli.  It was administered subQ.  So, basically it seemed to have all the necessaries for generating an immune response to itself.  However, no binding antibodies were observed and certainly no neutralizing antibodies, and no allergic responses were observed for a factor whose administration or whose activity skews to IgE mediated responses.  So, this was a surprise and it may reflect the sensitivity of the assay.  It may reflect the dosing schedule.  This may be the subject of further inquiry.
Again, another surprise was with regard to IL‑12 which is a potent immune activator.  IL-12 in this case is a recombinant human product produced in CHO cells, but injection of this product failed to produce antibodies that were perceived in the binding assay.
So, a few surprises here that don't quite fit what the expected activities are.
One product that's approved for wound healing is platelet-derived growth factor.  It's a recombinant human product produced in yeast.  It has been used to treat diabetic foot ulcers and the route of administration is topical.  2 of 475 patients showed some activity in the binding assay, but in this case the nonspecific binding could not be excluded.  No neutralizing antibodies were perceived in the use of this product.
So, within our office and our Center, we have agents for which we expect preexisting immunity.  This was touched on earlier.  I mentioned streptokinase is one.  In addition, we have an IL-2 diphtheria toxin conjugate molecule which is recombinant produced in E. coli and used to treat cutaneous T-cell lymphoma.  In the binding assay, 39 percent of persons prior to study had antibodies to diphtheria toxin, and by the end of the third course of treatment, virtually 100 percent of patients had antibodies to diphtheria toxin, measurable ones anyway.
What's of interest here is that by the end of treatment, 50 percent of patients had antibodies detectable to IL-2.  Given the dosage here, one wonders whether or not the diphtheria toxin acted as an adjuvant to elicit immunity to IL-2.  The neutralizing antibody certainly is neutralizing for diphtheria toxin, and that made a difference in terms of the pharmacodynamics and kinetics in vivo.  However, it's not clear whether or not there were neutralizing antibodies to IL-2.  There's a 2 percent incidence of allergic reactions.  
The other product that is of bacterial origin is asparaginase used to treat acute ALL.  It's a bacterial product produced in E. coli.  Although there were few details -- in fact, no details -- provided in the package insert on the incidence of antibody, nonetheless the very high level of allergic reactions, 3 to 73 percent and really tending on the higher side, indicate that such antibodies must in fact be present.  And this is with the first course of therapy.  In fact, the manufacturer has a scheme for skin testing and desensitization should skin tests be positive prior to therapy.
The peg-asparaginase product whereby you get pegylation actually appears to decrease the incidence of these allergic reactions, 11 to 12 percent, at least in non-sensitized patients.  The effects of pegylation on this product and on others may be to down regulate the immune responses.  However, in other circumstances, pegylation has the potential to increase immunogenicity, and this will be something that we would like to look into further.
I wanted to point out to you that we have some agents that are administered over a protracted period of time in patients.  Among these are, of course, epoietin in the setting of renal failure.  
One I haven't mentioned before is DNAse which is used to treat cystic fibrosis and it's administered by an inhalational route.  Binding antibodies were reported in 2 to 4 percent, and we don't have any information as to whether these had neutralizing activity.  This I think would be of great interest in persons who have to take this perhaps for the rest of their lives.  There is a certain incidence of allergic reactions manifested as rash, 3 percent in this case.
G-CSF is chronically administered to patients with severe chronic neutropenia.  Again, the incidence of antibodies -- I'm not sure how well it's been studied in that particular patient population.
That about wraps up the encyclopedic tour of the other biological therapeutics.  I think we've identified clear areas for further follow-up.  Particularly worrisome are the cross-reactive kinds of responses that we've seen with regard to TPO that led to thrombocytopenia in some instances.  I think the guidance from the committee would be of great help with regard to what is needed to prevent this in the future.
Thank you.
DR. SALOMON:  Thank you very much, Amy.
I had one question.  What does NA exactly mean in these?
DR. ROSENBERG:  I'm sorry.  It's not applicable.
DR. SALOMON:  So, I don't understand.  For example, if you've got interleukin-3 or interleukin-1 alpha, why would cross-reactivity on the native protein not be applicable?
DR. ROSENBERG:  No.  It would be applicable, but we don't see anything in terms of neutralizing activity.  So, with regard to that, the likelihood of cross-reacting on the native protein is virtually nil.  So, binding antibodies most commonly are specific to unique determinants as a result of the production; whereas, neutralizing really seem to hit the business end of the molecule.
DR. SALOMON:  I mean, there wasn't any data on binding antibodies, so I was getting a little confused.
DR. ROSENBERG:  Yes.  No, I'm sorry.  I was limited in part as to what I could retrieve.
DR. SALOMON:  I think you did a great job.  There's a lot of data here.
DR. ROSENBERG:  Well, thank you.
DR. SALOMON:  I was just trying to get a handle on it.
Yes.
DR. MILLER:  Can you comment on the IL-2 diphtheria toxin drug and comment on the clinical effects of the neutralizing antibody?  My understanding, looking at it, is that by the time you're done with the course of therapy, there's such a high level.  But looking at the data, there's no evidence that there's a continued response.  Well, there's a response, but whether or not you need all those courses.  Is there any data about why you should keep giving that drug with 90 percent neutralization?
DR. ROSENBERG:  I'm not as familiar with this as I'd like to be, but one thing that is mentioned in the package insert is that the administration in patients who did manifest antibodies didn't seem to correlate with treatment effect.  So, whatever effect it had on the tumor itself did not correlate with the presence of antibodies.  That I could glean.
But your question is a good one and I don't really have the answer to that.
DR. KEEGAN:  Dr. Miller?
DR. ROSENBERG:  Oh, Dr. Keegan may have a better answer for you.
DR. MILLER:  As you continue treating -- when you stop in a T-cell disease, your clinical response keeps going and going and going often if it's going to respond.  It can takes month after the treatment is done before the final plaques resolve.  So, I was just wondering from a utility standpoint about any -- I mean, I think that's something we're going to have to discuss.
DR. KEEGAN:  I'm sorry, Dr. Miller.  There was a question that was addressed as an area that we didn't have much information on at the time that this was presented before the advisory committee, and because of the lack of information, it was recommended and it has been made into a post-marketing commitment for the company to further investigate the impact of additional cycles/optimal duration of therapy relationships between antibody responses.
DR. SIEGEL:  You've touched upon a problem that has somewhat vexed us in this area.  I was thinking, as some of the questions came about, about what is the clinical significance, which is that in the chronic diseases or diseases which require chronic therapy, what we've seen -- and this has occurred on more than one occasion -- is, of course, the antibodies are generally, with some exceptions, as we've heard about, not there at present and may occur a few months into therapy.  If we're talking about an imaging agent, we may immediately know there are antibodies there.  You can get immediate feedback whether the drug is still working or not.  But a lot of biologic response modifying agents -- the time course of efficacy is not closely related to or the relationship is unknown of the time course of therapy and of having active drug on board to the response.  
So, if you're treating an immunomodulator to treat arthritis and you treat for three months and the arthritis is doing fine and antibodies come up and you see that the arthritis is still doing fine a half year later, you don't necessarily know that the drug is still active or whether three months of therapy is enough to give nine months of response.  So, it's often the case with these drugs that knowing whether an antibody response has a clinical impact is not so easy to determine.
DR. O'FALLON:  Until you can get to the point where you know the specificity is near 100 percent, however, you don't know whether you've got true antibody present or you're just dealing with a measurement that is detecting an awful lot of false positives.  What you just described as one possible explanation, another possible explanation is all those people were not really positive antibody responders after all.  It was just a very poor assay.
DR. SIEGEL:  Yes, in some cases that could be the case.
Often we have good information about specificity, and in some of these cases, we'll see pharmacokinetic changes so we know that antibodies are doing something, but we don't know what the clinical implications are.  So, the half-life of the molecule will be shortened.  We know that they're binding in vitro, but we don't know whether that has any meaning because again the association between the half-life and the pharmacokinetics and the efficacy are not well known.
Specificity is an important issue and a lot of companies have expressed some concern, I think appropriately, that assays may be picking up non-specific responses.  The concern, of course, is sometimes you can technically get around this, but usually there's a drug tradeoff between specificity and sensitivity.
DR. O'FALLON:  Of course, there is.  It's the way it works.
DR. SIEGEL:  In general, to investigate these problems, our preference is to cast the broader net and to look at sensitive assays and then try to investigate, when we see something, whether it has any clinical meaningfulness.
DR. CHAMPLIN:  In this example of the IL-2 diphtheria toxin, it could be antibodies to the diphtheria toxin won't matter at all since the IL-2 is what targets the conjugate to the cell and is internalized and the toxin may still be active.  So, you could actually test that in vitro without even needing clinical data to see if, in the presence of antibody, the agent would still kill cells.
DR. MILLER:  But the clearance of the protein ‑‑
DR. CHAMPLIN:  Clearance, yes, could change.
DR. KEEGAN:  I don't know which members from this committee were actually participants in the ODAC, but at least some were.  As you know, Dr. Vose, there was very clear data showing that the pharmacokinetic impact of the antibodies was very significant.  There were great alterations.  Dr. Sausville was there as well, as I recall.  So, these were likely not false positive results, but were results that impacted at least upon the pharmacokinetic effects of the profile of the product.
DR. SALOMON:  An interesting direction right now in cell biology is probably pertinent to raise here, and that is, there's been an assumption for a long time that a lot of these factors -- growth factors, for example, chemokines for another example -- act primarily as soluble molecules.  However, a lot of new data suggests that that's actually probably not true at all, and that most of these factors are being presented.  They're being presented by extracellular matrix molecules.  They're being presented by charged moieties like heparin groups on cell surfaces.  There's data for TNF.  There's data for IL-8.  There's data for STF-1.  There are a lot of results out there suggesting this is a factor.
So, measuring soluble concentrations or suggesting that antibodies enhance clearance may actually not be measuring the biologically relevant presentation of these molecules in the body.  That may be why you see that they disappear, you can't detect them any longer in plasma or serum assays, yet they're functional.
DR. ROSENBERG:  Yes.  Fred Finkelman's IL-4-11b-11 conjugate is of interest in that regard, and that's an antibody complex to IL-4 in which he sees actually more prolonged activity because of the release.  So, that's another one where that might figure.
DR. SAUSVILLE:  I would simply say that in reference to the IL-2 diphtheria toxin, Dr. Keegan mentioned that in that particular case the need for more studies was clearly part of the post-marketing activities.  But I think for each one of these products, though, the issues are so particular to each one that I think we're going to have to really think about these biologic issues that you raised in designing an assessment of these issues that are never, I think, going to be modeled very well in preclinical or early phase trials. 
DR. SALOMON:  A point well taken.
I'm sorry.  Yes, please.
DR. CHAMPLIN:  One last comment.  I recall six months or so ago there was an article about PIXI, an IL‑3/GM-CSF conjugate, whereas both of the independent drugs did not elicit antibodies, the conjugate actually did, which limited the ability to deliver repeated dosing.  I think Dan Longo was the author, if I recall.  
DR. ROSENBERG:  We have to revisit the package ‑‑
DR. CHAMPLIN:  And it raised the concept that even if the component agents are not immunogenic, when you make a conjugate of it, the binding factor perhaps was the target for an immune response.
DR. ROSENBERG:  Yes.  The data I have regarding PIXI was early and limited and should be revisited.
DR. SALOMON:  Well, I think someone earlier -- I believe it was Dr. Stein -- had mentioned the idea that there may be aggregations after oxidation.  No.  But anyway, aggregation, oxidation, and that you could even present it with human serum albumen, HSA, in the preparations.  So, the idea that these sort of aggregates could act almost like adjuvants is an interesting thing to bring up.
DR. ROSENBERG:  Yes, it's of interest in that IL-2 is actually aggregated; the therapeutic IL-2 is aggregated.  That may in part explain its --
DR. SALOMON:  Well, a lot of molecules, including peptides at high concentrations such as you give trying to reduce the volume you're giving to patients, will end up aggregating even though once -- the concentrations they would normally be in a biological fluid with loss of protein, there would be no aggregation, but in a normal saline or water, as you're injecting it in the patient or during the preparation, they're aggregated.
Thank you very much, Amy.
Then the last speaker before we get into the discussion of the questions in earnest is Dr. William Schwieterman, and he'll present a clinical perspective.
DR. SCHWIETERMAN:  Thank you very much, Dr. Salomon.
Actually I only have a handful of slides because I think the other speakers nicely covered many of the issues relevant to the clinical issues and that the committee has brought up a number of the issues already that I think bear some discussion.  It was quite clear early on in the organization of this session here for this particular committee that there were many, many issues that could possibly be discussed.  As Dr. Zoon mentioned in her introductory talk, it's very clear that we will need to come back to this committee periodically to discuss these various issues.  As Dr. Sausville rightly pointed out, many of the issues don't lend themselves to general discussion since they get down to the particulars of the product, the assay, the indication, the issue at hand.
So, what I'd like to do here today is simply describe in some broad brush strokes some of the issues that I think we felt were particularly important, whether because they were more common, more practical, practically oriented or more clinically relevant to some of the issues that are happening now, and then get right into the questions with the idea that we'll focus on some of these more pertinent areas, but that if others on the committee want to bring up other points of discussion with regard to clinical assays, with regard to treating through therapies, with regard to many of the things that we talked about in some of the telephone conversations earlier -- Dr. Salomon brought up today again about what to do when you see assays; how do you appropriately characterize what's relevant or not with regard to whether that has an adverse effect on either the safety or efficacy of a product -- that we can have that sort of a discussion.
So, with that, I'll simply start by saying that we have four questions listed for the committee in two different broad areas:  three with regard to product development, and one with regard to product labeling.  The three that are involved with product development involve a question, again a general sort of question, on preclinical issues.  We have a question on assay development.  Many of you understand the issues.  We've had something of a discussion already about this.  And the issue of repeat administration is something that I think that we would very much like input from this committee on given that many of the biological therapies that are now being brought to us, and they're even being approved, involve the treatment of chronic conditions with chronic therapies.
And then we'll end the formal discussion with our final question about product labeling.  This question essentially revolves around the issue that Dr. Auchincloss and others were talking about earlier this morning about the nature of comparing data and what ought or ought not go into the label for the label to become maximally informative for patient and caregiver alike.
With that, I'll simply go through now what I think are many of the issues we've discussed.  Again, this is a partial list.  I think it's clear that animal data often are non-predictive.  This is an issue not only for immunogenicity but for many other aspects of product development, but certainly one that's relevant for this discussion.
Secondly, PK and PD measures are very often helpful in phase I.  We've seen examples already of the kind of dissociations, whether it's in the initial volume of distribution, whether it's in serial measurements of PK/PD profiles after repeat administration.  PK/PD often allow you your first glimpse into what the actual effects of an immunogenic antibody might have, and they play a particularly helpful role early in product development.
Concomitant immunosuppressives is something we touched upon earlier and something that actually as a clinician in the FDA that we have to deal with on a fairly regular basis.  Really there are two issues surrounding this. 
One is what are the considerations about immunogenicity when the product itself is immunosuppressive?  You give an agent, it suppresses the immune response, and thereby is effective hopefully but also self-tolerizing in the sense that it dissipates any antibody responses that occur in the short term.  What are the implications of that for product development?  We'll get into this with repeat administration and so forth.
And secondly, I guess the second issue here is what about sponsors that want to pursue product development with combination therapy with other immunosuppressives?  It has been a rule of thumb that we have that we like to adequately characterize these products with regard to their immunogenicity so as not to default to a combination therapy that may not be necessary, in other words, to get some data.  But certainly there are judgment calls as to when and when not to ask for monotherapy when you could suppress the immunogenicity otherwise.
The second slide has to do with the one I talked about earlier, the repeat administration study.  There are obvious questions here, but the durability of safety and efficacy.  I listed here two examples.  I think there are several more you could easily think of, but the two that come up very often are should you require or ask for or think about readministration studies when you anticipate that there are going to be intermittent courses of therapy, whether it's a single therapy, for example, with a diagnostic agent, whether it's a chronic disease and the patient is going to be on that treatment for a long duration and therefore very likely to have certain periods of time when they would not be on that therapy for whatever reason, whether it's their own compliance with the product, whether there are drug holidays, for other reasons, et cetera.  When do we start asking sponsors to evaluate these likelihoods in the future given that there are implications for starting and stopping therapy with regard to immunogenicity and therefore the safety and efficacy of the drug profile in the long term?
The second point I brought up here is obviously something we discussed already.  Neutralization of endogenous function is a real concern when you're giving biologic therapies.  Perhaps it's one of the obvious distinguishing features of biological therapies from some other drug moieties.  We've heard some examples already today of when this actually occurred.  And there are other considerations with regard to idiotypic networks, and Dr. Salomon brought up with autoimmune disease and so forth, that are related to this particular phenomenon.  Biological therapies are very often ones that might actually involve risks with regard to these sorts of things, and I think that this committee has accurately pointed out some of these risks.
The third and final slide on the product development issues -- again, it's a partial list of things -- has do to with question 2.  The first item does.  Mainly, we very often have requests to companies to pursue improved assay development for their products.  An example is Enbrel for phase IV.  Immunex has been quite forthcoming in wanting to pursue a better characterization of their antibody profile, and we believe that this is something that is probably not likely to be the first time, as products come to market, that we attempt to get better handles on the assays and so forth.  
And we have a question to this committee, a general sort of question, on what they think ought to be proper recommendations in this regard since, obviously, it's very important that we get accurate information on this, particularly with chronic therapies.
The second point is something again that's not necessarily specific to immunogenicity.  Phase IV studies often help complete the safety database in a number of areas.  But I think it's safe to say that immunogenicity is something that we often look for in phase IV, just given the sheer numbers, ask for the other adverse events, and so forth.  Dr. Schaible again has pointed out that Centocor has experienced some post-marketing AEs, but they're actively pursuing studies of this.  I think of this as something that is again not going to be specific for any one product, but something that's likely to continue again in the future.
I'll just simply finalize the product development issues by saying that registries of studies of readministration may be helpful since, obviously, it's important to collect these data on these particular areas.
Two more slides on product labeling and promotion, and these all revolve around question 4, which I'll get to in a second.  Let me just make some basic points.
Immunogenicity data is required for the package insert.  It's the nature of the data that we need and how it's presented that really is at issue.
The location in the package insert varies somewhat.  It very often ends up in the safety/adverse events section.  Sometimes there are labels where the antibody data, immunogenicity data is in the clinical trials description section.  I guess the question to the committee, is this relevant, is this important?  Ought there to be a format that we use and so forth?  What ought to be the disclaimers?  Again, this is coming up in question 4.
The third point I just want to mention here is that we consider it important that the label include information sometimes on other kinds of therapies, other kinds of diagnostic tools that might be adversely affected.  This is a generic question.  If there's going to be a cross-reactivity of a particular kind of isotype or other kind of class effect that might somehow influence other therapies or other diagnostic tools, I think that that's something that needs to be considered.
Finally, but certainly not least, is the topic that started out today's discussion for this particular topic, and that is the comparison of data between products is difficult given the things that we've discussed today, the sensitivities of the assays, the nature of the kinds of assays that are being performed make any reasonable, meaningful comparison of differences difficult if sometimes not impossible.  This is relevant to the extent that it provides meaningful clinical information to doctors and to patients but also that sponsors quite often use the immunogenicity data to promote their particular product.  So, one of the questions to the committee is what is appropriate in this regard with regard to the label.
So, with that, I'll go back to the first slide that I put forward and simply say that we very much look forward to the input from the committee on these issues, particularly on the ones that we've outlined but I've certainly enjoyed the discussion and look forward to more input.  Thank you.
DR. SALOMON:  Great.  Thank you, Bill.
That's actually a great introduction to the discussions now that we hope to flow from this.  I think from the comments that we've already had -- I'm sorry.
DR. SAUSVILLE:  I had a question for Dr. Schwieterman.  In terms of the clinical issues, if you look over the large number of products that Dr. Rosenberg presented for which there is some information about immunogenicity, would the nature and type of the clinical phenomena associated with these be considered serious, life-threatening?  In other words, at what level do we consider -- when we say clinical issues, there's obviously different levels of gravity that one could conceive of.  If you could comment on that, that might be helpful.
DR. SCHWIETERMAN:  That's an excellent question.  I think the easy answer is that the range of adverse effects that you see from immunogenicity range from the inconsequential to the perhaps -- I do not want to be too alarmist, but I could conceive of life-threatening adverse events from anaphylactoid and other types of hypersensitivity responses and so forth.  I think that in fact therein lies some of the dilemma about how to pursue some of these concerns given that we have experience both with products that are immunogenic yet seem to continue to "work" in the clinic for long periods of time that don't pose these problems.  Yet, there are other kinds of data that come forward that compromise the safety and efficacy long term or pose risks to the patient's long term, for example, with the chronic therapies whether they were to go off that therapy and be retreated and so forth.  
I think that's why we're here today, frankly, is to get a handle on what the experts here around the table believe about these risks and how the agency ought to reasonably pursue recommendations to the committees with regard to that.  But I guess the literal answer to your question is it spans the gamut from nothing to really quite serious events.
DR. SIEGEL:  Let me attempt to do what is undoubtedly not impossible to do well, but to kind of give an overview I think of what we've seen as a whole over the last 15 or 20 years.  
I think it would be correct to say that the issue of loss of efficacy is an issue that arises frequently.  Dr. Zoon pointed out that it has been observed in some settings with the interferons.  Interestingly, she didn't point out when you lose efficacy, at least you also lose the adverse reaction profile and that's one of the --
DR. SAUSVILLE:  A surrogate marker.
DR. SIEGEL:  There you go.
(Laughter.)
DR. SIEGEL:  Well, it is.  It can often be one of the first signs of an antibody response, is a loss of the flu-like reaction.
I think that there are a number of products where there are suggestions of that, a number of settings we've talked about where it's hard to tell, but enough settings where the half-life of the product changes radically enough -- its clearance increases radically enough -- that that has to be a concern.
Now, when you get into the safety concerns, of course, many or most of these products have been developed in the setting of serious diseases and radical concomitant therapies.  It's not always clear to make attributions, but it's probably been limited.  The issues of immune complex disease, I think it would be fair to say, generally don't arise outside the setting of monoclonal antibodies because the actual volume of material given is usually pretty small if you're talking about an enzyme or a cytokine.  Streptokinase may be an exception to that rule.  And even amongst monoclonal antibodies, there haven't been that many examples of what are clearly -- we've heard about the issues with Remicade and streptokinase, but beyond that not many examples.
Then the other major safety concern is the impact of neutralization not on efficacy but the safety implications vis-a-vis neutralization of the endogenous analogue.  That has been in our minds for the last -- I've been at the agency for 17 or 18 years.  We've always talked about that and not seen clear evidence of it.  Frankly, I'm not sure that we would know it if we were seeing some modest amount of neutralization of endogenous interleukin-2, interleukin-11, interferon, because of all of these issues we've talked about of multiple redundant pathways for many activities.  I think that the observations with TPO and some related molecules, though, have brought to the forefront and in part led or one of the impetuses that led to calling this meeting, the realization that we are looking at the potential -- and it's no longer just theoretical -- for some significant adverse reactions in that regard.
DR. BROUDY:  Just to answer very specifically, the neutralizing antibodies against MGDF dropped the endogenous platelet count to 10 percent of the normal levels, and that's the same level that you get to in a TPO or an MPL knock-out mouse, so completely neutralized endogenous TPO levels, and had a very significant impact on the platelet count.
DR. CHAMPLIN:  In that regard, very few molecules are in fact so important, and the lives of many post-docs have come to naught because the knock-out model of whatever gene they're studying has no phenotypic difference.  With only rare inclusions can you identify really critical molecules for certain functions.  So, G-CSF and TPO and EPO are critical, but GM-CSF, the knock-out mouse has got very few manifestations, alveolar proteinosis, and the blood looks pretty good.  
I think my own sort of major reflections on the conversation so far is that for the most part these immune reactions don't have monumental consequences.  It's the rare patient where the normal homologue is going to be affected in a way that is meaningful, but clearly there are symptomatic adverse events, or if the long-term efficacy of a product is affected, that is honestly a major concern.  The rather relatively innocuous antibodies don't seem -- nonbinding or other binding, but non-neutralizing antibodies often don't inhibit activity much.  
So, I think one needs to look at this much as you look at any toxicity.  Is it a grade 0 or grade 1, just sort of a minimal problem, or is it a major problem that needs to be considered in the grand balance of the efficacy versus adverse effects of the given product.
DR. SALOMON:  The follow-up on that is I would just for intellectual discussion take the position that I don't agree with what you said at all.  This is an intellectual point.  I think you've made a lot of good points.
But here you're saying that, well, we've got to see this really dramatic thing where you basically knock-out TPO, and that's what we have to worry about. 
I'm looking at a future where biologics will be employed repeatedly and many different kinds of biologics in patients.  And then these patients -- some of them might be children -- would have 20, 40, 50, 60 years left.  If you find out that knocking out IL-2 may not make the patient fall down and turn purple and that's not dramatic enough for us, but what if they have a 10 times increased incidence of breast cancer 10 years later?  In other words, we should be very careful that we don't arrogantly interfere with these complex biological processes and then reassure ourselves that we haven't seen an effect acutely.
DR. CHAMPLIN:  My point was that if IL-2 has a dramatic clinical benefit in renal cell cancer or whatever, that we shouldn't say that the theoretical concern should prevent it from going forward.  So, you should consider it in the context of all of the attributes and negatives related to a given product, but not overreact to an asymptomatic presence of antibodies.
DR. SIEGEL:  I think we'd all agree on that.  But there are a lot of issues on a day-to-day basis that we face in the development of these products that we're seeking guidance, and they're outlined in these questions.  When is the concern high enough that we should ask for a primate study --
DR. SALOMON:  I thought as soon as this sort of died down, I would get us focused on the exact questions, though.  It seemed like people had some concerns they wanted to start off with of more general content, so I didn't want to stop yet.
DR. SAUSVILLE:  So, with those two polar, shall we say, points of view -- 
DR. SALOMON:  It was done intentionally.  I hope --
DR. SAUSVILLE:  I would ask representatives of the agency then what seems to be emerging is a sense that this area, because of the longevity of immune responses, the capacity for recall, all these things, in a sense you may be in the position of developing a relationship with a marketing entity that may need to exist over several years.  Do you have the authority?  Or is it possible for you to say we've got to measure whatever for the next 10 or 15 or X number of years?
DR. SCHWIETERMAN:  Well, we certainly have authority to monitor the safety and efficacy of the product.  If we think the concerns are such that they'll significantly affect those two parameters, then they need to be asked.  I guess it sort of begs the question, though, and it comes back to this committee, what should we be asking these sponsors to do in this regard for the reasons that you pointed out, that the chronic therapies are here now, that we're starting to get a lot more biologics in phase III, and that there are real concerns about adequately characterizing these aspects before they're put out to a broad population.
DR. SAUSVILLE:  The key issue is the "before" because I don't see the relatively limited testing that you do with any entity, drug or biologic, that before is going to be realistic in terms of the total universe that these products eventually run into.
DR. SCHWIETERMAN:  Well, many of them, you're right, will not be realistic beforehand.  I think, though, that before you would simply say that most of them come afterwards, you would simply want to know the likelihood of the thing you're worried about and the effect that thing has on the overall safety and efficacy.  For example, if you had a highly immunogenic protein in phase I that potentially caused anaphylactoid reactions and so forth, you might want to very carefully analyze in phase III many of the -- I mean, we do this for most of our products anyway, but I'm just giving you an obvious example where you might want to really know all about the safety and efficacy of that profile over the long term before putting it on the market.
But you're absolutely right.  If there are less real concerns and there's no real reason to be concerned about an overall risk/benefit, then you could reserve those questions for phase IV, which we often do.
DR. SALOMON:  I think just another thing that's coming out here is we need to talk about things in several different time frames, and as we go further along, we're basically expanding the time frame.  Right?  I think what Dr. Sausville is saying, very properly, is there's a series of things that you are going to request sponsors to do before you license the drug.  Then there's going to be this phase IV which is going to enrich our understanding of the drug, but shouldn't hold up its use.  And then there's going to be an argument whether or not a year -- and looking at sort of follow-up versus perhaps what I'm suggesting that some of these effects may be 10 years later.  And I know at this point the sponsors and the FDA are both very unhappy with me, so I'll just sort of leave it at that.
DR. SIEGEL:  The simple mechanistic answer to your question, though, as I think came through, is that we do have the mechanisms, most commonly at time of approval, to request and receive commitments for long-term studies as are appropriate or even after approval.  To parallel what Dr. Zoon said about once you're on an advisory committee, we've got our hooks into you for life, once you get a drug approved, you're pretty much dealing with the FDA for a long time.
(Laughter.)
DR. SALOMON:  Dr. Miller?
DR. MILLER:  Well, I want to comment not just on the safety but the efficacy endpoint.  These drugs are, in fact, often very, very expensive.  So, I think it's very important that you make sure that you're giving a protein that is still active because the diseases many times that we are treating with these biologics are the more chronic diseases, and I think you're subjecting your patients to a long-term, number one, expense unless you make them say, what happens when you give it six months down the road.  Is there biologic activity still left?  I think that's a major question that we don't know about some drugs that are out there that are very expensive.  So, I think that's important as well as safety.
DR. SALOMON:  Abbey?
MS. MEYERS:  In terms of the long-term monitoring, maybe you ought to think about utilizing something like the Clozaril registry which has turned out to be so valuable.  The patients are registered and you just keep track of where they are.  I was reading the other day that there's some concern that maybe Clozaril is connected with the onset of diabetes.  No problem.  They know where every patient is and they can just follow up with thousands of patients.  So, you might think in those terms. 
But the other thing, which is a naive scientific question is, is there a way to develop appropriate tests so that physicians can test people before they put them on it or maybe even before a rechallenge with the drug to find out whether they have these neutralizing antibodies?
DR. SCHWIETERMAN:  Yes.  It actually is one of our questions here about assays --
DR. SALOMON:  We'll get to that.
DR. SCHWIETERMAN:  -- so I think we'll get to that.
DR. SALOMON:  Dr. Vose?
DR. VOSE:  I just want to make a small comment.  I think that it is very important for us to put any of this in the context of the patient population we're treating because what's appropriate for a very end-stage CTCL patient, for example, with DAB IL -- you know -- DAB may not be appropriate in another clinical situation where the patient is going to live 60 years.  So, unfortunately, you're going to have to be very specific in each situation about that sort of thing.
DR. SALOMON:  Dr. Champlin.
DR. CHAMPLIN:  I just wanted to return.  On one of your slides, you indicated that you shouldn't be studying these drugs with premedication, and I think you listed Benadryl.  For many of the antibodies, particularly that target either tumors or T-cells, it's a biologic effect of the antibody to produce fever, and Pertexamab, for example, in the first dose produces lots of symptomatic effects that tend not to occur as frequently or as severely thereafter.  So, I think once one has defined that that phenomenon occurs, then it's the standard care for many drugs we use to give premedication, and it shouldn't be something that should be --
DR. SCHWIETERMAN:  The question is one of definition, though.  Many sponsors want to, at the very first time of introduction of the product into humans, use a cocktail of immunosuppressive regimens to suppress whatever effect they're anticipating.  If it's a dangerous enough one and they're in an indication, then that's appropriate.  But I was just pointing out that very often we have very little data with which to expect those things to actually occur and would rather have some data about that.  Of course, it is a fine line.  The minute you have a clue that something is actually causing adverse effects and you have a reason to understand it, then it's entirely appropriate to begin suppressing those AEs.
DR. SALOMON:  What I'd like to do now is turn to the three or four specific questions that the FDA would like us to address.  I think we've set a good context for that.
I just wanted to add there's a brief statement regarding CBER's intent on the committee discussion, and I just wanted to read that quickly, if nothing else, just to focus us a little bit further. 
So, the sentence is:  "In particular, the committee will be asked to discuss the amount and type of data that sponsors should collect during the product development, what information should be included in the package insert, and what phase IV studies might be appropriate for sponsors to conduct."  So, I guess in a way it's a reminder to us that we may be very interested in some of these broad-ranging scientific issues, and I think that's what we're supposed to be interested in.  
There are also some practical matters here of great importance and that is just what should a sponsor be responsible for.  And we have to think again, I think as Dr. Vose reminded us, of the patients that are going to be getting this and try and give some guidelines that are practical as well.
So, the first issue that we should discuss is what has been entitled preclinical issues.  Let me read this, kind of paraphrasing it.  Species differences limit the value of assessment of immunogenicity in animal models.  While the potential importance of these species differences must always be considered, studies of relatively well conserved molecules in non-human primate species and studies of analogues of human molecules in the homologous species can still yield important information.  So, here's the typical problem.  How far can we go with animal models in terms of establishing things in the run-up toward a phase I/phase II clinical trial? 
So, the question is:  Please discuss the role of animal studies in the development of protein therapeutics.
Dr. Champlin.
DR. CHAMPLIN:  The rare examples that we talked about of the critical protein being neutralized actually was seen with both TPO and G-CSF in animals.  So, for these type of single gene critically important pathways, those can be defined sometimes in animal models, whereas clearly the general concern that the proteins are different, the immune responses are different certainly comes into play.  So, certainly not seeing something in an animal doesn't mean it won't happen in man, but you can identify pathways perhaps as opposed to specific immune toxicities.
DR. AUCHINCLOSS:  Good work.  You answered my question, which was, is there any example in which a mouse model would actually give you enough information that you'd learn something, or an animal model in general would give you information that would be useful?  In general, I would think these events were so species-specific that you'd have to be looking in your human population.
DR. SIEGEL:  Well, the specific question here would be relevant to studying murine homologues in mice or non-human primates.  Most of these molecules have a high degree of commonality with most primates, sometimes 100 percent for certain factors often in the high 90s.
DR. AUCHINCLOSS:  I understand, but you wouldn't want to use any mouse data or even non-human primate data to predict whether or not you were going to lose --
DR. SIEGEL:  No.  The way we utilize animal data would generally not be -- this question, of course, is focused on immunogenicity, although the "please discuss" doesn't say that.  But the way we'd use it for any animal toxicology would rarely be to say we shouldn't do the human study or draw a conclusion, but rather to focus the concern, in some cases, to cause a more deliberate approach in terms of dosing or regimen exploration or numbers of patients exposed.  You might want to expose a small number of patients and get several months of data when, if you had a higher level of concern based on animal profiles and so forth.  So, that's basically what we're talking about, not using it to answer the question, but to focus on how to -- whether they should be used to focus on how we address the question --
DR. AUCHINCLOSS:  Let me back up.  It seems to me that in the big picture the data that you presented us, which I think is fantastic, gives you the sense that there's an extraordinary lack of toxicity from new treatment in antigenicity of these biological products.  The one that jumped out was neutralization of the endogenous molecule, and you gave us the example that that could in fact have been predicted in an animal model.  So, bingo.  That's something you clearly wanted to look for.
But the other big generalization is that the critical feature is the efficacy, the bioavailability of your products when you retreat because of an antibody response that may or may not be clearing the product.  And I don't see how you can ever address that anywhere except in human patients.
DR. SAUSVILLE:  I had a question for Dr. Champlin in this regard.  So, the animal model that picked up, for example, the occurrence of the single gene adverse effect, was that one animal model?  Was it more than one?  The question that comes up invariably is, do we do one or do we do two?  Do we do some number?  
Let me preface this by saying that I actually agree with the thought that in a sense minimizing the number of animal models one uses before collecting the essential information is obviously of great importance to both sponsors and also not making a bad decision in terms of not bringing forward something that should be.  But I would be curious as to what species that was and could we, for example, only get away with preclinical studies in a most relevant species, which with these products would likely be non-human primates.
DR. CHAMPLIN:  Well, first of all, knowing what the knock-out mouse phenotype does can show you what is a critical factor.  But for many growth factors, the knock-out mouse has no clear phenotype but a phenotypic difference.  So, neutralizing the endogenous factor wouldn't be expected to do any harm.  On the other hand, those where the knock-out mouse has a major clinical adverse phenotype would raise your concerns that that would be one that would need some special examination.
Now, in terms of the examples, the Amgen group had given human G-CSF to dogs and then seen neutropenia in the dogs.  I believe TPO produced it in monkeys.
DR. SIEGEL:  But again, that confirms the criticality, but in the case of G-CSF, we haven't seen that in humans and so it may be that the immunogenicity due to the species differences --
DR. BROUDY:  That's the exact point I would make, is that the studies did show human G-CSF given to dogs made the dogs drop their endogenous neutrophil counts three weeks into treatment, but that hasn't occurred in humans.  So, in a sense it proved that it was an important single gene, but it did not predict any adverse effect.  If you think of all the people who have been treated with G‑CSF for stem cell mobilization, normal volunteers with no abnormal immune system, they haven't gotten any problems with loss of G-CSF function.
DR. SALOMON:  I think I'd also like to voice a little bit of caution.  I don't think Dr. Champlin was specifically meaning to say that you can take a knock-out mouse and if it doesn't have an obvious phenotype, then we don't really have to worry about that particular molecule.  I'm sure you weren't trying to imply that, but I wouldn't want anyone to think that.
DR. CHAMPLIN:  Yes.  My implication was that if there is a phenotype, then you should be more concerned about it.
DR. SALOMON:  Right.  But, I mean, we have recombinase deficient animals that have no T-cells and they're perfectly fine in our animal colony.  But I don't think any human being would do very well without any T‑cells.  We can all come up with multiple examples of clotting factor deficient animals and growth factor deficient animals that don't have such gross phenotypes, but it has to do with the reality these animals are living in.
DR. BROUDY:  I think the other problem is if you give a -- the glycosylation differences may be very, very important.  So, depending on what cell line you produce your species in, then it may be immunogenic in one mammalian species and not immunogenic in another mammalian species.  So, I really agree.  If we see a big problem in the animal studies, that would lead to more caution in humans, but these studies I think do have to be done in humans and all the data collected.  The animal studies are not perfectly predictive.
DR. SALOMON:  You know what?  I'm sitting here listening.  A couple of weeks ago we were in the same room.  I was sitting there.  Dr. Auchincloss was chairing, and we were at each other's throats over the idea of how could we imagine experimenting on human patients with xenotransplantation because these complicated baboon and monkey transplants models weren't giving us one-year survival.  And here, we're sitting in the same room, slightly different cast, and we're going, no, you can't use non-human primate models really.  Do a couple, but don't take it too seriously.  You got to get it into humans.  
(Laughter.)
DR. SALOMON:  Abbey, I believe you specifically accused me of experimenting on humans.
(Laughter.)
DR. BROUDY:  I believe I still see the scars.
(Laughter.)
DR. MILLER:  Well, putting in a new heart is a little bit different than giving a drug.  I think there are gradations.
(Laughter.)
DR. SIEGEL:  It's more cutting out the original heart that is the problem.
DR. SALOMON:  Well, if you're dying of end-stage heart disease, you might not consider it all that different, but anyway.
DR. VOSE:  It clearly depends if you're a surgeon or if you're an internist.
(Laughter.)
DR. MILLER:  I was impressed with Dr. Rosenberg's review, the fact that the antibody in animals really was so non-specific except for the one case with TPO where it predicted but there was also -- in most other species, it predicted the knock-out effect or the one-gene effect.  But the antibody studies, if you looked through the list, almost every animal species study was positive for antibodies.  So, I'm just wondering how important those studies are, if they're not going to be specific, unless you ask are they going to give you neutralizing antibodies. And the answer appears to be yes in the animal, but it doesn't predict the human. 
Now, the question you're asking is an important one, but that really wasn't the object I think of these studies that they did which was looking for neutralizing antibodies.
DR. CHAMPLIN:  I think you need to see what clinical effects of the antibodies would be in humans.  I agree entirely that just producing antibodies in animals doesn't provide much information at all.
MS. MEYERS:  Does anything besides testing in humans provide the information?  Is there any other way to get that information?  So, you have to give it to a human to see.
DR. CHAMPLIN:  Yes.
DR. VOSE:  Unfortunately, I think that a lot of the information that's coming down to, both for efficacy and for a lot of the toxicity, that animal models are not very predictive both ways, either positive or negative, and I think that's the only way that we can do it is to actually get it into patients and test it.
DR. SALOMON:  So, if I try and summarize what I've heard so far from the committee -- and I do this only to make sure that I have some sort of general consensus reached to communicate to the FDA -- what we're saying here is that probably sponsors shouldn't waste significant amounts of resources in preparing animal data on this topic prior to coming to the FDA to talk about an IND for a phase I trial.
DR. CHAMPLIN:  I think particularly if you're looking at human factors being given to a non-human species, there you expect to get some immune responses.  So, that has very little informative value with the exception of animals, their neutrophils completely because of neutralization of a critical factor.  But antibodies in that situation is expected and shouldn't be viewed as a negative feature.
DR. SCHWIETERMAN:  Yes, thank you.  That's helpful.
DR. SIEGEL:  I don't want to read in things that are not there, but the converse at least to what you're saying, though, is that there might be limited circumstances where there's high degree of conservation and where there's suggestion that loss of endogenous function might be important where you would gain information as to at least what loss of endogenous function might potentially look like and relevant information regarding that concern.  Maybe that's an over-read.
DR. SALOMON:  Well, let's get at that.  Dr. Sausville?
DR. SAUSVILLE:  Yes.  Well, to follow on on that point, one could imagine molecules or treatment programs that by their nature might entail this sort of thing such as, for example, a molecule that, as one expression of its action might induce a continuing immune response, raising the specter that you would be able to actually induce an autoimmune disease of one sort or another.  As examples -- and again, it might not be in this committee's purview, but certainly there are vaccination strategies that seek to combine antigens with co-stimulatory molecules.  There I think there might be merit to actually try and more precisely define an animal model to mirror in some respect the long-term effects of continued stimulation.  And maybe that's what you're trying to get at, that you'd have to look and conceivably define worst case scenarios, as it were, for each molecule.
The contrast for that, a growth factor or something directed against a tumor antigen that is expected to act in an antitumor sense, if we're talking about cancer, there that to me is less on table for that type of molecule.  There I think very limited studies would be very appropriate.
DR. SALOMON:  So, I guess what concerns me -- I'm willing to drift to go on to the next topic except for the nagging concern that if the message to the FDA is that we don't have to do a lot of these preclinical animal studies, and that then gets propagated to the sponsors, and then they come back to an expert advisory committee, and all of a sudden the expert advisory committee goes, why didn't you do this in a non-human primate.  
I mean, there's nothing hard for animal modelers if Dr. Champlin's point is well taken.  Okay, fine.  You make the primate equivalent of thrombopoietin or GM-CSF or any of these others.  The genes are easy to clone.  You can synthesize these things relatively straightforwardly.  If we thought that that was an important transition before going into human studies -- okay.  I just want to get this on the table because if someone comes back with a study and you guys then nail them for why didn't you do this, then we've not done our job.
DR. SAUSVILLE:  Yes, but there are converse examples like the mouse TNF story where basically it's different biology than what we've seen in humans.  So, I think to tie inexorably a human experience to what goes on in a species would also not be, I think, a right message to send.
DR. VOSE:  Yes.  It also doesn't take 50 monkeys to find this out.  
DR. SAUSVILLE:  That's right.
DR. VOSE:  You can do it in three monkeys and find out the answer.
DR. SALOMON:  Well, I wasn't discussing the number.  I just want to focus us here.  Are we talking about no studies in this area are necessary because you won't be able to interpret the data anyway?  Because monkey studies, A, have ethical issues.  I do monkey studies, and I don't want to do them if they don't have any bearing on the process that follows.  Right?  I mean, I do them because I think that they're contributing to safety in human patients when we move forward to a clinical trial, but if in this area our advice is it won't do it, then let's spare the monkeys.  The monkeys have to be protected too.
DR. VOSE:  I think actually that we should require a non-human primate model just for a small number because I think that if something is going to be predictive, that would be the model that would be predictive.
DR. BROUDY:  But we're just talking about immunogenicity studies here, but they're still going to do tox studies in animals for sure.
DR. SALOMON:  See what I'm listening to -- I think Dr. Champlin made a really critical point and Dr. Sausville picked up on it, and that is if you're trying to do a human study, so you're going to use human GM-CSF, and you give that to the monkeys, which is usually the way they do these tox studies, that's really not the model, is it?  The model is monkey GM-CSF made in the same yeast you're going to make the human GM-CSF.  And that's an important message to the FDA and that's relevant to what the sponsors do, if that's the message the group wants to give.
DR. BROUDY:  Well, I guess I'd just like to say that some hematopoietic growth factors are very highly conserved.  For example, human erythropoietin works marvelously well in the mouse and the monkey and every species in between.  So, you really wouldn't need to clone a monkey -- I'm sorry.  A monkey EPO is what I'm talking about.  You wouldn't have to clone a monkey erythropoietin to do these studies.  So, it varies a lot from growth factor to growth factor.
DR. CHAMPLIN:  Or you may get immune responses to the human EPO for the non-conserved amino acid sequences and that might be neutralizing, but be totally irrelevant to the human-human experience.
DR. SALOMON:  And that's the funny thing here.  Just specifically this immunogenicity issue, close may not be enough.  You may have to have it exact.
DR. SAUSVILLE:  But I do think implying that sponsors would have to clone the animal X equivalent of whatever X is and have a whole set of studies before even thinking about doing the clinical, that to me would be the wrong message.  It's not supported by the available data.  Although one could conceive of various scenarios, such as the autoimmune thing that I went through, that might impel you in that direction, I think in the main that would be the wrong direction to go.
DR. SALOMON:  So, let's just put a scenario out.  First of all, we all recognize that each of these biologics is being targeted toward critical pathways.  We're not screwing around here.  Right?  They are major things because if they weren't major things, they wouldn't be worth targeting.  Right?  I mean, you want to cure this or save that.  
So, here we are going to do a study where there's not a lot of animal data here, no preclinical.  We go right into a human study, and the first 10 patients all get cancer or they all die.  They never get their platelet count back or whatever horrible thing I can imagine happens.
DR. SAUSVILLE:  It would suggest we have a problem.
DR. SALOMON:  And Abbey comes back to us and says, you guys didn't even do animal studies on this.  You went right to patients.
DR. SAUSVILLE:  No, no.  What you'd say is we did the same animal studies that we've done for, you know, whatever dozen or other types of products, and in this unfortunate circumstance, there was an adverse outcome.  Adverse outcome doesn't mean bad decisions are made.  Right?  You try and avoid --
DR. CHAMPLIN:  Virginia made the point that you're going to do tox studies, just sort of general tox studies in animals, and this is one of the toxicities you'd be screening for there.  
I think vaccines are very different than what we're talking about here.  With vaccines, the whole idea is to stimulate an immune response, and they need to be thought of separately.  
But here you're talking about giving biologicals and now you have an unwanted and often unexpected immune response.  So, I agree that I wouldn't force companies to do this in a monkey before doing it in humans.  I know again, with the rare exceptions that we had talked about, that animal models are not predictive and the only thing that counts really is humans.
DR. MILLER:  Not predictive of the immunogenicity.  I think you have to be very clear that we're not saying don't do animal studies --
DR. SALOMON:  No, no, no.  
DR. MILLER:  Okay.
DR. SALOMON:  I hope I keep repeating the immunogenicity.  That's what we're talking about.
DR. SIEGEL:  Primate studies are frequently done as part of development and for a variety of toxicological reasons.  When they're done, usually immunogenicity data is collected and looked at as appropriate.  But this question really was focused on -- but they're not always done in biologics, in particular because of species barriers, but in any drug development program, because of the costs involved, the times, the other issues discussed.  
So, really we are focused on to what extent should immunogenicity concerns lead to an additional push toward a requirement for primate studies, and I think we received a lot of useful feedback on that issue.
DR. SALOMON:  Well, I hope everyone forgives me for being the devil's advocate on that one.
The next question is on assays.  Here CBER proposes the following approach regarding immunogenicity assays. 
Sponsors should test all patients in clinical studies with -- key word -- sensitive assays for total antibody and, where relevant, neutralizing antibody prior to applying for marketing authorization.
Two, immunogenicity assay data should be carefully examined for suggestion of correlation of the presence, type and amount of antibody.
When such studies suggest important effects or are inadequate to exclude important effects of concern, then additional studies should be required.
And if data indicate that antibody status of an individual patient may be clinically important regarding the use of the product, then the sponsor generally should ensure that an assay is available in the post-marketing period.
So, assay issues.  It raises a lot of interesting points. 
Dr. Auchincloss?
DR. AUCHINCLOSS:  I thought it was a good outline of reasonable steps to take, but I thought it was overly focused on antibody responses.  As I think you've demonstrated to us very nicely, there isn't a good correlation between antibody responses and either bioavailability or bioefficacy of many of these products, so that the antibody assays you would do, but they shouldn't become the absolute focus.
In particular, point 4 in your outline there, which is before you got out there, you need to have the antibody assays sort of in place and available to everybody, let me just use the example of OKT3 where we know an antibody response to the product very significantly affects the bioavailability, but clinically I use OKT3 all the time without an antibody assay against OKT3, the assay to determine an antibody response to OKT3.  I measure the effectiveness of T-cell clearing as my measure of whether I'm giving enough OKT3.  So, I don't need an antibody assay.  I need a way of determining bioavailability or bioefficacy.
DR. SALOMON:  Yes, that's a good point.
Dr. Sausville.
DR. SAUSVILLE:  I would say everybody would agree that where one has the relatively luxurious position of being able to just do a CD3 positive count, that's the ideal position to be in.  Unfortunately, many of the agents that we develop don't have that type of thing.
Here I think it's unclear to me actually whether mere existence of antibodies will or will not correlate with clinical phenomena.  
One thing that struck me from this morning's presentation is that many times the data is reported as titers, and I don't know what titers mean actually.  I would strongly try and encourage sponsors to develop ultimately mass based assays so that you can calculate back to an actual antibody concentration that mediating something.  Then I think there would be a firmer footing actually than to put with correlations in the clinical phenomenon.  Because again as we discussed briefly, it really does relate to the dose and how frequently you get above potentially a threshold of antibody that combined a certain amount of product.  I don't think you have any way of telling that unless you really devise an assay that can go after those quantitative endpoints.
DR. SALOMON:  Well, the problem with quantitative assays, of course, is that these are polyclonal immune responses, so quantifying the antibody in serum rather than titering it out is a big leap technically.
If we talk about assays for antibody, do we generally agree that it's not just antibody but it's actually neutralizing antibody that is important?  Do we want to make a distinction about that, or if you're going to measure antibodies, measure both?  Or does anybody care?
DR. MILLER:  Don't you measure the binding as a screen?  If the binding is negative, the neutralizing is never positive.
DR. SALOMON:  Okay.
DR. MILLER:  So, it's one step.  I think it should be a gradation.  We think these are potentially low risk.  We screen a lot of patients' serum, and so you want to have the first test to be as sort of easy as possible and then focus, at least talk about number 2 here specifically.  You have a screen and you see binding.  98 percent of the patients don't have any binding.  So, you can just ignore the rest of those patients.  But in the patients that have binding, then you have to look for patients that have neutralizing.
Then I think you should go then and repeat pharmacokinetics potentially because I think those are the patients that you really need to predict whether or not they are having the biologic effect, et cetera, et cetera.  So, you have a three-step approach doing the studies and you're not doing excess tests on any one --
DR. CHAMPLIN:  Although examples were pointed out where binding led to altered pharmacokinetics without neutralizing the biologic function.  So, if you've got binding, then at least you need to be concerned about alterations of pharmacokinetics.
DR. SIEGEL:  Yes.  I think we'd agree in most cases, the ELISA or whatever total binding assay is more sensitive than neutralization assays.  So, I think it's correct, we don't see neutralization where we don't see binding, and often if the company only tests for neutralization if binding is positive, that's generally considered an acceptable approach.
But I would also reconfirm that, that non-neutralizing antibodies can be clinically significant.  Certainly they can give rise to immune complex disease, and certainly they can alter pharmacokinetics and biodistribution of the product.
DR. SALOMON:  I'm cognizant of the fact that Dr. Goldsby is also with us, again the miracle of the -- this gray thing is Dr. Goldsby here. 
(Laughter.)
DR. SALOMON:  It's actually quite attractive.
(Laughter.)
DR. SALOMON:  A triangular, Star Trek looking thing.
Do you have any comments about this?  I realize it must be difficult for you to contemplate jumping into this discussion.
DR. GOLDSBY:  No, nothing specific.  Just a general comment that this is not exactly a new area we're entering now.  A great deal of experience has been built up over several years, and I think that probably ought to inform as well as temper our concerns in this area.
DR. SALOMON:  Thank you.
DR. SIEGEL:  Let me explain some of the phrasing of this question.  I think it has become increasingly apparent to us in reviewing the database that there hasn't been consistency in the types of data that have been asked for or collected over the years, and I think the committee, in looking at this, would also know that there are certain holes.  There are certain important questions that haven't been answered.
So, this has given rise to a little bit of thought as to what is a rational process for collecting data and how much should be collected.  Basically the process that's proposed here, which is what we do I think some of the time, maybe even most of the time, would be in the pre-marketing phase collect everybody's serum, test it for binding, and where appropriate for neutralization, and then use those data to look for correlations with whatever clinical data you have but not necessarily to do specific studies designed at exploring those correlations except where either there's a signal from -- you know, and to look at all of that and to be required to look at all of that -- I should go back a point -- at the time of marketing.  And then where either there's a signal there that it looks like there may be something there, or there's a signal from some other reason of concerns that animal data, pharmacological data that raise a higher level of concern, only in those specific cases we might then think about ought there be additional studies, either pre- or post-marketing depending on how high the concern is, what disease is being treated and so forth.  That's the general paradigm outlined here.
DR. SALOMON:  Dr. Champlin?
DR. CHAMPLIN:  Just reflecting that what often happens in real life is it works the other way around where instead of prospectively looking for antibody responses, people recognize syndromes, loss of interferon effect, your blood counts aren't coming at them anymore, the T-cells aren't being suppressed.  So, in looking at the clinical events with equal scrutiny from the outset may again tip off where you're losing biological efficacy for whatever reason, and so that in situations where that can be actually measured with each course of treatment, that would probably be the best screening test of all for antibody responses.
DR. SALOMON:  Abbey?
MS. MEYERS:  The binding test or whatever laboratory test.  We're talking here about clinical trials and then the sponsor would do these tests.  Let's say that throughout the test, he finds some patients have the antibodies and some don't or some have it worse than others.  If the result of that is that everybody who is on the drug, who gets on the drug after it's approved, should be tested every time they're rechallenged anyway, are these the kinds of tests that can be done on Main Street General Hospital or they have to be sent away to special labs?  What would the cost be to --
DR. SALOMON:  Well, I think part of the answer is that any general lab can do a well-developed and validated ELISA assay, but when you're doing a clinical trial, they're not going to have a well-developed, validated ELISA assay.  So, I think you will end up with central laboratories where samples will have to be sent.  You're not going to suddenly distribute hundreds of kits with recombinant antigen on them.
DR. SIEGEL:  There are two or three paradigms that can be followed.  This is sort of what we were addressing in the fourth bullet.  I think Dr. Auchincloss pointed out some important cautions, but there have been cases where it is clinically important enough that we think a test needs to be available.  Then we might ask or even require the sponsor to make that test available. 
It can be done in a number of different ways.  There are sometimes where you can make a commercial kit that measures, say, human anti-murine antibody.  You could have it as a service offered by laboratories, or it could be a service offered by the manufacturer of the drug product themselves.  So, there are different ways that can be achieved.  
I can't speak to what the costs involved might be.
MS. MEYERS:  Well, if this happens down the road -- and I'm sure maybe five years from now you might be retired.  Somewhere there should be a registry that under managed care you can send your blood off to the laboratory that you want to or your doctor wants.  You have to send it to the one that contracts with your managed care company, and that could cause a problem.  So, I ask you to remain sensitive to that so that if people need a repeated blood test, it does not run into the reimbursement problems that we're experiencing now.
DR. SALOMON:  So, again trying to get the drift of where this is going, I think Dr. Miller put it well in that perhaps we're all sort of thinking it should be staged.  You first screen for antibodies at all.  If you can't find an antibody with a reasonably sensitive test, you're probably done right there.  We made the point that antibodies isn't everything, but at least from the point of view of this assay aspect. 
Then if the antibody is present, do we all agree that we should look for neutralizing antibodies?  And then if the neutralizing antibodies are present or if antibodies are present, we ought to look at the pharmacokinetics of the molecule in question and compare that with some quantitative measure of the antibodies, whether it's titer or a molecular definition of it.  So, in other words, asking questions that high titer patients or high responders might have a different pharmacokinetic than intermediate or negative responders.
DR. SAUSVILLE:  But there are kinetics as well as dynamics because kinetics, in the absence of some dynamic quality, would be important.
DR. SALOMON:  Right.  So, I guess I was going to say that the fourth level would be to have some sort of biological parameter that would then, of course, be unique to the product and the patient population.  So, that we can't really define.  We'll do that I guess when someone puts something specific in front of us. 
I think that gets to something.  Dr. Auchincloss made the point.  I share his experience using OKT3 and more recently the anti-IL-2 receptor antibodies in transplant patients.  Again, we don't typically measure the antibodies.  We look at bioassays.
DR. CHAMPLIN:  One has to distinguish the clinical trial phase pre-approval and then long-term practice where in practice you're not going to do all these things.  During the clinical trial phase, you need to define the biology and what's going on.  Once those principles are established, then you can find some cost effective strategy to treating the patients and still gathering the same information.
DR. SALOMON:  Dr. Stein.
DR. STEIN:  I just wanted to comment that in many instances with monoclonals, because they are product-specific assays, that even in instances where there has been relatively few immune responses, we've asked companies at post-marketing that they make that assay available if a physician feels a patient has a reaction that they would like to know might be associated with an antibody response, that they have a place where they can send the serum to be tested.  This wouldn't be an assay for which they would charge necessarily.  It would just be a service.  This would be for products where it wasn't necessarily critical that this be measured in all patients, but just a service to be available if a physician would like to know whether an antibody response occurred.
DR. SALOMON:  Dr. Vose.
DR. VOSE:  Just a quick comment.  I think it's important again for us to keep in mind that these antibody responses need to be clinically relevant.  I've seen some examples of companies who use this information I think maybe improperly where they say, well, our antibody only has a 2.7 percent HAMA.  Yours has 2.8 or something like that.  I think that that's clearly not appropriate and it needs to be something that is clinically relevant for us to be concerned about it.  We shouldn't let the companies use that kind of information improperly.
DR. SALOMON:  Yes.  I think Dr. Auchincloss had made that point, and I agreed with that.  That came up in our pre-discussions about sort of things that we should get on.
So, let's go back to that specifically.  If we agree that there should be an assay, to what extent should we grapple with the idea of standardizing the assay?  Should there be standards for these assays?  I know Dr. O'Fallon had made several times now the comment of specificity and sensitivity.  So, to finish up this assay question, can we get some comments from the group on that?
How many different ways are there to do an antibody assay?
DR. SIEGEL:  There are not only an unlimited number of different ways to do it, but for every one of them, you can choose your cut-point of positivity along what is usually a continuum so as to modify the sensitivity and specificity to your liking.
Unfortunately, these claims -- and this really is at the heart of question number 4 -- have induced some sponsors, we believe, to intentionally choose insensitive assays so they can then promote low rates.
DR. SALOMON:  Right, but the question we're dealing with now, Jay -- we don't want to go on to question 4 yet -- is, is there anything that the committee can say constructively to the FDA regarding what we think should be done in terms of dealing with this sensitivity/specificity issue up front? 
So, I see a bipolar response here.  One would be no.  We can't tell you anything you could screw around with the assays in any way of a million ways and it's just impossible to standardize anything.  So, we'll just have to take it on a one-on-one basis and insist on some sort of validation of sensitivity on that particular study, go on to the next one.  Or that there's some way of standardizing this, some sort of molecular standardization that we could use or insist on.
DR. SAUSVILLE:  Most of the time there is some sense of what concentration of biologically active substance is actually acting at a receptor or whatnot.  I think as a minimum -- and I'd toss this out and get people's reaction -- putting it on the sponsor's shoulders to show why they can't develop an assay, that it would at least detect the drug acting as it's intended to.  If they can't, well, then that's interesting, and that becomes then a set of biological realities.  But most of the time you probably can.  Then that then becomes by definition a bar that sensitivity is going to be addressed for each agent and becomes one way of comparing across agents.  I toss that out.
DR. O'FALLON:  If we were looking at the results of a randomized controlled clinical trial, we'd demand that they'd quote us at least a p value and very possibly a statement of the power of the test that was designed.  Yet, throughout the entire day, I've not heard a single number quoted as to the sensitivity of any of the assays that we've discussed or the specificity.  I think at the very least we need them to document what those specific sensitivities and specificities are for those different assays.
DR. SIEGEL:  Yes.  The reality, of course, in most of these cases is there's no gold standard.  There's no one who can say this specimen truly does have antibody to the product and that one doesn't.  So, it's sometimes difficult to say which are the true positives and which are the false positives and what is the true sensitivity and specificity.
DR. O'FALLON:  Precisely my point and some of the points I've made.  You're talking an awful lot like everything that come out of these tests is the gospel, and yet it could be dramatically different from that.
DR. SAUSVILLE:  I would simply respond by saying, ah, but one can say that you have an assay that would detect an antibody that would interfere with this substance acting in its biologically active concentration.  So, that frames it more in terms of interfering with what you think the intended function of the biological is.
DR. SIEGEL:  There's probably a lot more role ‑‑ and I think Dr. Zoon alluded to this -- to standardization and even quantitatization of neutralizing assays because for neutralizing assays, you're looking usually at an active molecule and a cell line that's responding to it, and then you're looking for the ability of serum to inhibit that.  You can standardize what the molecule is, what the cell line is, a lot of the parameters, and that could be very useful.
For these ELISAs to detect binding antibodies or IRMAs, or whatever they are, the questions of standardization might be tougher.  But that's a point well taken.
DR. BROUDY:  But you can also know the standard curve.  Every assay has to have a standard curve, and so you know the lower limit of detection on the standard curve.  So, maybe that should be included, the standard curve and what the lower limit of detection is.
DR. SIEGEL:  The lower limit of detection.  You're suggesting again in terms of like mass units of antibodies.
DR. BROUDY:  Right.  Nanograms per ml or micrograms per ml or whatever because every assay has got a standard curve.
DR. MILLER:  I just want to go back.  I think Dr. Schaible this morning showed us that these things actually can be done.  You can quantitate an antibody, and then you can do a study to show that it is not clinically significant, which I think is what we really show.  I think that should be done actually, as much as you can, before the drug goes to market, if there are neutralizing antibodies shown, that you need to know what the clinical consequences of those are before you put it to market because I think that's the best chance of finding out really the data.  In a pre-marketing versus a phase IV study, you have a much better control over what you do.  So, I would say that that should be considered maybe a minimum if you find something.
DR. CHAMPLIN:  Yes.  Well, again, it has to occur in some sizeable fraction of the patients to be relevant.  If it happens less than 1 percent of the time --
DR. MILLER:  Right, but if you see something more than 5 percent -- I mean, there's something, some cutoff.
DR. SALOMON:  Dr. Stein?
DR. STEIN:  I'd just like to ask Dr. Broudy.  Frequently the standard curve is developed with an animal antibody.  We have a human product or humanized antibody or some other product that goes into a rabbit and you develop a standard with a rabbit antibody.  Does that bother you if you see that the lower limit of detection if 10 nanograms per ml of rabbit antibody?  That is frequently the way these are developed.  
Unless you have a patient that had an adverse reaction, you went back and looked, and found they had a high titer serum, and you could use that antibody for the standard.  But frequently that's a limited amount and not one that would be available again.  So, it couldn't be used for a standardized assay over a long period of time.  
There may also be monoclonal antibodies as well, and they have a limitation that they would only detect a single epitope unless you made a large cocktail to try to approximate a polyclonal.
So, I guess the question I have is would you be concerned if it were an animal antibody that were given as a specification.
DR. BROUDY:  Well, I think those are concerns and I think we can't really get into that right here.  But you'd have to look at the specific ELISA tests that were designed for each reagent and how it was set up and think about what curve they're using to call something a positive or a negative.  And I think those are concerns.
DR. SALOMON:  Kathy?
DR. ZOON:  Just from some experience over the past 25 years with interferon, to kind of frame where we evolved in the interferon field, because we have probably the most knowledge, and whether or not that's relevant to the broader cross section of therapeutics may be applicable in some cases and may not be applicable in others.
Over the years, it was recognized that having a standard assay for neutralization was very important for interferon.  In fact, a great deal of effort was put into it by a Dr. Kuwadi, who's currently in Japan, to develop a standardized assay that everybody would adopt as an assay for determination of neutralization by interferon alpha and can be used for some of the other interferons.  In general, that was picked up by most investigators and most clinical investigators.  
It also became aware of the need to have a standard human antibody preparation.  In fact, one was made and was actually viled and is used as a reference reagent by WHO.  
Maybe one of the questions, as these products evolved, is it important that either WHO or FDA or somebody encourage the use of more standardized assays where appropriate and encourage the development of some of these reagents as a way to promote some standardization, recognizing that it may not be relevant in a lot of areas.  The question maybe might be worthwhile discussing if the committee feels that would be relevant in some cases and should that be supported and promoted to the level that is feasible.
DR. SALOMON:  My comment would be from the way I see the committee going, I think some of this has already been discussed.  I think what the committee is saying, again looking for consensus -- correct me if I'm not stating this properly -- is that just finding antibodies, even just finding neutralizing antibodies are not necessarily relevant.  However, they could be.  Where the committee's attention would become focused is when there's demonstration of a pharmacodynamic or a biological effect that then becomes relevant.  Then the big question would turn back on is the antibody predictive of that.  I think that that has been said a couple different times.  If that were true, then I think the energy to develop standardized tests would be immediately appropriate.  However, to use resources to develop those kinds of standardized tests in the absence of any correlative I think would be an unnecessary burden.
DR. CHAMPLIN:  Yes.  Interferons are so widely used now for such a broad range of diseases, but there's a need for that type of thing.  But the assays for antibodies to the anti-CD40 ligand, who knows?  It's a smaller spectrum of studies going on.  So, when you really need the information is the very early point in development where you don't have the standards.  So, it's a catch 22.
DR. SALOMON:  I guess the other thing I wanted to make sure the committee agreed -- I think that I'm hearing from everyone -- is that in the process of a sponsor coming forward to initiate the first clinical trials, probably a tremendous amount of results pre-clinically is not going to be relevant, and that a lot of this then should be the focus of the clinical trial period to establish these different elements.  So, a lot of the assay design issues will be fluid during the run-up from phase I to the pivotal phase III trials. 
DR. CHAMPLIN:  And my guess is that in only a small fraction of the products coming forward is this going to be highly relevant.  Most of the things that you showed have a low level of antibodies being produced and they're not often of biologic importance.  So, to put a lot of emphasis on it before you know it's even a problem seems misguided.
DR. SIEGEL:  That may be the case, but more and more of the products are moving from relatively acute settings into more chronic use.
DR. CHAMPLIN:  Not to say that it shouldn't be looked at at all, but I wouldn't sort of make it a deal breaker for the pilot study.
DR. SAUSVILLE:  And here is where collecting the samples, having planned ahead of time to be able to go back and make some sense out of all this once you've got the clinical data put together, I think is going to be very important.
DR. SIEGEL:  What I think I'm hearing is -- but let me clarify to make sure it's what I'm hearing -- in terms of the concerns about the clinical significance, as several of the speakers have noted, I think is something not far from or perhaps quite similar to what we're proposing.  So, let me just go over that and bounce that off you again and see if, in fact, I'm sensing the committee right.
DR. AUCHINCLOSS:  I was just going to jump in there because I was just going to make that point.  I think what we've said is what you've written down here.
DR. SIEGEL:  That's what I was thinking.  What we've written in the second bullet is that if you're collecting the specimens from the start, that by the time of marketing, if you have a sensitive assay so you can pick up low titers, high titers, whatever, and neutralizing and non-neutralizing, that those data should be explored for suggestion of correlation between those findings and PK, PD, efficacy, or safety.
Now, of course, if half of the patients have antibodies and half don't, you're going to have some amount of power such as another assay we always do, which is looking at effects in men and women.  It's not likely to be sensitive to every significant effect, but it will be sensitive to large effects.  If you have only two patients who developed antibodies, you're going to be guessing what to make of it.  But on the other hand, what it means may be less important if only two people have identified it.
So, the approach would be to routinely do that, collect the data, routinely analyze the data for correlations, and then make a determination if those studies suggest either that an important effect may exist or inadequate to exclude an important effect where there's a particular concern for any of a number of reasons.  That's when additional studies should be considered.
You're saying that is, in fact, your sense too of what the committee is saying.
DR. AUCHINCLOSS:  I thought what you wrote down here was excellent.  The only point was a minor one.  In number 4, you got hung up on an antibody assay -- 
DR. SIEGEL:  We don't always need an antibody assay if there's a clear clinical sign that can be used.  Yes.
DR. AUCHINCLOSS:  (Inaudible.)
DR. SIEGEL:  Yes.  Point well taken.
DR. AUCHINCLOSS:  But I really do think that what you wrote down is sensible and reflects what the committee has been saying.
DR. SIEGEL:  It sounds like that reflects what I've been hearing.
DR. SALOMON:  What I'd like to do -- there are a couple of people that are going to have to leave at 4:00, and I'd like to then take a small chairman's prerogative to jump over question 3 to question 4, the product labeling and promotion issues just because -- I may be wrong, but I'm guessing that might be a little more contentious than question 3. 
I guess I'm being informed Dr. Goldsby is leaving already.  Thank you.
So, question 4 is on product labeling and promotion issues, and again, everyone has it in front of them, so I don't see a point in reading it. 
But it raises a whole number of different questions about what we feel is appropriate and not appropriate for sponsors to claim based on these data, albeit we've identified a lot of unknowns in the product, and if so, what kind of guidelines can we give the FDA on this? 
Dr. Auchincloss?
DR. AUCHINCLOSS:  You have completely changed my mind.  I came down here, after reading this, saying, oh, come on, just let the sponsors say whatever is true. 
(Laughter.)
DR. AUCHINCLOSS:  I must say, along with Julie, I've really changed my mind.  The statement that my product has less of a HAMA response than your product is truly a meaningless response is what I think I've learned today and therefore should not be included in the promotional --
DR. VOSE:  That's not exactly what I said.  I said that they need to prove that it is meaningful for them to say that. 
DR. AUCHINCLOSS:  Fair enough.
DR. VOSE:  And it might be, but most of the time it probably isn't.
DR. SALOMON:  So, Jay gave us the guidance that the question for the committee is not to put immunogenicity data in the product labeling.  It is going to be in the product labeling. 
DR. SIEGEL:  Well, wait a second.  
DR. SALOMON:  I thought you said that.
DR. SIEGEL:  Somebody, I think Bill, may have said that.
DR. SALOMON:  I thought you said it's required.  I wrote it down.
DR. SIEGEL:  Bill may have said that. 
I think what will be on the product labeling is anything we know about clinical correlates of immunogenicity.  If we know that there's loss of efficacy or safety concerns, that will surely be in the labeling.  But what we're left with is a long history of putting a lot of numbers, percentage numbers, in labeling whose ability to inform is uncertain and whose ability to misinform has in cases been demonstrated.
DR. SALOMON:  Right.  Yes.  No, I agree with that.
So, the question is if we're going to discuss immunogenicity, what kind of guidelines are we going to make for discussions of immunogenicity.  And I don't think we're really disagreeing.
So, again, we get back to should there be a disclaimer in the product insert in bold, much like we have on a pack of cigarettes -- 
(Laughter.)
DR. SALOMON:  -- that says based on the current technology of these kind of assays, we cannot make any prediction on the relative immunogenicity of our product versus any other product in its class.
DR. MILLER:  I don't think you should go that far.  If you have a 90 percent immunogenicity, people need to know that.  I think you can say mild, moderate, severe.  You can put criteria on that so you can't compare.  But I think that if everybody is going to get an immune response to it, I think people need to know that.
DR. VOSE:  But I think they also need to know if it does or does not make any difference to the patient.
DR. SAUSVILLE:  Right.  I mean, that's the issue.
DR. MILLER:  Right.  But I think saying that you're going to require that they have it, I mean, yes, if it has a difference, a clinical -- I think that we need to know that before you go to marketing whether or not it does have clinical correlation.
DR. VOSE:  Right.
DR. SIEGEL:  If it doesn't, are you still saying, though, the numbers belong in the labeling?
DR. MILLER:  That's true.  If it doesn't, it shouldn't be.  I changed my mind.
DR. VOSE:  I don't think unless it has a clinical correlate that people need to be putting those numbers on the label because what happens is it gets out in the community where physicians don't understand what those numbers mean and then drug representative X comes and says, oh -- 
DR. SALOMON:  Look right here.
DR. VOSE:  Yes.  It's right here on the label.
DR. SAUSVILLE:  It's immune.  It's scary, anaphylactoid, et cetera, et cetera.  
Besides that, it then gets into this whole quagmire of how hard do you look basically.  If you have an assay that tests one level of sensitivity and another assay that -- if we're going to start allowing claims to be made A versus B, it gets into this issue of how comparable these things were.
So, I actually like the idea --
DR. CHAMPLIN:  I think this may be a unanimous thought here because I don't see anyone objecting.
DR. SALOMON:  So, we're going to do the cigarette labeling approach?  We make no claims.
DR. SAUSVILLE:  Maybe in slightly less bold letters.
(Laughter.)
DR. SIEGEL:  I think what I'm hearing is not to put a disclaimer but even to suggest that we may not need to put rates in at all if there has been some reasonable looking for clinical correlates and not finding any.
DR. SIEGEL:  Well, I think seriously what I was trying to articulate is I think that what we're saying is if there is a clear immunogenicity, then it has to be specifically spelled out in the product.  However, if at the time at which the drug is approved, the data is such that at the final data cut that experts do not agree that this is significant, then we should not allow this kind of data to be there that then can be abused in marketing.
DR. MILLER:  I'll go back to why I'm harping on this.  I'm very concerned from a clinical standpoint about the precedent, a drug being approved and out there on the market with a known 90 percent neutralizing antibody at 3 months and the clinicians being left to decide whether or not that means anything, which is what state we are in now with a drug.  So, in that case I think that that information needs to be there.
Now, if we know that based on this we're going to say that you have to know the answer, then I think you cannot have the information in there.  In that setting, I think you need have it.
DR. CHAMPLIN:  I think we all agree if there is clinical immunogenicity, where the immune response alters the response to the drug, that has to be in the label, and it has to be in the label if it occurs in most people or rarely. 
So, I like the sort of the semi-quantitative terms which then prevent comparison of 23 and 24 percent by drug reps and still imparts meaningful information.
DR. SALOMON:  Of course, we'd have to set numerical limits to define mild, moderate, and severe, which then of course could be repeated by drug reps.  These are like the 1 plus 2 plus 3 plus things we have all done in certain times in the dark areas of our careers.
(Laughter.)
DR. SAUSVILLE:  Then maybe the fall-back position is to say something to the effect, here's the immunogenicity data.  This has not been compared head to head with any other particular item, and that, therefore, to claim that item X is better than item Y based on this type of test hasn't been scientifically established.
DR. SALOMON:  That's the disclaimer approach.  Put the data there and then put the disclaimer.
I actually don't mind the mild, moderate, severe.  I think the point is well taken.
DR. CHAMPLIN:  I don't think anybody the disclaimers.
DR. VOSE:  Yes.  Nobody is going to read the disclaimer.  They're just going to say, oh, 24 percent.
DR. SIEGEL:  Well, actually if we put a disclaimer in that about -- well, there are two types that we might be thinking of here, one that the clinical implications are unknown, but a disclaimer about that these data should not be used for comparisons actually sends a message other than to physicians because it sends a message to sponsors that is up front in case they haven't heard it elsewhere or could claim not to have heard it, that any claims they might make have been determined by the agency not to be appropriate claims.  So, there is a role.
In fact, as you all know as practicing clinicians, label reading is not perhaps one of your major endeavors.  But we're trying to fix that actually by making much more informative and better labels, and I hope we'll succeed.  But labels are also used by lawyers, by promotional people, by patients, but there's a lot of consumers --
DR. SALOMON:  But I think I would say many of us actually, the first time we use a drug that's as serious as some of these, would read the label.  I don't think I would want to be tested on it later, but --
DR. SIEGEL:  And importantly, what's in the label forms the basis -- that was the point I was making -- of what is or isn't considered acceptable promotional information.
DR. SALOMON:  An issue that came up in our discussions was how does the process chosen to produce these proteins actually influence the immunogenicity.  That has come up a couple times in our discussions.
DR. SIEGEL:  Before we leave this topic, let me just make sure I understand.  It sounds like there's support in this committee that the notion of just giving numerical rates that do not have clinical implications and could be misused, the committee recognizes problems with that and supports it sounds like either of two approaches which might be either not to include those rates or to use a semi-quantitative approach with rates with perhaps some, if not disclaimer, information about what implications of those rates are or are not appropriate.  
Is that a fair recapture, that you might see -- Dr. Miller, for example, in the case you might feel that it would be useful to say most patients developed antibodies.  However, with the limited data available, no impact could be discerned on safety or efficacy or PK.
DR. MILLER:  Right.
DR. SALOMON:  I think that's important in that we can't exclude the possibility that at the time a drug gets approved, there might be 60 percent of the patients developing an antibody response even with a significant neutralizing antibody response.  But still there's no evidence of a biological effect, and we therefore downplay it in the original product labeling, but we at least put it there.  Then maybe three or four years later, talking about the doomsday scenarios that we were kicking around earlier on, all of a sudden there's a 20 percent incidence of some horrible event that took four or five years to emerge.  At least it's in the package insert.  Right?  We can't always know all the downstream implications of what we're talking about.
I wanted to get at the process thing a minute because it does relate in some way to the product labeling.  It also goes beyond the questions here.  So, before people left, I wanted to bring it up.
One of the things that concerns me is that we talked about identifying that there's an antibody response and how we would identify it and then how we'd even label it and advertise it.  But what we haven't really talked a lot about is what energy should be put on determining what that antibody response is against.  
So, if I make a product that I get an antibody response and we follow it down, if it's against an aggregate, shouldn't we identify it against an aggregate and then put pressure on the sponsor to develop an aggregate-free product?  In other words, where do we stop being passive about insisting on assays and get more active in terms of saying what is the element of this?  Maybe it shouldn't be given subQ.  It should only be given IV.  Maybe it should be given with corticosteroids, et cetera.
DR. SAUSVILLE:  There we discussed the stepwise approach that Carole outlined, reverse binding and then neutralizing, then PK, then PD.  I mean, it would seem the logical progression of that is that -- 
DR. SALOMON:  Is next find out what it's --
DR. SAUSVILLE:  Yes, because it's important enough to change the biological properties.
DR. CHAMPLIN:  Although the aggregates usually are -- it's not just like it's binding -- the aggregate may stimulate the immune response but it will bind the soluble factor.
DR. SALOMON:  Right.  But then you would be -- perhaps if you could demonstrate that it was -- well, that is actually a fair point.  It's easy to say.  It might not be so easy to prove.
Certainly non-natural forms, denatured, disulfide bridge, broken forms that might expose cryptic antigens, those would be very relevant.  The aggregate question is relevant but more difficult.  That's a good point.
So, I don't know.  Not acting as the Chair now, my own personal thing would be that we ought to keep that in mind, that if an antibody response is discovered, even if it's not so clear it's biologically relevant in my opinion -- just because I'm a little concerned about the time frame in which we're going to define biological relevance in a field as complicated as biologics -- but if we find an antibody response, that there should be a phase in this phased-in process that we identify what it is against and consider ways to minimize it.
Well, we can return from product labeling and promotion to this last question, and that is study of repeat or intermittent usage.  I think to summarize that, the concern that the FDA had in our initial conversations was that a lot of these drugs could be brought to market with the idea that they'd be used once, and yet, once it's marketed, people will essentially start using it multiple times.  So, how big a concern is that in the context of immunogenicity, and to what extent should that be considered in the plans the sponsors provide, phase II, phase III versus phase IV?
DR. SIEGEL:  Let me just add as a background to that the agency -- those of you who have read the newspapers in the last year are aware that the agency has focused a fair bit -- Dr. Zoon could expound on this -- on the fact that a number of notable toxicities have come to light in the post-marketing period.  Where possible, it would be desirable -- it's not always possible in a feasible manner, but where possible, it would be best to identify them prior to marketing.  
In sum, I think the data you heard regarding Remicade, for example, about reuse was a case where the immune complex disease on reuse came to light essentially within the first few weeks after licensure of the product.  This licensed product was used in people who had also received it in clinical trials.
With that and as was pointed out with, say, imaging agents for cancer, which we know sometimes behave differently on reuse because of the development of HAMA, there's a reasonable guess that you could license them for single use, but that some people are going to want to use them a second time.  And the question is should we be more routinely getting those data pre-marketing.
DR. CHAMPLIN:  It's hard to think of too many things that you'd only do once.  In a transplant, modifying a transplant maybe.  But most things, imaging agents, anti-inflammatory drugs, almost anything you would at least have the potential to reuse, so that that should be explored in the initial studies.
DR. VOSE:  I agree.  I think once they've gotten to the phase II portion, they know what dose, and they're going to go on to do treatment, that they should have at least some retreatment information.  Again, we need to know if it's clinically relevant, though, as far as that's concerned.
DR. SALOMON:  Abbey.
MS. MEYERS:  One of the problems is more and more we're seeing with the new biotech products, the manufacturers really don't make an awful lot and have it on hand and there's usually a shortage.  Even if they give it away under a treatment IND, they have a very limited amount.  They only allow a certain number of patients to go through.  So, I can't see, unless you tell them up front that you want some people to be rechallenged, because the people who went through phase II are dropped when they start phase III.  That's it.  Nobody else can get it.
DR. SIEGEL:  Yes.  This I guess will be an issue that we would take up at early developmental meetings with sponsors so that they could plan it into their plan in terms of drug supply.  I think that's a point well taken because with the biologics in particular, as you well know, there's often an upscaling necessary to market.  In that period between the small scale production for clinical trials and the upscaling, there are these shortages.
MS. MEYERS:  And they don't want to invest in that until they get some sense from you whether the drug looks good or not.
DR. MILLER:  I'm actually going to take the opposite.  I think there are some situations where you're not going to be able to do that.  I don't think to require it in all situations is -- I mean, like the one that is for the acute chest pain syndrome.  You can't very well require people to be retreated because generally people get treated, they get PTCA.  Until you get huge numbers, I think that it should be recommended you can get the data, but I think that in some cases, especially if you have an agent that works, you may not need to retreat them for a year, two years.  So, it may be difficult.
I think that if patients are getting, in the clinical trial, repeated doses, that you make it imperative that you don't only test the first dose pharmacokinetics, you test the fourth dose immunogenicity and pharmacokinetics as well.  So, from that standpoint.  But in all situations, I don't think you can reasonably expect them to say, okay, we're going to wait around till somebody relapses, has a second episode of chest pains so we can give them the drug again.
DR. VOSE:  But I think if the sponsors know this that that's part of the overall plan and then they have a protocol that's already open and available, at least they'll get some patients that they can do that on and have a little bit of information.  I don't think you have to have a huge trial at the time that you're considering that.
That even, for example, has been done in some of the lymphoma antibodies, that they had a retreatment trial that was open like two months after the treatment trial was opened, and it has actually worked pretty well.
DR. SCHWIETERMAN:  It's more common to have open label extension studies following, say, a phase I or phase II for both safety and for even long-term efficacy in some cases.  So, we could easily include these sorts of things, measuring patients who went off the drug or had serial doses, whatever, or just measuring at the fourth cycle what the antibody levels were.
DR. SIEGEL:  I think that we see the spectrum in terms of pragmatics.  There are certain things like flares of multiple sclerosis or arthritis or Crohn's disease or whatever which occur reasonably regularly where you could collect some amount of data.  Imaging of tumors where you could certainly image before and after therapy and people are interested in doing that where one could expect to be able to collect those data.  I think waiting around to follow people for them to have an MI might be a more difficult situation.  We'll tone that with some concern about the pragmatic.  
Rejection episodes or organs is something where usually if you follow over the course of two or three years of development at least, you're going to get a second episode in a lot of people.
DR. SALOMON:  Dr. Auchincloss?
DR. AUCHINCLOSS:  Well, actually I think everything I was going to say has really been said.  So, let me just go one step further, and that is, in your question you say you want us to discuss the nature, extent, timing, and role of these studies, which I don't know if we've done that.  Do you have something sort of in particular in mind?  Because I do think in general, yes, studies of reuse should be part of percertification.
DR. SIEGEL:  Well, no.  That was just to open up broadly for you to provide input where you'd like.
There is one other aspect of this question which hasn't been touched on, though, which is there's one question which was raised in the presentation.  There's this question of one-time use and then repeated one-time use.  But there are also those drugs that are used chronically and the concern that although they'll then be studied chronically -- and we have guidelines and policies regarding how many patients for how long should be studied in different settings.  One thing that happens, once they're out of the clinical trial setting, is rather than chronic continuous use, a patient may be on it for several months and then be off for a period of time and then be restarted.
DR. AUCHINCLOSS:  I think intermittent use is a very important issue to cover, and you made that clear there.  But that probably does happen in most clinical trials also.  Again, if you've set up your protocol to look for those events and capture them when they occur, you probably see them, don't you?
DR. SIEGEL:  Well, we've seen some drug development programs which wouldn't have captured that information, in fact, failed to.  But I think it can be if one plans to.
DR. SALOMON:  Well, I think we'd all agree then, again trying to reach a consensus here, that there's no doubt with any immunogenicity experiment, whether it be in an animal or a human, that repeated dosing and the avenue of dosing are critical, but that repeated dosing, regardless, is a high risk factor for getting amplified primed responses.  Right?  
And certainly the clinical effects of a primed immune response can be profoundly different than that of the primary immune response, which is something that hasn't come up yet.  But it's also true.  Right?  Usually much different, more specific, higher avidity antibodies frequently.
Anyway, so the bottom line is I think that we just need to make sure that a trial in which the intention is obviously to treat repeatedly, that that be from the beginning incorporated in the trial design.
DR. AUCHINCLOSS:  I just wanted to ask the FDA for a little clarification.  In a sense this is a little unusual.  Right?  Because you're basically asking the sponsor to come up with information that goes beyond their request for labeling.
DR. SIEGEL:  Well, exactly.  That's why it's not quite the no-brainer that Dr. Salomon --
DR. AUCHINCLOSS:  No.  I don't think it's a no-brainer at all.
DR. SIEGEL:  Because in fact --
DR. SALOMON:  I wasn't characterizing it as a no-brainer.  I just thought this was appropriate policymaking.
DR. SIEGEL:  Nobody would deny that repeat use could heighten those issues, but one potential response to that is, well, we'll just put it in a caution, don't use repeatedly.  This is for one-time use only.  
DR. SALOMON:  No, but to me that's disingenuous.  You're not going to tell someone with Crohn's disease that had a beautiful response to your reagent that, well, I'm sorry, we can't treat you again.  I think that to me is a no-brainer.
DR. AUCHINCLOSS:  I wanted to clarify that because I think the assumption with which I approached this is that reuse and intermittent use is such a given with all of these products that you have to assume that's it --
DR. SIEGEL:  We should be collecting the data.
DR. SALOMON:  Yes, and I agree with Dr. Auchincloss on that.
Are there any other comments on this?
(No response.)
DR. SALOMON:  Then I think I'd like to thank everyone on the committee.  I hope that we've addressed each of the questions.
DR. SCHWIETERMAN:  Yes.  We very much appreciate the input.  Thank you very much.
DR. SALOMON:  At this point, we are complete with the open committee portion of today, and at this point we'll take a 10-minute break and come back to the closed committee discussion, the update of the research programs and a site visit report.
Again, I thank also the audience for their attention today as well.
(Whereupon, at 4:08 p.m., the committee was recessed, to reconvene in closed session, this same day.)