1

    DEPARTMENT OF HEALTH AND HUMAN SERVICES

         FOOD AND DRUG ADMINISTRATION

 CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

                       

                       

                       

                       

                       

                       

     OPEN MEETING WITH CORAR ON FDA'S DRAFT

            "GUIDANCE FOR INDUSTRY:

DEVELOPING MEDICAL IMAGING DRUGS AND BIOLOGICS"

            Monday, January 25, 1999

                   1:33 p.m.

            Conference Rooms 1 and 1 Woodmont 1 Building 1401
              Rockville Pike Rockville, Maryland

                                                           2

                      C O N T E N T S

AGENDA TOPICS                                         PAGE

Introductory Remarks                                     3
Desirability of Separate Guidance for
     Radiopharmaceuticals                                    7
                                 
Criteria for Group 1 Status for
 Radiopharmaceuticals

          AND

Safety Testing Requirements for
 Radiopharmaceuticals designated as
 Group 1                                                16

Proper Role of Clinically Blinded
 Readings                                               68

                                                                3 1

 P R O C E E D I N G S

 2             DR. MILLS:  Good afternoon.  It's 1:30 and I would

 3   like to open the meeting today.  I'm Dr. George Mills from

 4   the Center for Biologics, and a member of the

 5   Radiopharmaceutical Document Development Group within the

 6   FDA.  Today's meeting is a working meeting between FDA staff

 7   and CORAR.  The agenda has been provided at the door and a

 8   sign-in sheet has been provided at the door, and I'm also

 9   aware that I'm supposed to remind everyone to please sign

10   in.

11             In the interest of making this process as public

12   as possible, we have invited members of the public to attend

13   this meeting as observers.  Members of the audience will be

14   given the opportunity to comment on the discussions at the

15   end of each topic.  Everyone should be aware that the

16   comment period for the guidance document is currently open

17   and will close on February 12, 1999.

18             The purpose of today's meeting is to have a free

19   exchange of information at the working level.  This meeting

20   is not attempting to reach consensus on how to provide

21   specific guidance on radiopharmaceuticals, but to exchange

22   information regarding the foundation on which guidance can

23   be based.

24             On Thursday of last week, we received a faxed

25   letter from CORAR that described talking points on several

                                                                4 1

 issues.  The FDA has had limited time to review this

 2   information prior to this meeting.  Copies of that

 3   information have been provided by CORAR at the door.  Please

 4   be aware that the issues and input must be restricted to the

 5   guidance document.  The comment period for the

 6   radiopharmaceutical regulation and development is closed.

 7             To facilitate this meeting, I'm asking CORAR and

 8   Richard White, the individual, to identify their speakers,

 9   issues, and to conclude each topic for us to identify time

10   to allow public comment prior to the next topic.

11   Introduction of the CORAR representatives will be in just a

12   moment.

13             Let me advise you of the physical layout and what

14   structure we'll be using today.  This is a live microphone

15   which everyone in the room can hear.  There are microphones

16   that are on table 1 and table 2 and table 3 for the

17   transcriptionist.  There is one live microphone which Betty

18   is standing there with right now.  She's going to be passing

19   it to CORAR for their introductions, then it will move

20   around the table for the representatives of the FDA to do

21   their introductions.  Then I'll turn to Richard White and

22   ask him to make the introductions and develop CORAR's first

23   presentation.

24             Thank you.

25             MR. WHITE:  Thank you.  I'd first like to start

                                                                5 1

 off by thanking the FDA and everyone here for the process

 2   that we've gone through.  We'd like to commend the FDA for

 3   this process and we think it has gone very well so far, from

 4   the development of the reg to now the guidance document.

 5             I'd also like to start off by introducing some of

 6   the people around who represent CORAR, which is the Council

 7   on Radionuclides and Radiopharmaceuticals, which comprises

 8   most of the manufacturers of radiopharmaceuticals in North

 9   America.

10             DR. CARRETTA:  I'm Bob Carretta.  I'm the

11   President-Elect of the Society of Nuclear Medicine and I'm a

12   community practitioner of nuclear medicine in a suburb of

13   Sacramento, California, and I'm here at the invitation of

14   CORAR today to give some input from the clinicians who use

15   the radiopharmaceuticals that the manufacturers provide.

16             MR. KIRSCHENBAUM:  My name is Alan Kirschenbaum.

17   I'm with the law firm of Hyman, Phelps and McNamara.  We are

18   outside counsel to CORAR.

19             MR. WHITE:  Again, if I didn't say, I'm Richard

20   White from the Alpine Group, consultant to CORAR.

21             MR. NUNN:  Adrian Nunn from Bracco Research,

22   representing CORAR on issues 2 and 3, on which you'll be

23   hearing a lot from me in a minute.

24             MR. WOLFANGEL:  Bob Wolfangel from Mallinckrodt,

25   Incorporated, and representative of CORAR.

                                                                6 1

 MR. MORGAN:  Bob Morgan from DuPont

 2   Pharmaceuticals, representing CORAR and presenting on item

 3   4.

 4             MS. OLINGER:  Susan Olinger from Nycomed Amersham,

 5   representing CORAR.

 6             MR. BRUNSWICK:  Mark Brunswick, CBER, Office of

 7   Therapeutics, Division on Monoclonal Antibodies.

 8             DR. LOVE:  Patricia Love, CDER, Division of

 9   Medical Imaging and Radiopharmaceutical Drug Products.

10             DR. RACZKOWSKI:  Victor Raczkowski, Center for

11   Drugs, Office of Drug Evaluation III.

12             MS. AXELRAD:  Jane Axelrad, Associate Director for

13   Policy in the Center.

14             DR. MILLS:  Yes.  I'm Dr. George Mills from the

15   Center for Biologics.

16             Richard, would you like to use the podium or would

17   you like to use this microphone?

18             MR. WHITE:  As George said, the representatives of

19   CORAR put together some talking points to facilitate this

20   meeting and to get at some of the issues that we have major

21   concerns with regarding the guidance document produced by

22   the FDA.

23             We will start out by combining agenda topics 2 and

24   3.  But, first, Alan Kirschenbaum will talk about one just

25   briefly to just set out how we view this process, not so

                                                                7 1

 much the specifics of the issue, but just--it sorts of

 2   frames our viewpoint and carriers over into the other issues

 3   we'll talk about and sort of evidences why we think there

 4   should be a separate guidance for radiopharms.

 5             MR. KIRSCHENBAUM:  Well, the first thing I would

 6   like to say which should be in the background throughout the

 7   rest of the discussion is that we think that the draft

 8   guidance that FDA issued in October is a very well-thought-

 9   out and very useful document.  The reason that we requested

10   a meeting is that, as you know, the statute sets out some

11   specific requirements or criteria that FDA is supposed to

12   take into account when it reviews radiopharmaceuticals.

13             We think that the guidance document could be

14   revised to better implement the mandate under FDAMA Section

15   122.  The criteria that Section 122 requires FDA to take

16   into account are three.  One is the proposed use in the

17   practice of medicine, the second is the pharmacological/

18   toxicological activity of radiopharmaceuticals, and the

19   third is the estimated radiation dose.

20             In addition, the legislative history identifies

21   two characteristics that it terms unique to

22   radiopharmaceuticals, one being typically minute doses, and

23   the other being the typical infrequent use.  And it directs

24   that FDA should take into account these unique

25   characteristics.

                                                                8 1

 FDA issued a proposed rule in May.  We were glad

 2   to see that within the rule itself there was an undertaking

 3   to categorize  radiopharmaceuticals according to risk

 4   characteristics.  And in the preamble, there was a mention

 5   that FDA intended to issue a guidance to define what those

 6   characteristics might be and to describe what the safety

 7   data requirements would be for each category.

 8             When the guidance was issued, I guess our reaction

 9   was that the criteria that are included in the guidance

10   don't sufficiently distinguish between radiopharmaceuticals

11   and other in vivo diagnostic products, and also that the

12   safety data requirements are not specified in the guidance,

13   as it appears they would be from reading the proposed rule.

14             In previous discussions with FDA, we, I guess,

15   anticipated that the guidance document would be more

16   specific in sort of prescribing what the--not only what

17   criteria a product had to meet to be categorized in Group 1,

18   but also what would happen when Group 1 designation was

19   made; in other words, what the safety and other requirements

20   would be specifically.  The guidance, I think, we feel,

21   doesn't sufficiently do that.

22             There are a number of differences between

23   radiopharmaceuticals and other diagnostic imaging products

24   that I think need to be recognized more strongly in the

25   guidance document, and FDAMA Section 122 really requires

                                                                9 1

 that they be recognized more strongly, we believe.  These

 2   are examples that people will be talking about throughout

 3   the meeting, at least representatives of CORAR, but I just

 4   wanted to mention a few of them briefly.

 5             One issue is that the criteria that FDA has

 6   included in the guidance document for Group 1 status applies

 7   to all medical imaging products without distinction between

 8   radiopharmaceuticals and contrast media.  And I think as a

 9   result of that failure to distinguish between the two, there

10   is a safety factor criterion that is largely unworkable for

11   radiopharmaceuticals and probably will not be met by any

12   radiopharmaceutical, so that the effect of that is to remove

13   Group 1 as a possibility for radiopharmaceuticals.

14             The criteria that FDA has drafted also would

15   require that the "no observable effect" level be established

16   in part through repeat dose toxicity studies.  We believe

17   that because of the--where you have a radiopharmaceutical

18   administered in a minute dose with rapid and complete

19   elimination and used infrequently, that repeat-dose toxicity

20   studies aren't necessary for this product, whatever their

21   necessity might be for contrast media.  And, obviously,

22   we'll talk further about that later.

23             In terms of non-clinical studies required under

24   the draft guidance, again, FDA doesn't really distinguish

25   between radiopharmaceuticals and contrast media in a number

                                                               10 1

 of areas where distinctions ought to be made.  I guess

 2   primary among those is the requirement for traditional

 3   pharmacokinetic studies.  Analytical methods as they are

 4   today don't really permit traditional ADME studies to be

 5   done with many radiopharmaceuticals.  So we believe that in

 6   those types of--that really radiopharmaceuticals should be

 7   subject to measuring gross elimination rate instead.

 8             On the clinical side, in terms of the clinical

 9   study requirements for Group 1 radiopharmaceuticals, again,

10   I think there need to be distinctions made between Group 1

11   radiopharmaceuticals and other medical imaging products.

12   For example, we believe there's no need to administer

13   increasing mass doses in Phase 1.  There's no need for mass-

14   dose-ranging studies.  And as I mentioned before, the

15   difficulty in doing traditional pharmacokinetic studies in

16   animals applies equally to human studies.

17             One additional example of distinctions that

18   probably should be made under the statute in the area of

19   blinded reads--one of the standards in the draft guidance is

20   that the presentation of images to readers should be made in

21   random sequence.  We think this makes less sense for

22   radiopharmaceuticals, which are frequently used to measure

23   biochemical processes, and you need to read images in

24   sequence in order to determine what--you need to know what

25   the sequence is in order to read, make readings that make

                                                               11 1

 sense in terms of the process.  Radiation dosimetry

 2   obviously doesn't apply to contrast media, and there are

 3   other examples that will be mentioned and discussed later in

 4   the meeting.

 5             We think that separate guidances for

 6   radiopharmaceuticals and other in vivo diagnostic products

 7   would be preferable, and the reason is that it would force

 8   both FDA and industry to focus on the product at issue and

 9   make the relevant decisions for the product at issue.  I

10   think it's possible that the issuance of a single guidance

11   document is--you know, the October guidance document, you

12   know, applying across all product categories might have

13   raised a problem in this regard and might have not--might

14   have caused FDA not to focus on the relevant distinctions as

15   much as we think they should have.

16             I think that's all I want to say on point 1.  I

17   probably should mention that the other product category

18   that's covered by the guidance, namely the contrast media

19   industry, has told us that they're supportive of the notion

20   that there should be separate guidances for the two product

21   categories.

22             With that, I think we ought to move, unless there

23   are questions.

24             DR. MILLS:  Richard, are there other comments from

25   CORAR on topic 1?

                                                               12 1

 MR. WHITE:  I don't think so, but I think there is

 2   probably a comment from the public.

 3             DR. MILLS:  Okay.  FDA comments from over here?

 4             [No response.]

 5             DR. MILLS:  No.  Then we're open for public

 6   comment at this time.  I would ask people from the public

 7   who would come to the microphone at the front, address us,

 8   identify who you are and who you represent, and make your

 9   comments.

10             MR. CARVLIN:  Good afternoon.  I'm Mark Carvlin

11   from Bracco Diagnostics and I'd just like to comment for a

12   couple of minutes about the breadth of the guidance document

13   that has been issued.

14             The medical imaging and radiopharmaceutical drug

15   products industry was taken somewhat unawares when the draft

16   guidance was issued in October of 1998, and that is because

17   our expectation was that the draft guidance would be

18   specific for radiopharmaceuticals in keeping with the

19   stipulations contained in the FDA Modernization Act of 1997,

20   as was mentioned, Section 122.

21              We feel that the "Guidance for Industry:

22   Developing Medical Imaging Drugs and Biologics" is so

23   important that we request that the comment period be

24   extended by 30 days.  This extension will allow for a more

25   in-depth consideration of the points raised in the guidance

                                                               13 1

 document.  A contrast media industry group is just now

 2   forming and a cohesive consensus position is being

 3   developed.  This group has worked closely with CORAR to make

 4   certain that properties similar among or peculiar to

 5   different medical imaging drugs would be considered.

 6             Finally, we are concerned that the draft guidance

 7   has been prepared primarily with today's medical imaging

 8   drugs and biologics used in conjunction with today's medical

 9   imaging techniques in mind.  The scope, the indications, the

10   general considerations for safety and clinical evaluation of

11   efficacy relate most directly, we feel, to intravenously

12   administered iodinated compounds and/or paramagnetic metal

13   ions.

14             Now, in these aspects we feel the guidance served

15   as a good template for developing medical imaging drugs and

16   biologics that are similar to those already in use, or have

17   uses that are similar to the ones that are currently

18   approved.  However, we feel the guidance needs to serve

19   equally well for new imaging techniques, those that are just

20   emerging on the horizon, and we could look at things such as

21   optical tomography or fluorescence imaging or electrical

22   impedance imaging as new techniques in that category; for

23   innovative, new products; for new or alternate routes of

24   administration; and for new uses of approved products.

25             With all of these points in mind, we look forward

                                                               14 1

 to working with you to address these important issues.

 2   Thank you.

 3             DR. MILLS:  Thank you.  Are there other comments

 4   from the public?

 5             [No response.]

 6             DR. MILLS:  Other comments from CORAR or FDA?

 7   Jane Axelrad?

 8             MS. AXELRAD:  Yes.  I just wanted to very briefly

 9   address this.  I don't want to spend a lot of time on this.

10   I was just sort of surprised by CORAR's comments that there

11   should be two separate guidances because the draft guidance

12   that everybody was working from even before Section 122 came

13   out was the medical imaging guidance document that had been

14   worked on and presented at the Medical Imaging Advisory

15   Committee.  And everybody, I think, that I was discussing

16   this with understood that that was going to be the basis for

17   the development of the new guidance.  So it's sort of

18   surprising to hear you say that you really expected separate

19   guidances.

20             But that being said, I think that what's really

21   important is to focus during the discussions today on what

22   the differences are and where you think that what we wrote

23   in the guidance in terms of a one-size-fits-all is

24   inappropriate because either imaging agents are different

25   than radiopharms or it doesn't fit for radiopharms, or

                                                               15 1

 whatever the issue is, to sort of focus on the specifics as

 2   we go through the discussion.

 3             MR. KIRSCHENBAUM:  Could I just--

 4             DR. MILLS:  Alan Kirschenbaum.

 5             MR. KIRSCHENBAUM:  Yes.  Jane, as you said, I

 6   think everybody is aware that there was a process initiated

 7   several years ago working through the advisory committee,

 8   and I think everybody also understood that FDA was trying to

 9   develop a guidance for medical imaging drugs.  But I guess

10   that we thought, in light of the statute and in light of

11   the, you know, proposed rule that was to implement the

12   statute, that there would be a guidance that focused on

13   radiopharmaceuticals, in addition to what other--or in

14   addition to other guidances that addressed other products.

15             DR. MILLS:  Robert Carretta?

16             DR. CARRETTA:  I have to agree with Alan's

17   comments.  We in the nuclear medicine community were under

18   the impression that there would be a separate guidance

19   document for radiopharmaceuticals.  Because of the special

20   nature of radiopharmaceuticals, because of the physiological

21   and metabolic activity versus the anatomical and imaging

22   characteristics of contrast agents and other imaging

23   modalities, we were concerned that the attention needed for

24   radiopharmaceuticals would be diluted in a dual-track

25   document rather than in a separate radiopharmaceutical

                                                               16 1

 document.  And the Society and the American College of

 2   Nuclear Physicians and the Institute of Clinical Path are

 3   all reviewing this current guidance document and will have

 4   further comments during the comment period.

 5             DR. MILLS:  Any other additional comments from

 6   CORAR?  Robert Morgan?

 7             MR. MORGAN:  I would just like us to keep in mind

 8   that when we were developing the original regulation, the

 9   first draft that CORAR presented to FDA included a lot of

10   the specifics that we're talking about in the guidance

11   document; that we during negotiations felt that it was

12   appropriate to take out of the regulation itself because we

13   wanted that document to be very workable and malleable.  And

14   I think what we're looking for here is some of the things

15   that we talked about in the original regulation showing up

16   in the document here and that's what we're missing.

17             DR. MILLS:  Are there any other comments from the

18   public?

19             [No response.]

20             DR. MILLS:  Not seeing any, we'll move to the

21   second topic, Richard.

22             MR. WHITE:  I'm going to turn it over to Adrian

23   Nunn, who's going to combine agenda topics 2 and 3, and

24   we'll allow, I guess, public comment after that.  And,

25   obviously, at any time we want people to interrupt to ask

                                                               17 1

 questions while Adrian is giving his presentation because

 2   it's really one to elicit responses, not just to be

 3   presented.

 4             MR. NUNN:  First, I'd like a bit of housekeeping.

 5   When I mention the guidance document, it's always in

 6   italics, as quoted.  Everything else is not from my own fair

 7   hand.  I'm just a representative, so try not to be too

 8   aggressive to me.  There is other people here that are also

 9   part of the blame.

10             First, to address the issue of diagnostic

11   radiopharmaceuticals as a subset of medical imaging drugs,

12   in the guidance document, as you see there written, it says

13   that Group 1 diagnostic radiopharmaceuticals are a subset of

14   this group.  And whereas we think it's laudable to attempt

15   to include non-radiopharmaceutical imaging drugs into the

16   idea of Group 1 drugs with reduced safety testing, it's

17   unreasonable to presume that they should have the same

18   criteria, considering the great differences in mass and

19   concentration administered.

20             Radiopharmaceuticals are typically formulated at

21   10 to 100-plus times lower concentration than the physical

22   contrast agents, such as MR or x-ray.  And the mass

23   administered of drug substance is 10-to-the-3 to 10-to-the-5

24   times less.  Thus, if there is a case to be made for

25   establishing Group 1 for non-radiopharmaceuticals with

                                                               18 1

 reducing testing requirements, we think it should not be

 2   assumed that the criteria for entry should be the same.  And

 3   you shouldn't need me to point out that the idea of

 4   different criteria has already been considered in the

 5   context of biotechnology-derived products, as quoted here,

 6   for S6 and ICH.

 7             DR. RACZKOWSKI:  I don't intend to interrupt your

 8   presentation, but I don't want to miss the opportunity to

 9   make a few comments, and I thought that it would be helpful

10   if we laid out some of our thinking when we made the basic

11   distinction between Group 1 and Group 2--I'm getting a lot

12   of feedback--between Group 1 and Group 2.

13             I thought what I would do is lay out some of the

14   basic thinking that we went through when we went and tried

15   to delineate what the distinctions were between Group 1 and

16   Group 2 agents.  And what we were faced with, in essence, is

17   trying to define some sort of criteria prospectively that

18   are objective that, once met, would provide enough or

19   sufficient scientific data to ensure us that the product

20   would be then safe for subsequent clinical development and

21   subsequent clinical use for all time.

22             And so the emphasis there is really on trying to

23   gather data, as well as the objectiveness of the criteria

24   that were specified.  And a few of the speakers have

25   mentioned that the distinction between radiopharmaceuticals

                                                               19 1

 and other imaging agents hasn't been adequately appreciated

 2   in the guidance document.  And I would argue that by virtue

 3   of including dose in and of itself, recognizing that

 4   diagnostic radiopharmaceuticals are given, in general, at

 5   lower mass doses than many medical imaging agents that are

 6   given today, that by including that as a criterion, in fact,

 7   that meets the objective of the statute.

 8             In other words, by virtue of being given at lower

 9   mass doses, it's unlikely for another medical imaging agent

10   that is given at higher mass doses to be able to meet the

11   criteria for Group 1.  Now, I don't know if that's clear,

12   but if we're starting at a higher dose with another medical

13   imaging agent and we multiply that by 1,000, you're much

14   less likely to meet the criteria for Group 1 than a

15   diagnostic radiopharmaceutical which would be given at a

16   lower mass dose.

17             And so I'll stop there and perhaps we can--

18             DR. CARRETTA:  Bob Carretta.  Just one comment.

19   One of the issues that was raised by Adrian's slide is the

20   issue of toxicity.  And, basically, when you're looking at

21   diagnostic radiopharmaceuticals, you're looking at tracers

22   which have no effect on pharmacological or any other type of

23   issue.

24             And, for example, we routinely use iodine 131 or

25   123 in patients who have a known allergy to iodinated

                                                               20 1

 contrast agents to look at renal function or assess thyroid

 2   function.  And these are tracer principles and so that's why

 3   the Society and the nuclear medicine community are concerned

 4   that looking at the guidance document without a separate or

 5   specific radiopharmaceutical component doesn't quite meet

 6   the spirit of the FDAMA regulations in terms of treating us

 7   as special and distinct agents.

 8             DR. RACZKOWSKI:  Again, in my earlier comment I

 9   emphasized the importance of having some sort of scientific

10   data to demonstrate empirically that a product has no

11   biological or pharmacological activity.  I think that our

12   guidance document was based on if you can demonstrate from

13   pre-clinical animal studies that there are no observed

14   effects at certain multiples of animal doses and that is

15   sufficient data upon which to base subsequent clinical

16   decisions about whether the use of the drug is safe.  And,

17   for example, there are many receptor agents or analogs of

18   certain highly potent drugs, morphine and cocaine, which,

19   when given in very, very low mass doses, can actually create

20   pharmacological effects.

21             MR. WHITE:  Richard White from Alpine Group.  I

22   think our confusion around--while dose was considered in the

23   guidance document, the 1,000xNOEL led us to believe that--

24   well, one, we would say that no radiopharmaceutical

25   currently approved would meet that.  So it led us to view

                                                               21 1

 the document as not really taking into consideration the

 2   specific and distinct characteristics of a

 3   radiopharmaceutical.  So while you did take into

 4   consideration dose, we think by trying to deal with all

 5   modalities, you've failed to make that distinction.

 6             MR. KIRSCHENBAUM:  I think that will become clear.

 7             MR. NUNN:  I must say from an etymological point,

 8   it seems to me a little odd to set up a class of compounds

 9   of which radiopharmaceuticals is only a sub-class, but the

10   main class, as you just admitted, couldn't meet the

11   requirements.  So that, to me, says that

12   radiopharmaceuticals are not a sub-class of this other

13   class.  They're actually distinct, but let's proceed on.

14             Okay, so what are we talking about here?  To be

15   included in Group 1, a medical image drug should have the

16   following: an adequately documented margin of safety between

17   nonclinical and clinical use.  The NOEL is appropriately

18   adjusted to be at least 1,000 times greater than the maximum

19   dose or doses to be used in humans, and this to be

20   determined in expanded acute single dose, short-term repeat

21   dose toxicity studies and safety pharmacology studies in

22   animals.

23             If you run through the numbers here, most approved

24   and proposed radiopharmaceuticals are, in fact, administered

25   to a standard 60 kg individual--I wish I was one of those--

                                                               22 1

 with a dose in the nonradioactive ligand, excluding

 2   excipients, of about 1 to 20 milligrams at about 1 ml.  If

 3   you then adjust this dose, the two ranges here, up for

 4   surface area times 7 using Freirich numbers or times 2 for

 5   dogs, the same source, then the Rat NOEL must be--you've got

 6   to get 117 milligrams per kg into the animal, or in a dog

 7   we've got to get 33.3 milligrams per kg on a dose-adjusted

 8   basis.

 9             But as noted above, the concentration of the drug

10   substances in most radiopharmaceuticals is only 1 to 20

11   milligrams per ml.  Thus, these doses would require

12   injections into rats or dogs, or you can use other

13   adjustments for other species, of 117 ml per kg in rats and

14   33 ml per kg in dogs.

15             Now, the maximum intravenous injection volume

16   recommended by the Toxicology Subcommittee of the

17   Association of the British Pharmaceutical Industry is 5 mils

18   per kg for the rats and 2.5 mils per kg for the dogs.  This

19   is for tox studies.  As a result of these volume

20   limitations, the average mass dose for the drug substance

21   for the usual radiopharmaceutical drug product of low

22   toxicity--this is historical--than can be injected into

23   animals is of the order of 50 to 100 times the expected

24   human dose.

25             Now, this has been attained not by using these,

                                                               23 1

 but by pushing the limits and getting up to 10 to 20 mils

 2   for kg.  We are getting more and more resistance from our

 3   animal care and use committees both internally and

 4   externally that this is unreasonable for the animals and

 5   that we must cut back.

 6             So under these conditions, many approved

 7   radiopharmaceuticals still exhibit no observable effects in

 8   single dose acute or repeat dose studies in rodents or

 9   higher animals, and no dose response curve can be generated.

10   So, clearly, no radiopharmaceutical, when formulated in the

11   same manner as intended for clinical use, can ever meet the

12   proposed 1,000xNOEL criteria.  Therefore, there is no such

13   thing as a Group 1 compound.  I don't believe this is what

14   the FDA had intended.

15             And, in fact, CORAR believes that a more

16   reasonable figure is 25xNOEL, as defined later, based upon

17   the fact that radiopharmaceuticals of Group 1 will have the

18   characteristics of low mass single administration and rapid

19   elimination.

20             DR. RACZKOWSKI:  I wonder if you could briefly

21   comment on what you feel the limitations are in preparing a

22   drug, a diagnostic radiopharmaceutical, in a more

23   concentrated form and then using that in animal studies.

24             MR. NUNN:  Yes.  Well, the first thing, of course,

25   is this is not testing the drug in the manner that the drug

                                                               24 1

 would be used clinical practice, which is one aspect of

 2   FDAMA.

 3             The second thing that we must bear in mind is that

 4   most of these compounds, most of these radiopharmaceuticals,

 5   are freeze-dried preparations.  When you increase

 6   concentrations to increase volume as you would like, you

 7   also increase the concentrations of all the excipients, and

 8   there are traditionally quite a number of those.  You might

 9   run into solubility problems which will again limit your

10   dose, and also the very fact that we're lyophilizing means

11   that you're actually changing the drug and could change the

12   drug in a manner which you do not fully understand.

13             DR. DeGEORGE:  Joseph DeGeorge, FDA.  It's

14   certainly standard practice in pharmaceutical testing to use

15   drugs in concentrations and in formulations as part of

16   testing that are not necessarily the clinical.  Clearly,

17   it's important to include clinical formulations, and also

18   perhaps to use, as you would say, over-concentrated

19   excipients in active ingredients to distinguish between

20   those effects and the effects exhibited by the drug itself.

21   So that's part of the standard approach.

22             MR. NUNN:  Yes, I understand, but you have to

23   remember that we're doing chemistry in the vial that other

24   therapeutic formulations are not.  So ours is a much more

25   difficult and more complex situation than therapeutic drugs

                                                               25 1

 which are just reconstituted and injected.

 2             DR. LOVE:  You've provided a number of

 3   calculations and as we were looking at them, we were looking

 4   at some of your assumptions that were made.  I'm wondering

 5   if you could just go through them.  Do you have any slide

 6   that talks about them?  When we did the calculations and

 7   looked at our assumptions, we were getting some different

 8   numbers.  I'm wondering if you could go through that for us,

 9   please.

10             MR. NUNN:  Well, I don't know how you did your

11   calculations.  But, essentially, if you start off just on a

12   dose basis, a 1-milligram dose equals 016 milligrams per kg.

13   You just divide by 60.  If you then have to adjust for

14   surface area using Freirich, which I know you use and we

15   use, then the factor is you've got to multiply it by 7

16   because the surface area to volume ratio of a rat is

17   different than that, and so this increases.

18             Multiply that by 1,000 to get up to what you would

19   have to show had a "no-observable-effect" dose and you get

20   117 milligrams per kg.  The same for the dog, is a factor of

21   2, so this increases here.   Then we know that the

22   concentration is 1 or 20 milligrams per kg.  The

23   concentration doesn't make much difference to the volume.

24   So it's very simple that you come out with 117 milligrams

25   per kg if you've got a 1-milligram-per-ml dose.

                                                               26 1

 DR. LOVE:  No.  We just wanted to know the

 2   assumptions.  Some of our numbers or the assumptions we use

 3   for some of the calculations are slightly different.  So we

 4   just wanted you to state that for the record.

 5             MR. NUNN:  Well, these are taken from Freirich,

 6   the original.

 7             DR. LOVE:  Right.  We just needed it for the

 8   record.

 9             MR. NUNN:  Okay, good.

10             DR. LOVE:  If I might, before you go forward to

11   your next slide, there's something that you've talked about

12   both here and earlier, some of the other speakers, and I

13   just didn't want us to get too far along before we lose

14   sight of some of those.

15             Part of it had to do with your comment initially

16   just before you put this slide on about the fact that the

17   radiopharmaceuticals may be a subset of a set that may or

18   may not exist.  So I just wanted to share a little bit about

19   our thinking there.

20             When we looked at this, we started from the

21   perspective of the radiopharmaceuticals and what Section 121

22   requires of us to try to clarify what those specifics might

23   be.  At the end of that process, we looked to see are there

24   other products, perhaps contrast agents, that might fulfill

25   some of the same criteria, and is it appropriate or not

                                                               27 1

 appropriate perhaps to eliminate them.

 2             And although as Dr. Raczkowski was saying, many of

 3   the currently used iodinated contrasts or heavy metal

 4   products used in MRIs may not be able to meet those

 5   criteria, there are other contrast agents that are being

 6   developed that might be able to meet those criteria.  So

 7   part of our thinking was looking at what are the criteria

 8   themselves and what is the goal in setting a set of safety

 9   criteria, meaning the goal is to determine which products

10   can or cannot move forward with a limited safety database

11   being developed and not so much whether or not they are

12   contrast agents or the like.

13             It also goes back to some extent to the indication

14   issue that was raised.  There are a number of diagnostic

15   imaging agents now that are in the future going to be

16   developed for metabolic purposes, regardless of the basis of

17   the product, whether it is a radiopharmaceutical or a

18   contrast agent, because they're being designed to take

19   advantage of receptors, metabolic processes and the like.

20   So, again, in an analogous manner we are looking at what is

21   relevant for all contract agents, and then looking at what

22   may or may not need to be identified for one or another of

23   the different groups.

24             So as you talk, could you continue to identify

25   what are the consequences, perhaps, of putting these in one

                                                               28 1

 category and looking at the principles behind it as opposed

 2   to just saying this is what you need for radiocontrast?  But

 3   one thing that may be down the line is we have to have

 4   guidances for radiocontrast agents, for microbubbles for

 5   gadolinium or heavy-metal products, for iodinated contrast.

 6             So if you could think about that as you're

 7   commenting, which issues are principle-based and which ones

 8   may be specific to a unique class or chemistry that's

 9   guiding something.

10             MS. AXELRAD:  I'd just like to briefly address the

11   issue that was raised that FDAMA somehow requires us to use

12   different methods for testing radiopharmaceuticals and other

13   agents.  And I don't read Section 122 as providing for that

14   at all.  Although it does say that the regulations should

15   take into account consideration of the proposed of the

16   radiopharmaceutical in the practice of medicine, it also

17   says separately that we should also take into account the

18   pharmacological and toxicological activity of the

19   radiopharmaceutical, including any carrier or ligands

20   compounded over the radiopharmaceutical.

21             It doesn't say anything about how we should

22   determine the pharmacological or toxicological activity any

23   differently than we would for any other kind of an agent.

24   It just says that we have to take into account that to the

25   extent that we do this in the regulations.  So I think we

                                                               29 1

 may have some difference of opinion here on what the law

 2   requires in terms of different kinds of testing for

 3   radiopharmaceuticals.

 4             MR. NUNN:  Yes.  I think no matter what the law

 5   says, what I've pointed here on this slide is the

 6   practicality that radiopharmaceuticals as we do chemistry in

 7   the vial, which even if we could get a similarly massed MRI

 8   agent, let's say, we don't do, and so for that reason we

 9   can't mess around too much with concentrations per unit

10   volume.

11             DR. LOVE:  Excuse me.  Just one question, then.

12   You're saying you can't.  I guess when I'm listening to the

13   dialogue between what you were saying a minute ago and what

14   Dr. DeGeorge was just saying, you can make adjustments on

15   the basis of adjusting the concentration.  It may not be the

16   identical formulation that's going to be administered to

17   humans, but technically you can make adjustments in the

18   concentration that's administered.

19             So my question would be what are the consequences

20   of doing a study that looks at worst-case assessments to try

21   to get enough information to know, going forward, that here

22   are your worst-case scenarios and then giving some back-off

23   that gives you a no-effect level.  You may mean you'd use

24   different concentrations of the product or different

25   formulations of the product to try to get that information,

                                                               30 1

 but what's the consequence of doing that?  It would seem

 2   that it provides a basis for making the decision that you

 3   have enough information to move forward into clinical

 4   studies without requiring more clinical human data.

 5             MR. NUNN:  As I said, one of the consequences is

 6   that we are doing chemistry in that vial, and we have gone

 7   to a lot of effort to establish that lab chemistry will

 8   occur in the manner that we desire under a whole range of

 9   circumstances.  This is not something that you do for the

10   other contrast agents.

11             If we start changing concentrations, then we could

12   easily change the chemistry and so that we might get an

13   answer which is the correct answer but on the wrong

14   formulation because the chemistry is different.  So what

15   you're asking us to do would be that to then try to

16   establish that the chemistry is the same and that takes a

17   tremendous amount of effort.  For instance, you're talking

18   about different analytical procedures and the like.

19             Okay, animal studies.  The tox profile so far

20   we've been talking about is being done based upon animal

21   data, and the draft guidance said that the NOEL should be

22   established for radiopharmaceuticals in both expanded acute

23   single dose and short-term repeat dose toxicity studies.  We

24   believe that is excessive, as these two studies can

25   substitute for each other in your own regulations in M3.

                                                               31 1

 Especially as an alternative to two-week studies, single-

 2   dose tox studies with extended examinations can support

 3   single-dose human trials.  Thus, following the dictum,

 4   studies should be designed to use the minimum number of

 5   animals, we believe that one of these studies is not

 6   necessary.

 7             Now, the requirement for repeated dose toxicity

 8   studies does not acknowledge, in our view, the fact that

 9   radiopharmaceuticals are commonly administered at low masses

10   and as single doses.  If the elimination rate for the drug

11   substance is rapid and complete, there is little chance for

12   the administered material to build up to toxic levels in the

13   body.  And this, after all, is the reason for being of

14   repeated-dose studies.  They are written with the idea of

15   therapeutic drugs in mind where there are multiple doses

16   given, and therefore the potential for build-up of active

17   substances.

18             Therefore, we believe that if the elimination of

19   the drug substance has been shown to be rapid and complete

20   in appropriate animal studies, repeat dose tox studies are

21   not representative of the manner in which

22   radiopharmaceuticals are normally used.  We don't do repeat

23   dose.  CORAR believes, therefore, that an expanded acute

24   single-dose tox study in non-rodents is sufficiently to

25   satisfy this portion of the requirements.  And I'll get on

                                                               32 1

 to in a little while why we believe that non-rodents is the

 2   best way to go.

 3             DR. RACZKOWSKI:  The purpose of the ICH guidances

 4   for pre-clinical testing--and Joe DeGeorge can comment more

 5   on this--is to provide at any given stage of clinical

 6   development enough assurance that in those people who are

 7   going to be exposed at that particular time during

 8   development that it's safe to do so.

 9             And so whereas it may be okay to substitute an

10   expanded acute toxicology study for--a two-week single-dose

11   toxicity study for the purpose of determining whether it's

12   okay to introduce the drug into humans, it is still

13   important to--those studies are not substitutable for other

14   purposes.

15             DR. DeGEORGE:  Joseph DeGeorge again.  It turns

16   out if you read that guidance, N3, it specifically states

17   that that is in relation to clinical testing; that, in fact,

18   it's an international standard that for single-dose

19   indications or marketing that I believe it's one month of

20   toxicology studies are the standard, not the one single-dose

21   acute expanded.  So, certainly, there's a belief that

22   there's a different value.  And, in fact, it's not just

23   accumulation of the drug that one is concerned about, but

24   accumulation of toxic insult that may be below that which

25   can be detected as a single administration in a relatively

                                                               33 1

 insensitive study that is five or ten animals per dose

 2   level, and that versus a more repeated insult where one can

 3   detect that effect more readily in that size study.

 4             So the studies do serve different purposes.  As

 5   Victor pointed out, it is to allow initial clinical trials

 6   where, in fact, people are using that design specifically

 7   for therapeutic testing of kinetics of principle rather than

 8   actually for evaluation of full-blown safety assessment for

 9   human--

10             MR. NUNN:  Yes, I agree.  But up to this point, I

11   think we're talking about the initial phase of qualification

12   of a compound to become a member of Group 1, not approval.

13   And so therefore I think that there should be a separation

14   between that, initial studies, and approval.  And therefore

15   this absolutely complies with the regulations.  Your own

16   regulations say that you can go into man with the single-

17   dose expanded.  At any time, if you get more tox data or

18   clinical data, we, CORAR, believe that you can be knocked

19   out of being Group 1 if the data so suggests.

20             DR. LOVE:  Are you suggesting, then, that--maybe

21   we just need to try to make sure we understand your

22   proposal.  Are you saying that if you do just one study,

23   that's sufficient to go into man and that still as part of

24   Group 1, you'd do a second study?  Or are you saying you

25   would stop at that point and not have to do any additional

                                                               34 1

 studies, pre-clinical studies?

 2             MR. NUNN:  Well, without getting into point 3,

 3   let's just stick to 2, qualifications for Group 1.  We

 4   believe that only one study is necessary to get you into

 5   Group 1 and doing clinical studies.

 6             DR. CARRETTA:  Bob Carretta.  The issue I'd like

 7   to focus on in terms of the utility and the uniqueness of

 8   the diagnostic radiopharmaceuticals is, again, the tracer

 9   potential and the fact that in clinical practice they are

10   usually done one time.  If they're done serially, they're

11   usually done months apart rather than days apart, and that

12   again we're dealing only with diagnostic agents, nothing

13   that has a therapeutic or pharmacological effect.

14             DR. LOVE:  I guess what we're trying to

15   understand, because we want to make sure we understood your

16   proposal, you're saying this is what you need to get into

17   Group 1.  Are you saying that you do or do not need to do

18   the other study, the repeat dose study, at all,

19   consequently, after you're in Group 1 and while clinical

20   studies are ongoing?

21             MR. NUNN:  We believe that there's a case to be

22   made for not doing repeat studies at all based upon the

23   characteristics of radiopharmaceuticals.  I think we can get

24   back to that later and not get bogged down to now, which is

25   really getting up to doing clinical trials and not going all

                                                               35 1

 the way to approval.  If we try and keep that separation

 2   between all but the last three on my slides, I think--and

 3   I'll signal when that happens--I think we'll get ahead a bit

 4   easier.

 5             MS. AXELRAD:  Okay.  I just don't want to lose

 6   track of what we said in the guidance, draft guidance, on

 7   page 34 where it says, "This guidance defines two categories

 8   of medical imaging drugs, Group 1 and Group 2.  The extent

 9   of clinical safety monitoring and evaluation differs for

10   these two categories.  Medical imaging drugs classified as

11   Group 1 medical imaging drugs may be able to undergo a more

12   efficient clinical safety evaluation during development.

13   Group 2 medical imaging drugs should undergo a complete

14   clinical safety evaluation," blah, blah.

15             But, anyway, basically I think that we were trying

16   to lay out in the distinction between Group 1 and Group 2

17   what kinds of testing had to be done in the development

18   program.  We weren't just laying out what you needed to do

19   to get into Group 1 in the first place, and that's why I

20   think it may be okay--maybe later, it will become clear, but

21   the focus on this was really to say for these Group 1 drugs,

22   you don't have to do this perhaps at all.

23             MR. NUNN:  Yes.  Here's one we agree on.  We

24   believe--we agree with the guidance document that you need

25   to do some safety pharmacology.  And as you'll see, this is

                                                               36 1

 one of the reasons why we chose to do non-rodents because

 2   it's difficult to do in rodents.  But we believe that, as

 3   permitted, they can be performed as part of the other

 4   testing and that there should be no requirement for separate

 5   studies.

 6             DR. RACZKOWSKI:  The guidance documents didn't

 7   specify that they needed to be done as separate studies, and

 8   so there is, in fact, no such requirement, although I would

 9   say that if you are doing a safety study in the context of a

10   toxicology study, you have to be sure that the safety data,

11   the specialized safety data, is gathered appropriately.

12             In other words, if you're getting an EKG on an

13   animal 24 hours after the drug is administered, that might

14   be fine for toxicology, but it may not be sufficient for the

15   safety pharmacology of evaluating the acute cardiovascular

16   toxicity of the drug, or potential cardiovascular toxicity

17   of the drug.

18             MR. NUNN:  Yes, we agree, and those sorts of

19   details will be sorted out in pre-IND meetings and things

20   like that.

21             Now, the second part of the guidance criteria for

22   Group 1 includes clinical studies, as I've recorded here.

23   And as part of that clinical requirement, it says that human

24   pharmacokinetic trials also should provide data that allow

25   adequate comparisons of exposure--this is mass exposure and

                                                               37 1

 not radiation exposure, although that's somewhat included--

 2   to be made between humans and the animal species used in the

 3   nonclinical studies.

 4             Now, this presents a problem because we really

 5   cannot do pharmacokinetics in man, and so we cannot compare

 6   the human and animal pharmacokinetic data.  And the reason

 7   why we cannot do this is that radiopharmaceuticals are

 8   typically given at the very low masses, and if concentrated,

 9   for instance, a hundred percent excretion into the urine,

10   the non-radioactive drug substance is below the detection

11   limits of available analytical procedures.  We just cannot

12   give enough.  One milligram, you know, micromolar or less is

13   just not enough to be able to detect it.  This is

14   particularly true of the technetium compounds where, of the

15   thousands of peaks in, let's say, the urine, even if a

16   hundred percent of the dose was excreted unchanged, we

17   couldn't identify it in the human condition.

18             Due to the limitations of current analytical

19   procedures, it's also difficult, next to impossible, to

20   perform complete pharmacokinetic studies--i.e., speciation,

21   metabolism, the traditional animal studies--on the

22   radiopharmaceutical drug substance in animals at a suitably

23   adjusted, normally administered dose.  We just don't give

24   enough.  This is a case where radiopharmaceuticals are again

25   different to MRI or CT.  They give a lot more and so they

                                                               38 1

 can develop analytical procedures that will work at the

 2   masses that they inject.

 3             CORAR believes that for Group 1, a

 4   radiopharmaceutical must be rapidly and quantitatively

 5   excreted, and that this, coupled with the fact that

 6   radiopharmaceuticals are commonly administered at low masses

 7   and as single doses, supports the idea that there's little

 8   chance for the administered material to build up to toxic

 9   levels in the body.

10             Thus, we believe that it is sufficient to measure

11   the gross elimination rate in animals using C14 or

12   something.  It does not seem sensible to us to try and

13   measure the same thing in humans.  The idea of adding C14

14   ligand just doesn't seem to work for a radiopharmaceutical.

15   Now, it is possible to measure the distribution of

16   radioactivity, and in the past we have been somewhat loose

17   in our terminology and we have called this pharmacokinetics

18   and it's really not; it's pharmacodynamics.  It's the rate

19   of change of signal, which in this case happens to be

20   radioactivity.

21             We can do this for a radiopharmaceutical in man

22   and compare the derived dosimetry to that previously

23   measured in animals.  And in the past, if you look at all

24   the data, there has been very little difference between the

25   human dosimetry predicted from animal data and that derived

                                                               39 1

 from actual human data.  Thus, we can adequately assess the

 2   radiation safety aspects of radiopharmaceuticals, but we

 3   cannot compare the pharmacokinetics in animals and man of

 4   the mass injected.

 5             DR. RACZKOWSKI:  If I may, I wanted to make a

 6   brief comment as to what our thinking was when we wrote

 7   that.  As I said before, when we were classifying diagnostic

 8   radiopharmaceuticals into either Group 1 or Group 2, there

 9   was an emphasis on the preclinical animal data, the safety

10   data and the toxicology data.  Now, in order for that data

11   to be meaningful in humans, there has to be some sort of

12   linkage and one way of establishing such a linkage is with

13   toxicokinetics and pharmacokinetic assessments.

14             And I wonder if you could comment on some of the

15   current analytical techniques which are available which can

16   measure substances at very, very low doses or very, very low

17   mass doses on levels of nanograms or picograms, and whether

18   that would be sufficient or not to be able to detect

19   diagnostic radiopharmaceuticals and to do pharmacokinetic

20   studies using sufficiently sensitive analytical equipment.

21             MR. NUNN:  Yes.  One of the problems, of course,

22   is you can have an analytical method that has wonderful

23   sensitivity, but you first have to pull that species out of

24   the rest of the junk that's in the urine.  If you don't know

25   where that appears, then you cannot apply your very

                                                               40 1

 sensitive analytical technique.  So sensitivity really

 2   doesn't matter.

 3             And in this case, I think the non-technetium, the

 4   non-metal radiopharmaceuticals, are a little better off in

 5   that for an iodinated compound or a PET compound, let's say-

 6   -and I ought not to mention that name here, but let's use

 7   it--if it's radioactive, then that has a mass equivalent in

 8   there.  So if you do HPLC on the urine, where there's

 9   radioactivity, there's a very good chance that there's also

10   mass and you can identify the peak and quantify it.  We

11   don't have that luxury in this case.

12             And I might add that in the biological--in CBER,

13   they've already had this problem where the idea of linking

14   animal and human tox path--where there is no epitope in the

15   animal, what did it mean to do an injection into an animal

16   to measure tox?

17             DR. DeGEORGE:  Just a comment on the exposure

18   issue.  I think that largely the comparative exposure

19   parameter would be systemic circulating levels, not

20   necessarily urinary levels, although it certainly can be

21   useful for getting some information about comparative

22   elimination which might relate to metabolism.  But I believe

23   from the toxicologic comparison to the human setting, the

24   interest in the word "exposure," I believe, was more related

25   to systemic circulating levels.

                                                               41 1

 MR. NUNN:  Yes, I understand.  My point was that

 2   even if it's concentrated in urine, which is a relatively

 3   clean environment compared to blood, we can't measure it.

 4   Trying to measure it in tissue or in blood is a thousand

 5   times harder.

 6             DR. GREEN:  This is Dave Green from CBER.  I

 7   wanted to make a comment about the reference you made to the

 8   toxicological assessment and pharmacokinetic assessment in

 9   CBER, and that is I think there's two things which you've

10   put together which are kind of distinct for CBER.  And that

11   is there's the relevant epitope and relative binding of the

12   biological products that we assess for toxicology, and we

13   believe that a relevant animal model is most important for

14   determining toxicity.

15             Aside from all that is the issue of

16   pharmacokinetics and toxicokinetics, and oftentimes we've

17   found that the pharmacokinetics and toxicokinetics can

18   parallel then in humans aside from that which may be

19   considerations of toxicological assessment, because not all

20   the same mechanisms and receptors are involved in both

21   cases, and that there is merit to assessing pharmacokinetics

22   in animals relative to humans and that you need to do more--

23   let me take the other point--than just describe the

24   elimination kinetics because factors such as volumes of

25   distribution can vary among the species.

                                                               42 1

 And you need that factor, as well as elimination

 2   rate, to have any assessment as to whether those

 3   pharmacokinetics can be extrapolated or not, or whether

 4   they're appropriate or not.  And oftentimes, elimination

 5   kinetics are fraught with many technical problems, problems

 6   of measurement.  And also you get into the problems of when

 7   do you actually observe the elimination constant because

 8   certainly for biologics there are many parallel processes

 9   and those have different rates among themselves.  And

10   without characterizing the full profile, it's difficult to

11   know whether you truly have an elimination constant or not.

12   So for those reasons, you really need to characterize the

13   full pharmacokinetics.  That's my comment.

14             MR. NUNN:  Yes.  I would just add that in your

15   case you have the luxury that your antibody is radiolabeled

16   and so you can follow it.  In our case, if it's a metal

17   complex, our metal complex is not radiolabeled and that's

18   because C14 is in there.  And so we don't have the luxury,

19   as you, of actually injecting the very thing that we're

20   interested in as observers.

21             Is that not the way you measure pharmacokinetics

22   for a biologic?

23             DR. GREEN:  For a biologic, oftentimes it is

24   radiolabeled and we do take the inference based upon either

25   mass or as to whether we're talking about the parent

                                                               43 1

 compound or metabolite.  But oftentimes the agent is a

 2   problem for us.

 3             DR. LEE:  David Lee from Clinton Pharmacology,

 4   Biopharmaceutics.  As a bench-style biochemist when I was

 5   working for a pharmaceutical company, I had a chance of

 6   developing assay methods.  And my understanding is that

 7   right now even the HPLC combined with GCFS or what have you,

 8   gorification [ph] methodologies, we could--that was back in

 9   the mid-'80s, I guess; we were measuring down to pentogram

10   [ph] levels.

11             One thing that most people do not do is assay the

12   biological sample data and clean up the sample, and there

13   are various ways that you could clean up your sample.  And

14   in addition to that, you have built-in internal standards to

15   identify the different species.  So, therefore, there are

16   several ways that you could actually identify what you have

17   in the biological milieu.

18             From what Dr. Green said, I'd like to further

19   point out that there are different elimination mechanisms.

20   Elimination combines both the metabolism as well as

21   excretion, and from the metabolism aspect we do have

22   different P450 enzymes than animals.  That alone makes a

23   good point.

24             As far as the excretion of a whole species by cell

25   technology (?), if it's cleared 50 percent with no

                                                               44 1

 metabolism, we could either use plasma or urine data.  It's

 2   up to you, but there are methods and other analytical

 3   methods or the procedures that you could do in order to

 4   characterize the dirty cell.

 5             MR. NUNN:  Yes.  I would remind you that this is

 6   not a therapeutic.  This is a drug that we're going to give

 7   once in very small doses, and we believe that this is a

 8   therapeutic pharmacologist's view of a diagnostic

 9   radiopharmaceutical which is incorrect.

10             DR. RACZKOWSKI:  Okay.  Again, I'd like to just

11   make the comment that without a meaningful way to link the

12   animal data to the human data, it's really hard to know what

13   to make of some of the animal data sometimes, and

14   pharmacokinetics does provide such a link.

15             DR. LOVE:  I think that goes back to the question

16   we were asking earlier, and there may be just some

17   difference in understanding.  We're looking at this animal

18   data to help bridge that gap, to go forward to the

19   development of a limited safety data base in humans, which

20   means we're looking at finding as much information as

21   possible to try to answer those questions and then look at

22   that first study in humans to make sure that the data in

23   animal models is relevant to the humans, and on that basis,

24   then, minimizing future human safety data collection, which

25   means we really need to have data to try to bridge that gap.

                                                               45 1

 Otherwise, we are working in the dark.

 2             We have some of the information, but perhaps not

 3   as much to make us comfortable, and that's what we're

 4   looking at.  And what I was hearing earlier is you were

 5   looking at getting into Group 1.  We're talking about

 6   staying in Group 1, if you will, and going from that point.

 7             MR. NUNN:  Let's move on.  Okay, so this is the

 8   CORAR proposal now, which I'm sure is the page you all

 9   turned to as soon as you got the hand-out.  We believe that

10   it's reasonable to request and receive Group 1 status before

11   entering clinical trials based upon available animal data

12   only.

13             And the relative risk to the Phase 1 subject of a

14   low-mass, single-administration rapidly eliminated Group 1

15   pharmaceutical is--"comparable" is not even the right word;

16   it's less than that of a higher-mass, multiple-

17   administration therapy to drug.  We also believe that at any

18   time it's possible for the agency or the sponsor to revoke

19   Group 1 status, if it has been granted, based upon any new

20   data that comes along.  So I think this is the first major

21   difference.  We think that it's reasonable to get into man

22   with reduced testing based upon Group 1 status.

23             CORAR believes that the criteria for determining

24   Group 1 status should be as follows.  The "no observable

25   unexpected effect level" as defined below in a single-dose

                                                               46 1

 toxicity study of the radiopharmaceutical in one species of

 2   non-rodent only is at least 25 times greater than the

 3   maximum anticipated human dose of the radiopharmaceutical.

 4             Now, we defined the "no observable unexpected

 5   effect level" which is comparable to the NOEL of a

 6   therapeutic, I suppose, means the highest dosage level at

 7   which no unexpected biological effects, whether or not

 8   toxic, are observed; unexpected effects of those that are

 9   not anticipated based upon previous human and/or animal

10   studies of the radiopharmaceutical, its ligand, if there is

11   any, or an analog of the radiopharmaceutical or the ligand.

12             Now, we put this in mind because many of the

13   radiopharmaceuticals that are being developed now are

14   related to therapeutic drugs which are already out there,

15   for which there is a vast body of toxicological data.  So,

16   for instance, if we were to produce a radiopharmaceutical

17   based upon a drug that lowered blood pressure and as part of

18   the tox path profile we saw a reduction in blood pressure,

19   this would not be an unexpected effect.  And provided the

20   tox that the dose response curve--we knew about it and we

21   could understand the relationships, then this would be

22   perfectly acceptable to go and do clinical studies.

23             DR. RACZKOWSKI:  I had a question about the use of

24   the word "unexpected" in the phrase "no observable

25   unexpected effect level."  And I think what you said just

                                                               47 1

 helps somewhat, but for a new chemical entity or new

 2   molecular species, how does one know what is expected and

 3   what is unexpected without doing some sort of clinical

 4   study, or some sort of animal or clinical study?

 5             MR. NUNN:  Well, I mean if you are aiming to

 6   target to a receptor, then the biochemical or pharmacologic

 7   consequences of binding to that receptor are known.  And if

 8   you have a therapeutic drug or class of drugs on the market

 9   which already address that receptor, then you know what the

10   dose response curves are for that class of drugs and the

11   relative importance of the pharmacologic response.

12             DR. RACZKOWSKI:  And the other clarification that

13   I would like to pursue is on page 35 of the medical imaging

14   guidance document, it talks about two ways that you can get

15   into Group 1 and the second way says, "Alternatively, to be

16   included in Group 1 a medical imaging drug should have a

17   history of sufficient clinical use or previous clinical

18   trial experience that adequately document the following,"

19   and it goes on to give some specific criteria.

20             But how do you think--or how is your proposal

21   different?  You mentioned a circumstance where a drug might

22   have been used widely in therapeutics and this would seem to

23   cover that sort of circumstance.

24             MR. NUNN:  Well, we believe that this line really

25   addresses new uses for old radiopharmaceuticals, and that is

                                                               48 1

 not really what we're talking about here.  The tox profile--

 2   the clinical tox of an old radiopharmaceutical with a new

 3   use has been very well established by the clinical use.

 4   What we're talking about here is a new radiopharmaceutical

 5   targeted to some entity which is also targeted by

 6   therapeutic drugs, of which there is a large tox path

 7   profile.

 8             DR. RACZKOWSKI:  I'm sorry.  We're not--could you

 9   clarify one more time for us, please?  When you say that

10   what you're referring to here--are you referred to what you

11   have proposed or are you referring to the medical imaging

12   guidance document?

13             MR. NUNN:  We believe that the medical imaging

14   guidance document--that the only compounds,

15   radiopharmaceuticals, that can meet these criteria, and that

16   is that they have clinical trial information already, is an

17   approved drug for which you are submitting a new use, a new

18   indication.

19             DR. LOVE:  I think if that is the message that

20   came across, then we need to clarify that because that was

21   not our intent.

22             MR. NUNN:  How else can you have sufficient

23   clinical use if it's not approved?

24             DR. LOVE:  It may not be the radiopharmaceutical

25   itself that's approved.  It may be the therapeutic compound.

                                                               49 1

 MR. NUNN:  Okay, so you're talking about ligand or

 2   pharmacophore?

 3             DR. LOVE:  Yes.

 4             MR. NUNN:  Yes.

 5             DR. LOVE:  So that's the place we need to verify.

 6             MR. NUNN:  Okay.  The next part of the criteria

 7   that's here is data from elimination studies of the ligand,

 8   or for a non-metal compound of the mass injected, show

 9   complete and rapid elimination, as defined below.  And they

10   define complete and rapid elimination: elimination from the

11   body of at least 80 percent of the ligand or

12   radiopharmaceutical within 24 hours.

13             Now, we have selected this based upon the third

14   part.  The radiopharmaceutical is intended for

15   administration in a single dose or limited repeat doses.

16   Therefore, there is no chance for a build-up of slow-

17   elimination products that can cause toxic side effects.  And

18   limited repeat doses means any of the following:

19   administration of a dose first at baseline and subsequently

20   under changed conditions--e.g., cardiac stress imaging,

21   something we're all familiar with; the administration of

22   multiple doses where any subsequent dose is administered

23   only after a period equal to at least 10 effective half-

24   lives of the previous dose.  And the mass half-life--we're

25   not talking about the radioactivity--is determined in animal

                                                               50 1

 studies.  This again demonstrates or establishes that

 2   there's no propensity for build-up of material.

 3             Or the administration of multiple doses where the

 4   total anticipated human dose is less than 2 percent that of

 5   an analog used for therapeutic purposes during an equal

 6   period of time.  So if you label an anti-hypertensive and

 7   you give 2 milligrams, if a patient gets 50 milligrams a day

 8   of the same pharmacophore, then that explains that.

 9             DR. LOVE:  By "analog," you mean the actual--the

10   ligand is the same whether it's labeled or not.  Is that

11   what you mean or do you mean--

12             MR. NUNN:  No, no.  It means pharmacophore, so

13   that if you label an ACE inhibitor, then that ACE inhibitor

14   contains a pharmacophore which is the same pharmacophore as

15   used in any of the ACE inhibitor therapeutics.

16             DR. LOVE:  Would there be any requirement to show

17   whether or not one or another--the relative potency of these

18   different products?

19             MR. NUNN:  From the commercial point of view, I

20   think that would be wise both to satisfy your qualms and our

21   own.  And, of course, that would be a natural part of the

22   drug development process.  Before you even got into animal

23   studies, you know, you would be looking at the receptor

24   binding and things like that, so you'd have a lot of that

25   data already there.  And that is really what establishes

                                                               51 1

 whether there is a credible link between your pharmacophore,

 2   with the modifications you've made, and the known

 3   pharmacophore of a therapeutic group.

 4             DR. LOVE:  So is there some implied statement,

 5   then, that this is a product that is at least not any more

 6   potent than the analog that you're referencing?

 7             MR. NUNN:  Well, it may be more potent, but as

 8   it's delivered at less dose, then that would take care of

 9   these dose ratings.

10             DR. LOVE:  And the basis of the 2 percent is

11   derived from what source?

12             MR. NUNN:  I think I pulled it out of the sky.

13   No, no.  It's a 50-times factor on the therapeutic drug for

14   which there is a large body of clinical information.

15             DR. GREEN:  Thanks.  Dave Green.  I'm a little bit

16   troubled about the unexpected effect level from the

17   following standpoint, and that has to do with frequency of

18   observed events in a group.  When you start out with higher

19   doses than the NOEL, you sort of have an idea of what the

20   frequency is, as well as the intensity of those effects.

21             So if it happens at 100 percent at the highest

22   dose, you can back off down to a no-observed dose with less

23   frequency, perhaps, than the dose that you call it at, than

24   the no observable adverse level.  However, if you use this

25   approach with an unexpected effect level going to a top dose

                                                               52 1

 of 25 maximum human dose equivalent, how do you take into

 2   consideration the likelihood of observing a rare but

 3   significant event, because you could easily miss that by not

 4   going high enough to know what you should be observing, but

 5   it still could be clinically significant potentially?

 6             MR. NUNN:  I would say that none of the rare but

 7   significant events of any therapeutic or diagnostic has ever

 8   been predicted by animal data.  That's why they're rare.

 9   Think of contrast media toxicity, allergy, for instance,

10   allergic reactions.  That's not predicted.  That's a rare

11   significant event, and we're not going to get all of them.

12   I mean, there's just no way you can test for everything.

13   But I think what we're really talking about here is that,

14   obviously, the expected event has to be of a minimal

15   toxicological significance.  Death would not be an expected

16   event that you would live with, so to speak.

17             DR. GREEN:  Well, I think your answer addresses

18   the animal relevance issue to all toxicology testing.  But

19   one could imagine cardiac arrhythmias being observed not

20   commonly at one dose, but more commonly at the other, and

21   those could be infusion-dependent.  They may vary a lot

22   depending upon just small variations at the time that could

23   be overcome at a higher dosing, but not observed at a lower

24   dose.  But thanks for your answer.

25             DR. LEE:  David Lee from Clinton Pharmacology,

                                                               53 1

 Biopharmaceutics.  I guess I was just troubled a little bit

 2   here.  Your definition of at least 80 percent at 24 hours,

 3   and your number 2 says at least 10 effective half-life of

 4   man--I have a hard time understanding that concept, as well

 5   as the mass half-life.  You're talking about animal models.

 6   That implies to me that we don't really have to do any human

 7   pharmacokinetics; all human pharmacokinetic studies can be

 8   substituted by animal studies and we could just move away

 9   from human pharmacokinetics.  So, that kind of troubles me.

10             Again, I made a comment earlier that P450 enzymes

11   are different.  To me, animal PK studies are very, very

12   useful supportive studies, but we do not know what's going

13   to happen once the drug is administered in man.  Lastly, to

14   me, in your number 3, an analog, by definition, is a

15   different compound.  Pharmacologically, one could argue that

16   they have similar facts, but once any of the molecule has

17   been changed, by definition, it is a different drug product.

18   So I'm kind of troubled by that.

19             MR. NUNN:  What we're trying to do is to use the

20   very large body of tox path data and safety data for

21   pharmacophores that are used therapeutically and say that it

22   is unreasonable to ignore all of that data, and that if we

23   can establish a credible link between the proposed

24   radiopharmaceutical and the body of data relating to the

25   same pharmacophore in therapeutic use, then we should do

                                                               54 1

 that.  I mean, there's nothing scientifically unsound about

 2   that.

 3             When it comes to different metabolic profiles of

 4   animals versus man, I would remind you that we do have the

 5   pharmacodynamic data for the radioactivity.  We can compare

 6   animal to man for the radioactive material, and so we do

 7   have--which should be subject to the same or similar

 8   metabolic processes as the ligand.

 9             Now, it's true that you could get dissociation of

10   the radioactivity from the ligand, but essentially we have

11   never had any surprises when we compare distribution of

12   radioactivity, pharmacodynamics, in animals versus man.  So

13   there is a link there.  It's not that we're trying to break

14   the mold, so to speak.  We're acknowledging that analytical

15   procedures are just not good enough to be able to do this

16   sort of study in man, pharmacokinetics.

17             So those are the criteria.  Now, it's not all bad.

18   I think there is some overall similarity between the agency

19   and CORAR proposals before Phase I, if you acknowledge that

20   a compound can be classified as Group 1 before you do

21   clinicals.  And so here are the relevant draft guidance

22   before Phase I.

23             Safety pharmacology; we agree, yes, it should be

24   done.  Toxicokinetic, pharmacokinetic data; draft guidance

25   says yes.  We say yes, but practically elimination is the

                                                               55 1

 best we can do, but we think that that is sufficient.

 2   Single-dose toxicity, yes, here.  We believe one species,

 3   non-rodent.  Repeat-dose toxicity; we do not think that this

 4   is necessary to get into Phase I, and the existing

 5   regulations say that only enhanced single-dose is necessary

 6   to get into Phase I.

 7             Local tolerance; draft guidance says yes.  We say

 8   yes, but no special studies.  Genotoxicity; the draft

 9   guidance says yes.  We say no.  Dosimetry which establishes-

10   -goes back to 2 and establishes some of the

11   pharmacokinetics; you say yes, we say yes.  So there are,

12   however, differences of detail which I can get to next,

13   which is, I think, the last slide on this part, number 2,

14   and it's only two slides or two overheads after that, which

15   should be taken into account when considering Group 1

16   membership.

17             So CORAR believes that a NOUEL or NOEL--I can

18   never say that--of 25 times the anticipated human dose is a

19   sufficient margin of safety for a radiopharmaceutical under

20   these circumstances.  This is for a Group 1 rapid-

21   elimination, single-dose, or limited repeat dose as we've

22   defined it.

23             We've chosen a NOUEL rather than a NOEL because we

24   believe it's reasonable to accept a certain level and type

25   of biological activity of the radiopharmaceutical if the

                                                               56 1

 activity is concordant with the class of drug or

 2   pharmacophore to which the compound belongs--and you have to

 3   establish that--and if the pharmacology that produces this

 4   activity is understood, dose response, and is non-toxic or

 5   it doesn't have a safety aspect.

 6             Secondly, CORAR believes that a single-dose tox

 7   study of the whole formulation in one non-rodent species is

 8   sufficient to establish the tox of a radiopharmaceutical.

 9   Throughout the guidance there is a statement say that each

10   component of a formulation should have a tox path profile

11   down on it separately.  We believe by testing the whole

12   formulation, we have established the tox profile of every

13   ingredient in that formulation.

14             We've chosen a non-rodent so that the safety

15   pharmacology can be formed in the same group of animals,

16   given the caveats that we talked about--24 hours CG versus

17   acute.  Local tolerance would also be addressed solely in

18   this group of animals with no additional special studies

19   unless warranted by the results.  This study would be of the

20   expanded type of two weeks' duration, and so reproductive

21   issues would be addressed.

22             The radioactive drug would be examined in rodents

23   to generate the pharmacodynamic data on which the human

24   dosimetry estimates are based.  We'd do imaging, of course.

25   The drug substance, which we define as the ligand, or for a

                                                               57 1

 non-metal compound a mass injected, will be examined in

 2   rodents to determine the elimination after administration of

 3   the material in the form and at the doses expected for human

 4   use.

 5             If you do it like this, then it's very difficult,

 6   if not impossible, to do pharmacokinetics in the true sense

 7   of the word; i.e., speciation.  But we believe that by

 8   establishing essential elimination, rapid and complete

 9   elimination, that that is sufficient to show that build-up

10   of toxic metabolites or injected drug does not occur and is

11   not a safety issue.

12             DR. LOVE:  Thank you.  Just in listening and

13   looking at this, I think there may be something that we

14   would need to clarify or that may be confusing.  We have the

15   list of items on page 20, which was some of the different

16   studies, and then we have on another page the issues about

17   Group 1 and Group 2.  And I'm looking at this table that you

18   just presented a slide or two ago and there may be confusion

19   between the two different points.

20             One is a list of studies in general, and that's

21   part of what I think I heard from your recent statement.

22   And the other is what is Group 1 and Group 2, and which of

23   those studies puts you into Group 1.  And that's separate

24   and apart from getting started into the first study in

25   humans.

                                                               58 1

 And some of what you're talking about in terms of

 2   what you need to do before you start your first clinical

 3   study, in our mind, as we were looking at this, is a little

 4   different from what it takes to become Group 1 and stay in

 5   Group 1, so that what's listed on the pages later on for

 6   Group 1 and Group 2 is for products that are staying in

 7   Group 1.

 8             If you wanted to be classified as a Group 1, you

 9   met a certain set of criteria that as Group 1 you don't need

10   to necessarily do any other studies, and if the clinical

11   data--and I know we're going to talk about that in a moment,

12   but if the clinical data continued to confirm Group 1

13   status, then there isn't any reason to necessarily change

14   the development program or go back and do any other

15   preclinical data development, whereas what I'm looking at

16   here, you have it listed in terms of before Phase 1 and then

17   you had your Group 1 proposal.

18             So I guess I'd ask a couple of questions just to

19   help us understand here.  If we forget for a moment what you

20   have to do to start your studies before Phase 1 and the like

21   and you just focus on what you need to be a Group 1 agent--

22   and you're saying basically looking at elimination only, not

23   looking at their mass dose in humans, using the animal data,

24   though, to predict what happens in humans.

25             Some of the concerns that were raised by some of

                                                               59 1

 the other commenters is that we have a little bit of a

 2   circular question because we're using the animal data to

 3   predict the human, and on the basis of the animal data you

 4   wouldn't need to do much human evaluation because you've

 5   confirmed it in animals.  But we need a link between the

 6   human data and the animal data to make sure that the

 7   acquisition of limited human data from that point on is

 8   justified.

 9             If you look at it from that perspective and don't

10   think about what you need before Phase 1, but just what do

11   you need to stay in Group 1 without having to do any

12   additional studies, does that change your perspective on

13   what's needed?

14             MR. NUNN:  No.

15             DR. DeGEORGE:  Can I ask you one question on your

16   one slide?  It says "nonclinical studies."  It's a slide

17   that is a summary one; it's a long list of nine.  And I

18   would just like--to be very simple, is that what you

19   consider would be the entire package for nonclinical studies

20   for a chemical that was a Group 1 imaging--

21             MR. NUNN:  Yes.

22             DR. DeGEORGE:  Okay, so you basically believe that

23   you never do--you're proposing that you never do any repeat

24   dose studies and that you only do a single study in a single

25   species of the extended toxicology?

                                                               60 1

 MR. NUNN:  Yes.

 2             DR. DeGEORGE:  Okay.  I'm just going to put--

 3   you've seen that one--the clinical studies up here which we

 4   haven't really addressed because we've been trying to sort

 5   of get into Group 1.  But based upon the profile, we believe

 6   for the clinical safety assessment vital signs should be

 7   limited to 24 hours.  Limited ECG readings need not be

 8   taken. Readings may be stopped once they're equivalent to

 9   pre-dose readings.  This reflects the rapid excretion.

10             Limited blood and urine analyses may be performed

11   to 24 hours.  Of course, you're going to get most of the

12   results back, so you would go to 24 hours originally.  You'd

13   do the dosimetry; no mass dose ranging studies.  We normally

14   inject a whole vial.  The quality of the information is

15   determined by the radioactivity, not by the mass, normally.

16   No radioactivity dose ranging studies are required.  We can

17   predict changes in dosimetry by using the usual dosimetry

18   programs.

19             And no special population studies should be

20   required for safety or dosimetry purposes.  We can certainly

21   calculate the dosimetry easily by using the MIRD program and

22   anticipate what would happen if you have got no renal

23   excretion of a renally-excreted drug, for instance; to the

24   dosimetry, that is.  And given that radiopharmaceuticals are

25   administered in small doses with rapid elimination which

                                                               61 1

 equates to low exposure on single occasions, a change in the

 2   distribution of the material as a result of reduced renal or

 3   hepatic clearance, et cetera, would have to be unreasonably

 4   large in order to significantly change the exposure.

 5             So that's what we believe is necessary for

 6   clinical studies, and we would like this defined better than

 7   in the guidance document at the moment which is a little

 8   vague.  It just says to do studies, and in the past

 9   something as short as that is open to interpretation which

10   is always different between the different groups.

11             DR. LOVE:  So this is the proposal for Group 1 or

12   for all radiopharmaceuticals?

13             MR. NUNN:  Group 1 clinicals.

14             DR. LOVE:  You're saying, say, for number 1 where

15   you've looking at the 24 hours for the ECGs and such, when

16   you talk about where readings may be stopped once they are

17   equivalent to pre-dose readings, could you amplify what you

18   mean?  In other words, if the first reading you took after

19   injection was the same as the baseline, would that be where

20   you would stop?  Is that what means or does it mean

21   something else?

22             MR. NUNN:  Yes, yes.

23             DR. LOVE:  And so how does that affect the fact

24   that sometimes it takes a few moments before the body

25   adjusts to something that has just been injected?

                                                               62 1

 MR. NUNN:  Through metabolism and the like.  Is

 2   that what you're suggesting?

 3             DR. LOVE:  No.  I'm asking in terms of once a drug

 4   is injected, it takes a while for it to distribute.  It may

 5   take a while before receptor binding takes place and the

 6   like.  So the timing of your initial reading and follow with

 7   the readings in comparison to baseline has some relationship

 8   to the pharmacodynamics of the ligand and its binding.

 9             MR. NUNN:  Yes, and I think this will obviously

10   change from compound to compound.  But, in general, we have

11   in the past been collecting data which is essentially a

12   whole series of zeroes or no change from pre-, and we don't

13   believe that this is cost-effective, nor does it help image

14   acquisition.  So we believe that based upon the known

15   characteristics of the compound you're injecting, you should

16   be able to stop when there is equivalence to pre-dose

17   readings.

18             DR. LOVE:  One of your criteria is the rapid

19   elimination.  Would you assume, then, if a product, let's

20   say, met some of your other criteria--it had a very low

21   adverse event rate and you were able to document that

22   appropriately, but for whatever reason that particular

23   product had a longer half-life.  And maybe its half-life was

24   36 hours, let's just say, based on ligand binding.  Yes, the

25   radioactivity may be gone, but the ligand binding and its

                                                               63 1

 receptor activity might still be present.

 2             Would that product then not qualify for Group 1?

 3   And then if it does qualify, then how do you deal with the

 4   24-hour administration recommendation, observation

 5   recommendation?

 6             MR. NUNN:  It sounds like you're describing a

 7   prolonged elimination compound which would not qualify for

 8   Group 1.

 9             DR. LOVE:  So you would eliminate it, okay.

10             MS. AXELRAD:  I don't know if this is really the

11   appropriate time to ask the question, but I'm going to have

12   to leave in a few minutes so I wanted to ask this.  You

13   know, I'm not a toxicologist pharmacologist and so following

14   the no observed effect level, the unobserved effect level

15   and all that, I wanted to sort of put this in sort of simple

16   terms.

17             Can you give us some examples of

18   radiopharmaceuticals, I guess, using the ones that we have

19   approved now, that would fall into your Group 1 and some

20   radiopharmaceuticals that would fall into your Group 2,

21   because I also heard it said that, you know, we had defined

22   this so that no radiopharmaceuticals would fall into Group

23   1?  And I am just wondering that if you apply the criteria

24   that you're proposing, would all radiopharmaceuticals fall

25   under Group 1?  And if not, which ones would be in Group 2?

                                                               64 1

 MR. NUNN:  All the radiopharmaceuticals wouldn't.

 2   They could be eliminated based upon their prolonged

 3   elimination, for instance.  They could be eliminated based

 4   upon pharmacologic effect.  I mean, let's think about this

 5   no observable effect.  Metallic taste is a common side

 6   effect or pharmacologic effect of injecting metal chelating

 7   agents.  It is unreasonable to suggest that that has a

 8   safety profile that suggests that it should not be in Group

 9   1.  Dry mouth might also be a similar sort of thing.

10             So there is a certain class of effects which are

11   benign.  But under the terms of what the guidance document

12   said, that would be sufficient to exclude a compound from

13   Group 1 and we don't think that that is reasonable.

14             MR. WOLFANGEL:  I would just like to give a--Bob

15   Wolfangel--a few examples just off the top of the head of

16   what we categorize as Group 1 and those that would not

17   qualify.  Those that would not qualify as Group 1 would be

18   gallium, and I think gallium citrate.  The basis for that

19   would be the half-life.  Those are excreted rather slowly.

20             Examples that would clearly fall into the Group 1

21   would be the technetium mag 3.  They're administered in a

22   very small dose and excreted very rapidly.  I think another

23   example of a longer half-life isotope but with very rapid

24   excretion that I believe would qualify for Group 1 would be

25   I-131 hippurate.

                                                               65 1

 MR. WHITE:  And that's the CORAR proposal.

 2             MR. WOLFANGEL:  Yes, and that would be the

 3   definition as CORAR proposes it.

 4             DR. MILLS:  This concludes the presentation, as I

 5   understand it, from CORAR.  Are there other comments from

 6   CORAR?

 7             [No response.]

 8             DR. MILLS:  Are there comments from FDA?

 9             MR. KIRSCHENBAUM:  On this agenda item?

10             DR. MILLS:  On this agenda item as we have

11   submitted to this point.

12             DR. CARRETTA:  Bob Carretta, Society of Nuclear

13   Medicine.  The one issue that I would like to have the FDA

14   consider is that nuclear medicine, as practiced as a stand-

15   alone specialty, is not related to any of the other

16   compounds that you have been looking at when it deals with

17   magnetic resonance imaging or with CT and ultrasound and

18   contrast agents and things like this.

19             And I'm concerned as our specialty to look at the

20   availability of innovative new pharmaceuticals, both

21   diagnostic and therapeutic, as we look at the cost of

22   bringing a new drug, a new radiopharmaceutical to market, as

23   we look at the small market available for some of these

24   radiopharmaceuticals, that we do everything possible to look

25   at the safety and efficacy of these new agents through the

                                                               66 1

 FDA, but also be aware of the effect that this type of

 2   process has on our specialty.  And we think that FDAMA gives

 3   us all an opportunity to start anew in terms of becoming the

 4   world leaders in the use of radiopharmaceuticals for

 5   diagnosis and therapy.

 6             DR. MILLS:  Additional comment?

 7             [No response.]

 8             DR. MILLS:  We're open now for public comment.

 9   Prior to opening this, I'd like to make one announcement.

10   We're going to extend this period until 4:30 to allow at the

11   conclusion that there will be a public comment as CORAR

12   completes its presentations on items at 4:20.  That will

13   allow a 10-minute interval at the conclusion.

14             Is there anyone from the public that would like to

15   make a comment?

16             DR. CONTI:  Peter Conti from ICB and SNM.  The

17   document as described for class 1 pharmaceuticals would

18   virtually include all radiopharmaceuticals based on their

19   short half-life.  I just wanted to make that point for the

20   members of the FDA.

21             DR. MILLS:  I thought I saw a second hand.  Is

22   there not another public comment?

23             [No response.]

24             DR. MILLS:  Seeing no other, then we'll turn back

25   to CORAR for the third item.

                                                               67 1

 MR. WOLFANGEL:  I just wanted to make--this is Bob

 2   Wolfangel again and I just wanted to make one more comment.

 3   Richard asked me, and I didn't really understand his

 4   question, to classify what existing radiopharmaceuticals

 5   would fall into Group 1 under the medical drug and imaging

 6   guidance document.  And based upon the 1,000-fold multiple

 7   dose, based on surface area, I can't think of a single one

 8   that would, in fact, qualify and meet that criteria.

 9             DR. MILLS:  As it approaches 3:30, please bear

10   with FDA.  Certain representatives are going to have to

11   leave as per our previous schedule.  So we would expect

12   people to be leaving at this moment.

13             MS. AXELRAD:  I'd like to just ask Dr. Conti--

14   Peter, sorry, so you were saying that all PET

15   radiopharmaceuticals would be in Group 1 under the CORAR

16   proposal.  Are you saying that none would be in Group 1

17   under the FDA guidance draft as written?

18             DR. CONTI:  I think there might be a few things

19   here and there.

20             MS. AXELRAD:  Okay, so some of them might make it

21   under ours, okay.

22             DR. CONTI:  There's also a stipulation about the

23   positron PK as a potential eliminating factor for class 1

24   pharmaceuticals which should be struck from the guidance

25   document.

                                                               68 1

 DR. MILLS:  Could you restate that?

 2             DR. CONTI:  The positron component that's

 3   mentioned--and we're trying to find the exact page of that--

 4   that's in the guidance document that eliminates positron

 5   emitters, per se, because of the positive electron emission

 6   as a class 1 pharmaceutical--if that does exist, it should

 7   be struck from the guidance document.

 8             MR. KIRSCHENBAUM:  Page 36, point 3 on page 36.

 9             DR. MILLS:  Clarification for the transcript, he

10   said data emitters should be struck from the transcript.

11             Again, are there any other public comments on this

12   issue?

13             [No response.]

14             DR. MILLS:  Richard, I'll turn it back to you and

15   you're pointing to Bob Morgan.

16             MR. MORGAN:  Well, I've been asked to move things

17   on a little bit, so coming from Regulatory Affairs where our

18   time lines are always crunched down as we try to meet our

19   time lines, I'll try to do that and keep this brief.

20             What I've been asked to talk about is the

21   appropriateness of the way the blinded read is described in

22   the draft guidance document, and I think it's well-

23   recognized that diagnostic radiopharmaceuticals are often

24   non-specific with the types of diseases or processes that

25   they look at, but provide additional information for the

                                                               69 1

 clinician.  And it's the use of this additional information

 2   from the diagnostic radiopharmaceutical that is used by the

 3   physician to assess the patient and decide upon a final

 4   diagnosis or a treatment plan.

 5             The draft guidance as presented requires the

 6   sponsor to demonstrate efficacy primarily through the use of

 7   clinically blinded readings.  And, granted, there are two

 8   types of blinding here.  There is agent blinding where, if

 9   you're doing a comparison against a gold standard, another

10   agent, then you are blinded to which of those products is

11   giving you the information that you're evaluating.

12             The concern that we have has to do with clinical

13   blinding where the information that is received during the

14   clinical trials is read in a completely artificial

15   environment, one that does not in any way, shape or form

16   duplicate the type of image evaluation that occurs in a

17   clinical setting.  So while CORAR does not dispute the need

18   for blinding as part of the image analysis, we question the

19   utility and the extent of the use of image evaluation as

20   required in the guidance document.

21             What we are suggesting is a compromise between

22   what we are required to do now, strictly clinical blinding--

23   i.e., no additional information other than the information

24   presented to you--with what the agency has proposed as its

25   sequential unblinding technique.  Under that technique,

                                                               70 1

 additional information is provided to the clinician or to

 2   the person doing the blinded read.

 3             We believe that this is more appropriate.  It

 4   allows us to make an evaluation of the efficacy of the

 5   product in the light that it's going to be used in the

 6   clinic.  You have some patient information, and as part of

 7   the negotiations with the agency what that level of

 8   information should be is part of your negotiations over

 9   trial design, over your blinded read protocol, et cetera.

10             The other concern that we have with the way that

11   the document is being presented is in its strict requirement

12   that readers participating in the blinded read not have any

13   association with the clinical trial as it's being conducted.

14   We propose that as trials become more complicated, more

15   sophisticated, that it is appropriate for you to use

16   physicians that have participated in your clinical trials.

17   And your blinded read can be designed so that there is not

18   contamination in the sense that that physician is reading

19   his own data, that the trial be structured so that if you

20   are using an investigator that that physician be allowed to

21   read a portion of the data, which leads to the third

22   requirement in here.

23             Our interpretation of the regulation is that all

24   readers must read all images.  Again, as trials expand,

25   become more complicated, the number of images included in a

                                                               71 1

 blinded read become quite large.  It's a significant demand

 2   on the blinded reader, both from a time and effort and

 3   reliability standpoint, to read every single image that is

 4   being generated.

 5             So what we're proposing is that there be a way to

 6   include studies that are read in a more clinical format with

 7   some patient information, that that information somehow be

 8   included into the package insert.  And, again, that's the

 9   bottom line.  Right now, with the requirement on the blinded

10   reading, only information going out to the clinicians on the

11   blinded read, we think, is inappropriate and does not allow

12   the physician to truly understand the results that can be

13   expected from the use of that product in a clinical setting.

14             We also are proposing that blinded reads be

15   conducted that allow a reader to read a portion of a

16   clinical trial, not be required to read everything, and that

17   investigators that have participated in a clinical trial be

18   allowed to participate in the blinded read.  There are

19   instances with sophisticated products where a brief training

20   period of a reader that has been excluded from the clinical

21   trial does not prepare that reader for the type of data

22   analysis that he's being asked to perform under those

23   circumstances.  And we think that that can skew the results

24   to the negative in this case, that you're looking at the

25   worst possible case scenario.  And for us to go out and

                                                               72 1

 educate the community, promote our product with that as a

 2   basis, we think, is inappropriate.

 3             So regulatory condensed version of what is in our

 4   document and our position, and I'll open the floor to

 5   discussion.  Thank you.

 6             DR. CARRETTA:  Bob Carretta, Society of Nuclear

 7   Medicine.  As a practicing clinical nuclear medicine

 8   physician in a community and as a principle and co-

 9   investigator on multiple clinical trials, I think the idea

10   of blind reading, although it looks meritorious on its

11   surface, is fraught with significant problems, and Bob

12   Morgan has outlined some of those problems.

13             The people who become expert at reading the

14   clinical trials are usually the ones who are the clinical

15   investigators.  It's very difficult to bring in a physician

16   who's never been involved in the clinical trials or involved

17   in the new radiopharmaceutical development to be brought up

18   to technical expertise in a short period of time.  And this

19   can certainly be detrimental when you come in to read an

20   enormous amount of blind clinical studies, particularly if

21   the trials are 2 to 300 studies and you're spending a day or

22   two days trying to get through all the volume reads.

23             The other problem that I see in clinical practice

24   is none of the diagnostic nuclear medicine studies are read

25   in a vacuum.  We're looking for the information that can

                                                               73 1

 help make medical management decisions and we're looking at

 2   all ancillary information that we can have available--the

 3   results of anatomic imaging, such as ultrasound, CT or MR;

 4   the clinical status of the patient, something as simple as

 5   where does the patient hurt.  I would like to know that if

 6   I'm looking for blood clots and the patient is hurting in

 7   his right arm that I'm not looking at images of his right

 8   leg.

 9             So I think there are certain areas of clinical

10   trials and blind reads that are very, very disadvantageous

11   to the nuclear medicine community, and I think the CORAR

12   proposal is at least a start to look at modifications of the

13   blind read requirement.

14             MR. KIRSCHENBAUM:  I think this is a good place to

15   reiterate that Section 122 of FDAMA requires FDA's

16   regulations to take into account the proposed use of the

17   product in the practice of medicine.  And if you follow that

18   mandate, I don't think there's any way to justify basing

19   approval solely on a study that's conducted in an artificial

20   manner where readers are clinically blinded when use of the

21   agent in clinical practice will be far different.

22             MR. WOLFANGEL:  Bob Wolfangel.  Two other

23   comments.  One would be I think the part of the guidance

24   document that spells out to also blind with regard to time

25   sequence.  And I would certainly not like to see that

                                                               74 1

 carried forward as a requirement because at least in certain

 2   specific nuclear studies, the difference that appears on the

 3   appearance of an image is very time-dependent and also very

 4   diagnostic.  So I would bring forth the idea that that

 5   should not be a requirement.

 6             The other point that I would like to mention is

 7   that the blinded read, and particularly to have each

 8   investigator read all of the images, I think the thoughts

 9   proposed in the CORAR proposal should also extend to the x-

10   ray contrast media, the magnetic resonance.  These studies

11   tend to be larger and to involve more patients, and an

12   investigator reading a huge number--there tends to be

13   fatigue factors as well as other very relevant types of

14   situations that develop that make it impractical.

15             DR. MILLS:  From the standpoint of several things

16   that I'm hearing, I want to clarify and see if I understand.

17   Bob, you've done an excellent job in presenting it and I

18   want to understand the sequence that I hear from this input.

19             Number one, CORAR says indeed blinded

20   interpretation should be performed as part of the evaluation

21   of these drugs products.  Number two is that the sequential

22   unblinding model is the one that you are advocating for us

23   to look at in terms of the development of our review

24   process.

25             Let me then offer on those two bases of

                                                               75 1

 information that indeed the concept within the review

 2   process would be not unlike that which medicine and

 3   physicians are used to seeing in a grand rounds sequence.

 4   Number one, the interpretation of the images in the order in

 5   which they're presented in the clinic, but without any

 6   information first, for a completely blinded interpretation;

 7   then a presentation of all information that would be

 8   available in a clinical trial design which should be the

 9   clinical design that would be utilized in the clinic for the

10   use of this agent, such as that if this agent was going to

11   be interpreted with CT scans in concert, the CT scan would

12   be part of the clinical trial design.  And that would be

13   part of the clinical information that would be available to

14   the review in the sequential unblinded review.  Now, by

15   unblinded I mean that you have all the clinical information.

16   You still do not know the end result.

17             The other item that you're also stating is that

18   some of these trials are going to be very large in the

19   number of total films to be reviewed, and it's not realistic

20   to expect one individual can potentially read several

21   thousand images, and so that we need to address that and

22   look at that in terms of the guidance, and that from that

23   standpoint that there will be a situation in some trials

24   where there will be so many individuals who are involved

25   that you'll be limited in terms of the number of physicians

                                                               76 1

 who would be available to do this review.

 2             But in small reviews, it would be a potential that

 3   we could find individuals outside of that group possibly

 4   involved in earlier portions of the trial, but not involved

 5   in the pivotal Phase 3 studies that we're evaluating for

 6   final licensure which might be available to us, also.

 7             Is that an understanding of what you had said?

 8             MR. MORGAN:  I think that's a fairly accurate

 9   summation, though I think one point that we would want to

10   really emphasize is that--I think that's a fairly good

11   synopsis of what I said, though the goal of having the

12   sequential unblinding is to get that into labeling.  One of

13   the concerns that we have is what information do we take to

14   the clinician; what can they expect, you know, when they use

15   this product; how do we promote this.  And all of that comes

16   out of our package label, our pack insert.  And so as we

17   move forward, we want to get this information out to the

18   medical community.

19             The second point that you mentioned was the use of

20   investigators.  As we get into more sophisticated trials,

21   larger trials, the resources that we have to draw on can

22   sometimes not be available to us.  I mean, we're going to go

23   out and seek the best clinicians to do our studies as we go

24   forward and we don't think that it's unreasonable to try to

25   include those experienced, highly qualified physicians as

                                                               77 1

 part of the data analysis.  And with a concern looking

 2   toward bias, it's possible to set up a blinded read, for

 3   example, where that physician is excluded from reading a

 4   certain segment of the images, you know, things that he

 5   might have some knowledge of, whether it be through a

 6   colleague or through his own institution.

 7             So there's a lot of room for negotiation on

 8   exactly what the program should look like.  So we're not

 9   trying to put limits on it and say this is the only way to

10   do it, but the agency needs to walk away from the strict

11   requirement that the read has to be blinded and that is the

12   only information that we can work with.

13             DR. CARRETTA:  Since I am not a CORAR

14   representative, let me take a somewhat diverging view from

15   the nuclear medicine community, and that is that we're not

16   sure that blind reads, per se, are something that adds to

17   the efficacy of the product and that there are other ways of

18   looking at does the product do what it's supposed to do;

19   proof of principle, for example.  So if you're looking at an

20   infection agent, for example, does it go to sites of

21   infection if you label the white cells or any type of

22   inflammatory processes?

23             I'm a little concerned that you're getting into,

24   again, this issue of making the trial so expensive and so

25   rigorous in terms of time and resources that it will slow

                                                               78 1

 the regulatory process and the approval process down

 2   significantly.

 3             MR. WOLFANGEL:  Bob Wolfangel again.  Just one

 4   other point of amplification.  I think as far as the blinded

 5   reads, CORAR is not in favor of doing a strictly blinded

 6   read.  There should be maybe two sequences, one with limited

 7   clinical information, such basic information as the time

 8   sequence of the images, the sex of the patient, maybe even

 9   the age of the patient, things that you would expect a

10   physician to have no matter when the patient was seen or

11   examined.  And then the second stage would be with an

12   abundance of clinical information available.

13             But I just wanted to make it clear that zero

14   clinical information is not really what we were talking

15   about.  It would be limited clinical information and then

16   more abundant.

17             MR. NUNN:  Adrain Nunn.  I just wanted to clarify

18   that when you said all images were blinded, or you

19   considered that the first stage was all images were blinded,

20   those blinded images did not include the non-nuclear

21   medicine images.  They obviously can't be viewed on

22   blinding.

23             DR. MILLS:  That was my understanding.  Again, I'm

24   not giving you an exact position here for the FDA, but what

25   I was trying to do was clarify what Bob was saying.  And I

                                                               79 1

 would anticipate that that would be unblinded that he was

 2   trying to describe for the ancillary support.  And certainly

 3   I think in the design of any clinical trial, when you bring

 4   in your reviewers, they're going to have a certain set of

 5   basic elements that are going to be presented as part of the

 6   studies that they're going to review, which would eliminate

 7   the total blinded set of images, as I would understand it.

 8             From the aspect of what you're describing in terms

 9   of the sequence, I had made that comments in terms of what

10   Bob had put together that in radiopharmaceutical evaluation

11   the sequence of the images is what you are advocating, so

12   that they would be in a consistent order rather than a

13   random order, as what you were trying to identify, of

14   course.

15             Are there other comments?

16             DR. RACZKOWSKI:  I'd like to make a few comments.

17   And first, for Jane's benefit, even though she's not here, a

18   number of speakers used the word "requirement" in reference

19   to the guidance documents.  And the guidance documents

20   aren't requirements.  Requirements are laws and these are

21   guidance documents, and at the very first page or the second

22   page of the guidance document there's a disclaimer to that

23   effect.

24             One of the purposes of having blinded image

25   reading is, of course, to try to minimize potential biases

                                                               80 1

 upon the readers if they're aware of the patient's final

 2   diagnosis or if they might happen to know what another

 3   imaging modality shows.  And the purpose of introducing some

 4   sort of a blinded aspect to the readings was to in some way

 5   have the readers rely as much as possible on the image

 6   before them in order to make a determination about what that

 7   image shows.  So they're referring to specific, objective

 8   information that can be gleaned from that image.  The

 9   guidance as drafted certainly mentions sequential unblinding

10   as a possibility and it certainly did not exclude that as a

11   possibility.

12             Third, there was nothing specifically in the

13   guidance document--in fact, it was silent on this--as to

14   whether all images need to be read by all--whether each

15   blinded reader needed to read all images.  And I'm trying to

16   find that in the document, but I can see how that might be

17   misinterpreted by the way it's written.  But, in fact, the

18   intent was to be explicitly silent on that particular point.

19             Folks are referring to page 26 of the guidance

20   document that says that all images obtained in the studies

21   should be read by the readers.  And what that was intended

22   to say was that certain images should not be excluded from

23   the ultimate evaluation.  If you have images on every

24   patient, those images should be sent to the blinded readers.

25   The images shouldn't be held back from the blinded readers,

                                                               81 1

 as is sometimes done.  But I can understand how people may

 2   have read that to mean that all images should be read by

 3   each blinded reader.  That was not the intent of that

 4   statement.

 5             And, finally, I just would like to ask, one of the

 6   speakers mentioned that there may be alternative ways to

 7   approach the issue of some of the biases that might arise

 8   from unblinding and I wondered if folks could perhaps pursue

 9   that.  If someone knows the final diagnosis or if someone

10   knows the CT scan is showing a lesion at a certain point,

11   what are some of the alternative ways that could be used

12   instead of blinding or sequential unblinding that could

13   potentially remove those sorts of biases from a clinical

14   study?

15             DR. CARRETTA:  I'll answer one of his questions,

16   but I don't want to tackle that one yet, so if somebody else

17   wants to tackle that.

18             DR. MILLS:  While we're arranging, just one

19   moment.  I hear two comments over here that I wanted to

20   clarify the information.  One is I'm hearing that you

21   understand the concept of a limited amount of information

22   for blinded interpretation, and then a full, if you will, at

23   the other end of the sequential unblinding, but still

24   maintaining that there's no previous knowledge or bias

25   that's been introduced.  But they have full information from

                                                               82 1

 the design of the clinical trial as the agent would be used

 2   in the clinic.

 3             And from the aspect there, then I heard about the

 4   information that you wanted to project in the package

 5   inserts and the information, so that as I understand it,

 6   your concern is that the information in the package insert

 7   would reflect both information from, quote, "the limited

 8   blinded interpretation," as well as the complete sequential

 9   unblinding of the reviewer who's still unbiased by outside

10   information.

11             Am I clarifying both of your comments together?

12             MR. MORGAN:  That's one way to approach it, yes.

13             DR. MILLS:  Okay.

14             DR. RACZKOWSKI:  I have just one quick comment.

15             DR. MILLS:  I've got Victor back here and then

16   we'll go over to Bob.

17             DR. RACZKOWSKI:  I also wanted to comment that I

18   think when we tried to draft this section about the image

19   interpretation, we did try to leave room in there for things

20   like when it's appropriate to look at things in temporal

21   sequence to allow that to be done.  And perhaps it's not

22   coming through, but that was at least part of the intent.

23             DR. CARRETTA:  Bob Carretta.  I appreciate your

24   comment about the guidance document not being a regulation

25   or law.  However, the nuclear medicine community has had

                                                               83 1

 experience with other regulatory agencies where the guidance

 2   documents are taken by the inspectors as having a force of

 3   law or regulation, and we are held then to a standard that

 4   was not intended by the original guidance document.  And so

 5   we're a little bit reluctant to not bring up these issues

 6   early on because there may be a reviewer who would look at a

 7   guidance document as being the ultimate requirement for any

 8   clinical trial.  So I wanted to make that clear as to why

 9   we're a little concerned about some of the issues in the

10   guidance document.

11             The second issue is that, again, in clinical

12   settings nuclear images are not reviewed in a vacuum.  So we

13   need to try to evaluate the clinical trials similar to what

14   would be done in clinical practice.  And I think that's part

15   of the regulation, is to give some weight to what would

16   happen in clinical practice.  And so for these issues I

17   would, you know, urge you to be as open and liberal with the

18   section on blinded reads.

19             DR. MILLS:  Are there other comments?

20             [No response.]

21             DR. MILLS:  Then we'll open the floor to public

22   comment.

23             DR. GOLDENBERG:  I'm Dave Goldenberg from

24   Immunomedics.  I'm a member of CORAR, but I don't

25   necessarily agree with everything I've heard from my

                                                               84 1

 colleagues, so perhaps I can amplify.  I'm a little confused

 2   because neither CORAR nor FDA has explicitly said, to my

 3   understanding, whether the determination of efficacy is

 4   going to be based upon blinded reads or the on-site or an

 5   intermediary with some information.

 6             If you look at the 1994 points to consider in

 7   biologics, it said that information, random sampling for

 8   blinded reads should be made available and there was no

 9   requirement that that be the basis of efficacy.  If you look

10   at the 1997 points to consider, it's much stronger in

11   committing itself to the blinded reads being the basis for

12   efficacy.

13             I'm not clear now in reading this document whether

14   you're agreeing with the '94 or the '97 points to consider,

15   and so I would like to hear a little bit more clarity either

16   from my colleagues from CORAR--and I think I know where Dr.

17   Carretta is because I also am involved in practicing this

18   art, as compared with some of the chemists.  And I do

19   recognize, as I'm sure Dr. Mills from his practice, how

20   difficult it is in a vacuum to make a decision.

21             Now, do you want to put into the labeling the on-

22   site reading results as indicative of efficacy or do you

23   believe that there is a deterioration, as many of us know

24   happens--and I'll go into that in a second--of maybe 20

25   percent or more between the performance characteristics of

                                                               85 1

 the on-site to the blinded?  Does that mean that the product

 2   is so insufficient that it should not be approved, or is

 3   approved as efficacious for the indication?  These are

 4   questions we really grapple with everyday.  I don't hear any

 5   clarity at this meeting on that.

 6             And now I'll go into history with you because I

 7   did a little research before coming here.  And I'm afraid,

 8   Dr. Love, I only know the biologics, so I can't go into the

 9   other side.  I don't want to in any way be accused of

10   prejudice against drugs.  But I have looked at all the

11   publicly available information on the basis of approval of

12   biological agents on this very issue.

13             There have been five biological agents approved as

14   diagnostic imaging agents.  One of them was, of course,

15   ours.  I looked at the record as much as was available and

16   not blackened out.  Unfortunately, there has been some

17   blackening out that would have been helpful.  And there is

18   not one that I have found meets the criterion of two or

19   three blinded readers being used as a basis for efficacy.

20             The one that was perhaps looked upon as a good,

21   quote, "blinded study" had been in not the public

22   information at the advisory council, but in a clinical

23   review dated 9/7/74 authored by Dr. Mills, ended up saying,

24   quote, "The potential for the introduction of bias and lack

25   of a true, quote, 'pointed interpretation,' unquote, is

                                                               86 1

 apparent in this scant interpretation methodology."

 2             So I have concluded after looking at the whole

 3   history of the five biological agents, most of which were

 4   approved on the basis of the on-site, that the only one or

 5   two that had some semblance of approval for efficacy being

 6   based upon blinded were either not fulfilling the two or

 7   three readers you're proposing now in the guidelines or was

 8   a biased and faulty study based upon FDA's own comments.

 9             So now I would like to know is it practical, will

10   it work, or with what Dr. Carretta was saying and what I

11   have experienced and many others who know the field, that

12   you really only can rely on on-site readings that are

13   carefully done where there's very little information that

14   will bias in terms of the outcome diagnosis, that one should

15   do intra-reader and inter-reader assessments of variability.

16   It's very healthy and very important because we want to be

17   able to tell future users what the problems are, but not use

18   that as a basis of efficacy because I see nothing being

19   approved in the future, at least in biologics, if everyone

20   adheres to it honestly and properly.  And I read the record

21   to see that that may have not been the case.

22             DR. MILLS:  Any other public comments?

23             [No response.]

24             DR. MILLS:  All right.  Richard?

25             MR. WHITE:  I think at this point if there were

                                                               87 1

 any issues that came up in agenda item 2 and 3 that weren't

 2   necessarily answered to your satisfaction or that still

 3   remain out there, it would be helpful in the little bit of

 4   time we have left to open it up to the other group because

 5   we don't want to just have a presentation given and no

 6   feedback, even to the last question about blinded reads.  If

 7   there's something that still remains unclear from what we've

 8   presented in your minds, it might be a good time to see if

 9   it can be answered now.

10             DR. MILLS:  Are there any clarifications?

11             [No response.]

12             DR. MILLS:  Any other public comments?

13             [No response.]

14             DR. MILLS:  CORAR, is there anything in terms of

15   issue 2 and 3, and now 4, that need further clarification or

16   comment?

17             MR. WHITE:  I guess--and this is just from

18   listening to the comments--there seemed to be a question

19   about whether you'd actually change the chemistry when you

20   increased the concentration.  And, you know, I don't really

21   think that ever got answered on our side to your

22   satisfaction and I think it still remains a question.  Also,

23   about the linking to the human studies, I think that's still

24   another open area.

25             DR. LOVE:  Certainly, I think there are questions

                                                               88 1

 that have been raised by this dialogue.  Part of the goal

 2   was to hear your issues and try to share ours and not

 3   necessarily coming to closure because we're going to have to

 4   talk about these issues that you have raised.

 5             Obviously, there are some concerns and some of it

 6   may just be--it sounds to me like, at least from my

 7   perspective, what I'm hearing is one interpretation of what

 8   we were saying which may or may not have been what we were

 9   saying.  So I think, one, we'll have to see how much of an

10   issue is just one that needs clarification so what our

11   intent is is clear.

12             Also, from listening to you, I'm hearing perhaps

13   two different things.  One is what you need to start the

14   study; one is what you need to do in order to stay in Group

15   1 status.  I think we probably just need to talk.  I'm not

16   sure that I have another question at this moment in time,

17   but I do agree that I think it still probably is something

18   that's open and may need some more discussion.

19             MR. KIRSCHENBAUM:  Well, I just want to make sure

20   that this is not--this is probably not our last word either.

21   We do intend to submit written comments, and hopefully in

22   those written comments we'll be able to respond to some of

23   your concerns and issues that you raised today.

24             DR. MILLS:  It's 4:00, and as I said, you have

25   until 4:20 so that we'll have time to close with a 10-minute

                                                               89 1

 period.

 2             DR. LOVE:  Sort of along the lines of that,

 3   earlier there was a comment at the very beginning that

 4   requested an extension of the comment period.  I'd like to

 5   ask that commenter if you meant in relationship to the

 6   February 12th, I believe it is, closing period.

 7             MR. CARVLIN:  Yes.

 8             DR. LOVE:  Okay.  The answer is yes.

 9             DR. MILLS:  There was a "yes" from the public

10   commenter.

11             DR. LOVE:  I think we'll have to talk amongst

12   ourselves.  I can't commit us at this moment as to what we

13   would have to do.  Obviously, we want to be able to come to

14   closure on the document, but I hear your concern.  And there

15   are others, so we'll talk amongst ourselves, but obviously

16   we'll take this request extremely seriously.

17             DR. MILLS:  Any other public comments?

18             [No response.]

19             DR. MILLS:  If not, we will close that one, and

20   you're going to have another issue?

21             MR. WHITE:  I just wanted to follow up on what Dr.

22   Love said.  I think that what we hoped to accomplish today

23   was to highlight the fact that there are issues that we feel

24   are important, yet unresolved.  And they may be

25   misinterpretations or differing interpretations of

                                                               90 1

 something, or they may just be disagreements on the actual

 2   what's required.

 3             And so, speaking on behalf of CORAR, we would also

 4   propose some type of extension of the comment period to

 5   address just some of the issues we've addressed today, and

 6   possibly even another meeting that would incorporate some of

 7   the other modalities to talk about the differences and some

 8   of the areas that could be dealt with for both radiopharms

 9   and other contrast agents.

10             DR. LOVE:  And I think that is our concern as

11   well.  We recognize that these are not--many of these issues

12   are overlapping and affect contrast agents as well as

13   radiopharmaceuticals, and some contrast agents that are

14   newly emerging and are not yet fully identified and all

15   their issues are not yet fully identified.  So we want to

16   take that into consideration.  We just cannot commit at this

17   moment in time to exactly how and what length of time, and

18   so forth, but we will take this under extremely serious

19   consideration.

20             DR. MILLS:  Did you want to proceed with an

21   additional item this afternoon?  I see CORAR is in

22   discussion.

23             MR. WHITE:  Could we ask a helpful question?  On

24   any of those issues, would you find there are areas you'd be

25   interested in hearing more on?  We pretty much covered the

                                                               91 1

 nonclinical safety assessments.  There was some questions

 2   about the radiation dosimetry.

 3             DR. MILLS:  Right.  I think I just heard Dr.

 4   Morgan referring to the MIRD issue.  If he would like to

 5   comment on that, that would be an area that I--we had talked

 6   about dosimetry only in the preclinical area.  It might be

 7   of a value there.

 8             MR. MORGAN:  I think I can do that from here.

 9   Again, Bob Morgan from DuPont.  Our interpretation of the

10   guidance document was that it requires dosimetry

11   calculations to be done using both MIRD and ICRP.  And our

12   concern is that, to date, the standard method used for

13   calculating radiation dose has been MIRD and this has been

14   the procedure that's been used for quite some time.

15             There's a wealth of information detailing the

16   basic assumptions and calculations that go into the MIRD

17   method.  And quite simply, our position is that we don't

18   believe that the subtle differences, as best we can tell,

19   between ICRP and MIRD warrant calculating dose by both

20   methods, and that MIRD has long been accepted by FDA, is

21   used by FDA in conjunction with Oak Ridge.  The industry is

22   used to working with Oak Ridge and preparing those

23   calculations and getting that information to the agency.

24   And we believe this is a duplication that we can do without,

25   and suggest that, you know, industry move forward with MIRD,

                                                               92 1

 or if ICRP is appropriate, then that one as well.

 2             DR. MILLS:  Let me ask you to address several

 3   issues.  Number one is that MIRD or ICRP has not been,

 4   quote, "standardized" by FDA, although both sets of types of

 5   data have come in to FDA.  And the concern is always that

 6   from the aspect of the continuation of the development of

 7   these techniques.

 8             From our standpoint, looking at MIRD, certainly it

 9   is a well-established and well-developed type of procedure

10   which has come in on numerous occasions.  However, the

11   concern is as to whether or not Oak Ridge will continue to

12   support it and that the individual who has written a lot of

13   the code for MIRD now lives in Brazil.  And so the result is

14   it will be somewhat concerning as to whether or not it will

15   be continued in that manner.

16             So from that aspect, there are both MIRD and ICRP

17   which are currently clinically utilized in one area or

18   another.  So I'd like for CORAR to comment on the

19   feasibility of long-term support and development of these

20   two techniques and the concern that we'll get the best

21   information not only today in submissions, but three years

22   from now if one or the other tends to move ahead of the

23   other.

24             MR. MORGAN:  I think that's where you rely on the

25   support in MIRD.  I think when I go back to when I did my

                                                               93 1

 dosimetry training, Mike Stabin wasn't the only person at

 2   Oak Ridge that was doing these calculations and there are a

 3   number of individuals that are still there that are

 4   supporting MIRD, at least to the best of my knowledge.

 5             We're not saying choose one specifically over the

 6   other, but MIRD has been around and accepted by FDA and by

 7   industry for some time.  Industry understands what

 8   assumptions have been made to move the program forward, and

 9   we're suggesting that that's the place to start right now

10   and not require that both be done.  But, you know, as we go

11   into the future and we find that ICRP is moving ahead and is

12   more appropriate at that point, then the field will make the

13   change.  But I think right now requesting that both be done

14   now I don't think is appropriate.

15             DR. MILLS:  So as I understand, CORAR's position

16   is you would appreciate an either/or rather than both.  Is

17   that correct?

18             MR. MORGAN:  Yes.

19             DR. MILLS:  Are there other comments on this issue

20   from CORAR or FDA?

21             [No response.]

22             DR. MILLS:  Then we'll open for public comment.

23   Any public comment on this issue?

24             [No response.]

25             DR. MILLS:  Not seeing any hands, we'll close the

                                                               94 1

 public comment on that.  We still have another 10 minutes.

 2   I see a hand from the public.  We'll open up to public

 3   comment and then--

 4             MR. CARVLIN:  I just wanted to open a response

 5   period, really, to a question that Dr. Love had put to the

 6   group, and that was voiced really at the beginning of the

 7   meeting and that was a request for us to emphasize those

 8   aspects that were more principle-related and might apply

 9   equally well to all aspects of medical imaging versus those

10   concerns that might be unique to a particular class of

11   compounds.  And the class under discussion here was

12   radiopharmaceuticals.  There are other concerns as well.

13             So I think that there are some unifying principles

14   certainly having to do with modalities and technology,

15   having to do with the conduct of the clinical trials, the

16   concerns that were voiced by CORAR as far as the blinded

17   readings and the independent character of readers and the

18   temporal sequence of imaging and how we would properly

19   randomize the images applying equally well.  But there are

20   some physical, chemical and biological principles that

21   uniquely define class of agents.

22             Thank you.

23             DR. MILLS:  Any other public comments?

24             [No response.]

25             DR. MILLS:  Back to Richard.

                                                               95 1

 MR. WHITE:  If we want to, we would be willing to

 2   briefly touch on item 7, which is Images Taken Prior to

 3   Study Enrollment.  We are at this point pretty satisfied

 4   with the way the meeting has gone, so if you would find it

 5   helpful, we'd do that.

 6             MR. NUNN:  This is Adrian Nunn.  There's a

 7   requirement in there that says that images obtained before

 8   enrollment cannot be used as part of the blind data or the

 9   gold standard.  And we find this a little conterintuitive--

10   it's on page 32--in that if you, let us say, require as a

11   condition of enrollment a CT study for something, it doesn't

12   make sense to us then to have to have another CT study as

13   part of the protocol, radiation dose or contrast agent or

14   whatever aside.  It just seems to be excessive to exclude

15   absolutely everything.  We understand that there has to be

16   some temporal relationship between studies before enrollment

17   and after enrollment.  But to exclude all of them before

18   enrollment doesn't seem to be the right way to go.

19             DR. MILLS:  Bring the microphone back.  You're

20   framing, though, the concern about images with the actual

21   drug product or the ancillary studies that you were

22   referring to?  Now, in other words, the question I would

23   have if we're dealing with a radiopharmaceutical and there's

24   a CT scan, that would be ancillary or supportive information

25   in the clinical trial design.  That is the issue that you're

                                                               96 1

 concerned with that that CT scan be allowable in the

 2   clinical trial design.  Is that correct?

 3             MR. NUNN:  Yes.

 4             DR. MILLS:  It's not that you have the actual

 5   agent in use prior to coming into the trial.  Those would

 6   still be excluded.

 7             DR. RACZKOWSKI:  Well, let me just begin to see if

 8   I'm clear on what's being said.  I think the intent of what

 9   was written here was that if people are known to have a

10   particular disease--if the answer is known before that

11   patient is enrolled into a study, and then to only enroll

12   those patients into the study and evaluate your new

13   diagnostic radiopharmaceutical, that's not really a fair

14   assessment of the performance of that diagnostic

15   radiopharmaceutical if it has only been evaluated with the

16   answer being known.

17             And the intent was to try to reduce that potential

18   sort of bias in terms of patient selection, and let me use

19   an example.  For example, if you want to evaluate a

20   diagnostic radiopharmaceutical and compare its effects to

21   coronary angiography, let's say--and that's an example that

22   you actually cite in your comments--if the cardiac

23   catheterization is done first, then there's potentially or

24   likely to be a bias that only those patients who have

25   disease or significant disease based on the catheterization

                                                               97 1

 would subsequently be enrolled in the trial.

 2             And the intent was that if you wanted to make a

 3   true and fair comparison between cardiac catheterization and

 4   between a diagnostic radiopharmaceutical that you might, for

 5   example, open the trial up to patients who are expecting to

 6   go to cardiac catheterization, but you don't know yet what

 7   the diagnostic cath is going to show.  And so all patients

 8   who are enrolled get both the cardiac catheterization and

 9   the diagnostic radiopharmaceutical evaluation.

10             So, that's what was intended by that statement

11   about potential referral bias; that is, when a comparison

12   with another diagnostic modality is being made.  In another

13   context, certainly--and we've seen this--sometimes other

14   studies or other modalities are used as entry criteria for a

15   study protocol, and that is perfectly acceptable.  An

16   example might be is that a study for a diagnostic

17   radiopharmaceutical might enroll only women who have a

18   positive mammogram.  But then the labeling would

19   subsequently be limited so that the use of the diagnostic

20   radiopharmaceutical would only be used in useful--in those

21   patients who had a previous diagnostic mammogram done.

22             MR. NUNN:  On page 32 it says, "All images used to

23   determine the efficacy of the test drug and the comparator

24   drug or imaging modality should be taken after study

25   enrollment," okay.  So are you saying that in that case, if

                                                               98 1

 they have a positive, in this case, mammogram before

 2   enrollment, then in order to be used as the true comparator

 3   image, they've then got to have another one afterwards,

 4   because I don't know how else to interpret that statement?

 5   And then the first--I must admit that I've read the first

 6   sentence of this paragraph a dozen times and I still don't

 7   know what it means, if you could clarify that.

 8             DR. RACZKOWSKI:  Okay.  I haven't looked at this

 9   actual document for a while, but I'll try to do the best I

10   can here.  I think the intent of that first statement was

11   that if you want to say that your drug is better than CT or

12   your drug is better than MRI or some other modality that in

13   order to get a fair comparison of the two modalities, in

14   general, patients should be enrolled into the clinical trial

15   and then subsequently both modalities should be performed on

16   the patient.

17             In other words, the results of the comparative

18   modality shouldn't be used to enroll patients into a trial.

19   It gives an unfair--or if you want to even say you're as

20   good as, if you're only looking at--let me use an example,

21   and perhaps this is confusing and I use the mammography

22   example.  If the only women who have been enrolled in that

23   clinical trial are women who have positive mammograms, then

24   it's not clear how the test drug would perform in a group of

25   patients who have not had a mammogram.  And so to

                                                               99 1

 subsequently make a statement in labeling that our drug is

 2   as good as mammography, in general, is very problematic.

 3             MR. NUNN:  In this case, that's probably not a

 4   good example because mammography, of course, is used in that

 5   case as a screening modality.  And so what you're saying is

 6   that you would like us to go out and pull women off the

 7   street who have not had a mammogram and see how it compares

 8   in those.  One could almost predict the outcome.

 9             DR. RACZKOWSKI:  I'll give Dr. Love an

10   opportunity.

11             [Laughter.]

12             MR. NUNN:  But then the other issue is what if in

13   all the other cases where the imaging modality in this case

14   is not used in the screening but it's being presented--

15   somebody has chest pain and they come in and they have some

16   procedure.

17             DR. MILLS:  As we draw to a close, it's 4:18.

18             DR. LOVE:  Okay, I'll take a minute and give it

19   back to you for a minute.  I think the issue is what's the

20   proposed clinical use, the context in which the drug will be

21   used, and then also what is the claim, and I think we're

22   talking about both of those things here.

23             From the proposed use context, if it's going to be

24   used as a screening modality, then you'd design your trial

25   to test the screening process.  If it's going to be used as

                                                              100 1

 an adjunct to immediately follow something like a mammogram

 2   and maybe you then are trying to decide who's going for

 3   biopsy or not or what site is going to be biopsied, then you

 4   could use the mammogram as the positive entry criteria.

 5   Then you randomize the process perhaps if you're going to

 6   compare it, let's say, to CT or MRI for also localization of

 7   the site to be biopsied, or ultrasound.

 8             Then you might at that point--all of those tests

 9   that are being used as the comparator would be part of the

10   trial.  And when you start talking about what's blinded or

11   unblinded, then depending upon how the comparators may or

12   may not be used, that might dictate whether those should be

13   blinded or unblinded, and then you may ultimately go to

14   histology for your final comparison.

15             If, on the other hand, you want to look more at

16   the beginning where you're saying I want to take all comers

17   for a particular process, I want to see all patients with

18   chest pain and I predict the site of your lesion or whether

19   or not you have the lesion by this radiopharmaceutical

20   versus an angiogram, then the entry criteria is the chest

21   pain, not the positive angio.  Once the angio becomes the

22   criteria for enrollment, it changes the ultimate questions

23   that can be answered in the trial.

24             The point of this section is really to try to say,

25   given certain scenarios, here are the kinds of directions

                                                              101 1

 that one might take, but you wouldn't necessarily take the

 2   same direction in all trials because the question in all

 3   trials is not the same.

 4             Does that help?

 5             MR. NUNN:  Yes, but can we clarify the text?

 6             DR. LOVE:  I agree it needs clarification, yes.

 7             DR. MILLS:  So your final comment is clarification

 8   of the text?

 9             MR. NUNN:  Yes.

10             DR. MILLS:  It's now 4:19.  Any other comments

11   from the table?

12             [No response.]

13             DR. MILLS:  Ten minutes to go and we'll open for

14   open public comments.  CORAR certainly is invited, as well

15   as FDA, if there are additional comments that occur in this

16   last 10 minutes.

17             DR. GOLDENBERG:  Dave Goldenberg, Immunomedics.

18   I'd like to follow up on--sorry to bring up this mammography

19   again because it's a very interesting practical problem.

20   Obviously, you know there's a difference between screening

21   and diagnostic mammography, so this has to be put in that

22   setting, too.  But the way I follow your reasoning, Dr.

23   Love, is that in the setting of using a new test as an

24   adjunct to mammography, you might have to do a blinded

25   reading of mammography in order to assess the role of one to

                                                              102 1

 the other.

 2             Did I understand that correctly or did I over-

 3   interpret that?

 4             DR. LOVE:  Go ahead and finish your question.

 5             DR. GOLDENBERG:  The reason I'm mentioning that is

 6   because we have to take sight of what the reality is in the

 7   practice of medicine.  If you look at the variability

 8   between readers in mammography, it can go up to 35 percent.

 9   And as you know, even the same reader on different occasions

10   can vary 15 percent.  And so if we add this reality to this

11   kind of paradigm of development of an agent and evaluate its

12   clinical utility, it may be almost impossible to prove an

13   adjunctive value unless one takes the clinical reality of

14   the situation, as we do have 30 million mammograms, we do

15   have a couple million that are abnormal, and we do have 80

16   percent of unnecessary biopsies, et cetera, et cetera.  And

17   we can't really change that very much, but we can try to

18   improve it a little bit by having adjunctive tests without

19   reinventing the wheel of testing the reliability of

20   mammography.

21             DR. LOVE:  My comment about the things that may or

22   may not need to be blinded was not to be specific to any one

23   case, but just simply to say there are some situations where

24   blinding of the comparator is relevant and important.  There

25   are some situations where it's not and some situations where

                                                              103 1

 it's perhaps very difficult to do the blinding.

 2             I think mammography itself is a unique situation

 3   because of a lot of the history that's going on there.  And

 4   as you know, the Center for Devices is considering exactly

 5   how to address this particular issue of screening versus

 6   specifically identified adjuncts and following a specific

 7   sequence in a work-up versus the more non-specific adjuncts.

 8   So these are very specific cases that are under

 9   consideration as well.

10             DR. MILLS:  Are there any additional comments from

11   the public?

12             MR. CARVLIN:  Yes, Mark Carvlin speaking, from

13   Bracco Diagnostics.  I just wanted to draw attention to the

14   heading number 8, Special Considerations in the Clinical

15   Evaluation of Efficacy, in the guidance document, and

16   emphasize that there are five sub-headings within that

17   larger heading that have special, pragmatic concerns and

18   challenges for us as we develop new, innovative diagnostic

19   pharmaceuticals.

20             Chief amongst those is the use of a truth or a

21   gold standard to try and come up with an independent way of

22   verifying the results of the agents under test.  And when

23   you add to that the suggestion of using a comparator, we

24   have a number of different procedures that could possibly

25   have to be performed to get a new product approved; that is,

                                                              104 1

 imaging with a new agent, imaging with a comparator, and

 2   imaging with a truth standard.  And that was one of the

 3   concerns I think CORAR expressed as well, is this

 4   multiplicity of imaging examinations presents a practical

 5   concern as far as getting patients and having them go

 6   through all of the procedures, financial burden, and in some

 7   instances ethical concerns as well.  So we plan to study

 8   those particular points very carefully and provide our

 9   feedback to you.

10             Thank you.

11             DR. MILLS:  Are there other comments from the

12   public?  I don't see any additional hands.

13             DR. LOVE:  Just a quick comment.  Those sections

14   you were just mentioning are listed as types of things that

15   we might encounter in different trials, not necessarily to

16   imply that each and every one has to be in any one trial.

17   It all depends in large measure on the indications that are

18   requested and the claims that are being sought.

19             MR. WOLFANGEL:  Bob Wolfangel.  I would, I guess,

20   like to turn the clock back a little bit to where we began

21   and sort of recap at least what I heard as significant

22   agreements and significant differences.

23             First, I thought we have agreement on class 1 or

24   Group 1 classification for certain radiopharmaceuticals, and

25   one of the qualifying criteria for that was that there would

                                                              105 1

 be no observable effects at multiple dose levels, and we

 2   have not reached agreement on what that multiple dose level

 3   is.  I think in the guidance document it says 1,000 times

 4   and there's a CORAR position which is much less than that.

 5   But I think the basic agreement is that that should be a

 6   qualifying criteria that there would be no observable

 7   effects at multiple dose levels.

 8             The other similarity but yet difference is in

 9   terms of the--I think the FDA approach is to establish Group

10   1 criteria at the beginning that would remain throughout all

11   of the clinical studies and establishing criteria based on

12   that, where the CORAR position would be more to qualify

13   through the preclinical testing--to qualify as a Group 1

14   status and then perhaps remain vulnerable to maybe not

15   maintaining that status or to have that status withdrawn,

16   depending upon the addition of additional tests.

17             Those, I think, are the most basic--I wanted to

18   frame out the most basic agreements and disagreements and

19   that really ends my comment at this point in time.

20             DR. MILLS:  Then I wanted to clarify it in terms

21   of the discussion because you're going to have

22   representatives from the FDA today making characterizations

23   and comments.  But, again, we were not here to reach the

24   consensus.  We're here to understand the issues and many

25   times the comments would parallel, and I could understand

                                                              106 1

 from that aspect that that would be positive and supportive

 2   in terms of what you were hearing, but to please be clear

 3   that these were not to reach any consensus today.  No

 4   agreements have been reached today.  It was for matters and

 5   purposes of taking in input.  Certainly, we understand and

 6   hear many of your positions and understand that you, CORAR,

 7   have represented your opinion in a unified manner.

 8             Are there other comments?

 9             [No response.]

10             DR. MILLS:  Other public comments?

11             [No response.]

12             DR. MILLS:  The front clock says 4:28.  I'm going

13   to use that as the time to close this.  I want to thank

14   everyone from the public, from CORAR, FDA representatives

15   that have been able to stay throughout the afternoon and

16   those that had to leave earlier.  We appreciate the input

17   and the comments.  We're certainly going to have a lot of

18   information to digest from this.  It has been a very

19   positive type of meeting for us and a very informative

20   meeting for us.  We want to thank everyone again.  Have a

21   safe trip.

22             [Whereupon, at 4:28 p.m., the meeting was

23   concluded.]