So we have found, as an office, that with the flux of the field and also the commonalities between cell therapy products that in general broader guidances are generally -- we get good results with them and we hit more of our target audience that way.

            DR. TAYLOR:  Thank you.

            CHAIR URBA:  Thank you very much.  We'll move on to the next presentation about the guidance development program with Dr. McFarland.


            DR. McFARLAND:  Thank you, Dr. Urba.  I'm very happy to be here this morning to give you and the Committee an update on the Office's guidance activities because I think we really have a good story to tell on our activities over the last two years, and how we've used the input from the Committee to work into our guidance program.

            First, though, I'm going to spend  a few minutes describing the process by which FDA develops and publishes guidances, and then I'll go through the guidances that we've published and/or finalized over the last two years and highlighting a particular draft guidance that we published last summer.

            This came up, was sort of alluded to, in the questions after Dr. Benton's presentation.  FDA develops guidances under what's called good guidance practices.  Good guidance practices really ensure the proper development, formatting, processing, routing and use of FDA guidance documents.  It was mandated by the Food and Drug Administration Modernization Act, known as FDAMA, and has been codified in the Code of Federal Regulations, and with CBER we have a SOP to follow, which is available.

            One of the things inherent in good guidance practices is the public notification of the agency-wide Annual Guidance Agenda which actually gets published right now through, actually, a biannual guidance agenda in the Federal Register and what I will be concentrating on is when I get to the presentation on the guidances or the guidances that we have published since the last issuance of the Guidance Agenda in 2006.

            Guidance documents are prepared by FDA staff and they describe the Agency interpretation of a policy or a regulatory issue or they relate to the processing, content and evaluation/approval of submissions or to the design, production, manufacturing of regulated products and we have some guidance documents that cover all of those areas.

            What aren't guidance documents, which is important to know.  They're not internal FDA procedures, not reports, not general information provided to healthcare professionals or consumers, not speeches.  We don't make policy from the podium.  They're not media interviews, not journal articles, whether they be articles about our general regulatory process or scientific articles that come out of our research laboratories.  They're not warning letters, memoranda of understanding, any other communications or documents related to specific public health emergencies.

            What they are is, they're intended to represent our current thinking on matters discussed in the documents once they are final guidances.  CBER staff departs from guidance documents only with appropriate justification and supervisory concurrence, and when we get consistent deviations from guidance documents where we have to deviate from them, that's really a strong signal that we really should spend some time revising those documents.

            Most FDA guidance documents are called Level 1 documents.  Level 1 guidance documents, typically we have a Federal Register notice announcing the availability of the draft and a specific public comment period.  They are placed on our website and on the Agency's website.

            After reviewing the public comments, then we revise the guidance or we may revise the guidance and we issue a final guidance.  Only when we issue the final guidance does it represent our current thinking.  Although we have specific time frames in the Register, we'll accept comments on documents, be they draft, final, be they implementation guidance documents which are at any time.

            Immediate implementation allows us to issue guidance documents both in Level 1 and Level 2 guidance documents when we think that due to a reason, due to a statute, due to a public health emergency, that it's appropriate to issue them not in draft initially.

            What are Level 2 guidance documents?  Well, everything that isn't Level 1.  But Level 2, really you could think of as setting forth existing practices or minor changes or interpretation or policy or minor updates to Level 1 guidance documents.

            This was kind of alluded to during the question from Dr. Benton's talk.  How do we communicate with the public during the guidance development?  Well, when we're considering the development of a guidance, we can discuss the issues with the public.  Frequently, when we have topics that we bring to the advisory committee, they are things that we are considering.  They're issues that I think are worthy of public input and anything of general principal, anything that we bring public input, is something that at least potentially could become a guidance.

            If the issues that are addressed are particularly appropriate or controversial, we hold a public meeting and this is mentioned in the advisory committee.  We frequently use this advisory committee for issues that are controversial.  Yesterday is a good example.

            Before drafting the guidance, once the preparation of the draft guidance has really begun, the specifics of what's in the guidance we can't discuss to the public in order to keep the process fair and unbiased and so everyone has equal knowledge of what the Agency is working on.

            Once a guidance document is issued in draft, then we can certainly discuss the issues related to that particular draft guidance.  One of the things that we really don't talk about with any specificity once it's issued in draft is what our plans are in terms of finalization, in terms of timetables, in terms of which comments we've gotten and how we're evaluating those comments.  And as I said, we accept comments on any guidance at any time.

            The next few slides, I'm going to discuss the guidances that we have published or finalized in the last two years, since, well, 18 months since the issuance of the most recent guidance agenda on September 1, 2006.

            The first guidance here that we've published is the umbilical cord blood guidance  which we published in draft in 2007.  We've had advisory committee discussions long before the guidance was drafted in 2003 on this general topic and then, of course, last March, we had discussion of the cord blood guidance during the comment period after the draft guidance had been issued.

            Another guidance that we issued last year is the guidance for the products for cartilage repair.  I'm going to spend a little more time on that at the end of the talk.  So I won't belabor it here, but to mention that it was the topic of an advisory committee in 2005.

            This guidance is a validation of rapid microbial methods, a guidance document to facilitate validation of rapid microbial methods in our cell and gene therapy products for investigators.  It was published in draft in February.  And, although we haven't had a specific meeting related to that topic, the issues of rapid microbial methods has come up at various points during our discussions in the advisory committees over the last five years or so.

            Guidance that we published in January, certain HCTPs recovered from donors who were tested for communicable diseases using pooled specimens or diagnostic tests, this is a guidance that we issued for immediate implementation which was final, to deal with specific issue related to the implementation of the tissue-ables.  It has relatively limited applicability, but it is important for everyone who has products that might fall into this category to get the same advice.

            In addition to the guidances that we published that are in the guidance agenda, these are the topics that we anticipate working on guidances over a two year period.  Other issues come up during these two years and that we publish guidance on that may or may not make it into the guidance agenda, and on the next couple slides I'm going to list those guidances.

            This first one is also related to implementation of the tissue rules and has a very helpful question-and-answer format.  It answers very common questions on implementation of the tissue rules and it was an immediate implementation in August of 2007

            The next guidance, the eligibility determination for HCTPs is also directly related to implementation and exploitation of the tissue rules.  It's quite comprehensive and it was issued, finalized, I'm sorry, in August of 2007.

            The third guidance on the list here for cell selection devices for point of care of minimally manipulated, autologous peripheral blood stem cells deals with an interpretation of a provision in the tissue rules in terms of same surgical procedures.  It was issued in draft in July of 2007.

            The last one is a Class II special controls guidance for cord blood processing, systems and storage.  It was issued with immediate implementation in January 2007 and I think it was also discussed briefly in March at the day on the other cord blood guidance document.  This is related to a 510(k) submission and actually outlines the special controls that manufacturers would need to meet in order to gain a marketing -- to market these particular devices.

            Continuing with our additional guidances we've published in the last 18 months or so and this guidance, I think, was mentioned yesterday during the discussion as potentially a model for thinking along topics with embryonic stem cells, is the gene therapy clinical trials: observing subjects for delayed adverse events, known as a long-term followup guidance and was finalized last November -- November 2006.  Multiple advisory committee discussions touched on these issues and I listed the four most prominent ones, although I'm sure it has been mentioned, at least in passing, in various other advisory committees.

            The guidance underneath it, the supplemental guidance for testing of replication competent retrovirus in retroviral, vector-based gene therapy products and during follow-up was issued as an immediate implementation 11/2006, which is a revision to the supplemental guidance that was issued in 1999 and issued at the same time as a long-term follow-up guidance, so that our published guidance on retroviral vectors and general long-term follow-ups would be consistent.  So, many of the same advisory committees related to that and it's worthy to note that Carolyn Wilson was instrumental in getting these two guidances through the process and issued at the same time, so that we'd have consistent guidance to the industry.

            And as Dr. Benton mentioned, the recently finalized guidances this week, she mentioned the first one, The human somatic cell therapy investigational -- the CMC guidance for cell products.  On the same day, we also finalized the CMC guidance document for gene therapy products this week and really the advisory committee discussions for both of those topics are really too numerous to mention on the slide.  But, suffice it to say, because these two documents represent primary guidance for the chemistry, manufacturing and control for the two large, overarching classes of products that are regulated through the biologics license applications, these topics have been discussed at numerous meetings in the last decade or so.

            I'm going to spend a little bit of time now concentrating on the cartilage guidance.  It's important to look at the title here.  It's the Preparation of IDEs and INDs for Products Intended to Repair and Replace Knee Cartilage.

            Now what's significant in that is that, as IDEs are for investigation of devices and INDs are for regulations of biologics and drugs.  So inherent in the title is really the cross-center nature of this guidance.  It was written by a cross-center team with experts from Center for Devices and Center for Biologics, reflects closely the advisory committee input on the meeting in March 2005, which CDRH was completely involved in planning that guidance document.  It also leverages an ASTM -- several ASTM guidelines which points to the agency's leveraging of using of outside resources to provide guidance in our standards development process which we did in connection with CDRH.  So we participated according to the FDA policy for dealing with standards development organizations, in the planning of the ASTM document and then were able to leverage into an FDA document.

            I'm going to go through a little bit through the scope.  As I said, it's for both devices and biologics to repair or replace articular cartilage of the knee and also for combination products, that is, products that have device and biologic components.  It excludes several other areas and we wanted to focus primarily on articular cartilage and mainly focal lesions and it excludes the 361 products which are human tissue products, because you don't typically need IDEs and INDs for those.

            There's a brief section on manufacturing and CMC information.  But much of that information for manufacturing is either in other device guidances or in our newly finalized CMC document.

            The guidance document has two major sections, one on non-clinical data and testing, and we go through explaining what we see as the purposes of animal studies within the context of development of products for cartilage repair; durability of response that we expect; toxicology and dose response and mechanical testing; biocompatability, here leveraging both an ISO standard and an ASTM document.

            And a large part of the non-clinical data and testing in terms of surveying the potential animal models that are available, the cartilage defect locations in those models, descriptions of their limitations and aspects, much of that was discussed in this ASTM document, Standard Guide for the In Vivo Assessment of Implantable Devices.  You should read that as implantable medical products intended to repair or generate articular cartilage.  Being able to leverage that, in addition to communicating with industry during the development of that standard; it used the expertise in industry to have the details of the multiple, different models that would be more time-consuming for FDA to have written by itself.

            The rest of the guidance document really deals with clinical study protocols, which stress the importance of exploratory trials of both the design features of those trials and using the knowledge learned on the exploratory trials for your confirmatory studies, so that we expected -- we recommended randomized control trials; double-blinded, bounded evaluation; evaluations of major endpoints, but mentioned that alternative study designs would be considered but they need to be supported.

            Study endpoints: we went through study endpoints and we stressed that we would recommend clinically meaningful endpoints as primary in confirmatory studies -- improvement in pain and/or improvement in physical function.

            We went through what we would expect for examples of secondary endpoints that might be considered in development of these trials.  It's a long list and we go through in some detail in the guidance itself.

            It also has a section we point out that we would expect, in terms of the submission for IDEs and INDs, a detailed description of the procedures of the product administration, the surgical technique and the plans for the post-operative rehabilitation.  We think that those are important to describe in the IDE and IND in some detail.

            We mention our recommendations on follow-up, a length of follow-up to be based on in vivo and in vitro studies and a two year follow-up for, at least, a subset of the subjects in the trial.

            We go on to recommend our adverse event reporting in addition to reporting for the regulations for the IND or the IDE.  There are somewhat different regulations.  We wanted to stress our recommendation for reporting subsequent surgical interventions, revisions, removals or re-operations, as that applied to these products, and it's something that we'll take into consideration in these products when we're evaluating them.

            We'll say just that, that is a draft guidance at this point and we've received comments and we're in the process of finalizing it.  So it doesn't currently represent our thinking, but this is our draft.

            Similarly, to Kim's slide on resources on the web, there's the reference on the regulatory process that is updated periodically and, given all the recent guidances that we've published, I'm sure there's probably an update we need to do on it.  However, until that occurs and even when it doesn't occur, our cell and gene therapy guidances can be found at that link and our tissue guidances, also, at the link underneath.  I will point out that for cell therapies it's helpful to check both the cell therapy link and the tissue link, because there are some general ACTP guidances that also apply to cell therapies.

            So a quick summary, I went over quickly what GGP was, what our FDA guidance process is and how it's governed by regulations.  I went over very briefly our recent guidances that we've finalized and issued in draft, both in the Annual Guidance Agenda and those that have come to meet needs in the interim, and went into some details on the cartilage repair product guidance.

            So in conclusion, I'd say that I think we have an active guidance development program in the Office now that includes both strategic planning -- guidance planning -- which is reflected in our annual agenda, but also is able to respond to changing needs as times go on.

            We leverage many things in terms of our guidance development input from the advisory committee, other public meetings we have, notably the FDA Advisory Committee, at the NIH, workshops such as the ones that were mentioned by Dr. Epstein earlier, industry liaison meetings that we have, our cross-center efforts within CDRH -- within FDA, to CDRH and to CDER in terms of informing our guidance process and participation with the standards development organizations.

            And one thing that is so obviously that is so much of the DNA of the Office that I left it off the list, which was leveraging our research.  Our research reviewers, we had some discussion earlier about research reviewers and review load versus research load.  I would like to just stress their expertise in the relevant research.  It's really essential in many of these guidance development programs.  It helps ensure that we have the most up-to-date science underlying our guidance recommendations, particularly in those guidances that reflect specific product areas and development of applications.

            And although I don't have a thank you slide, I do thank you for your participation and your advice over the years.



            CHAIR URBA:  Dr. Allen.

            DR. ALLEN:  Yes, I have a -- actually, I have three questions but they relate to the draft guidance with respect to cartilage.  So I guess my first question is I understand it's not the arena of the FDA to tell sponsors exactly what to do and what will be acceptable.  But over the course of the time since this draft guidance has been released, I've had, I think, three calls from sponsors in this country and one from overseas asking essentially what they should do in order to get preclinical data.

            So one of my questions is just in a  general sense with the guidance deliberately be somewhat vague and loose on exactly what is required, what is the distinction with these cell-based therapy or cell based and combination therapies?  What determines whether the FDA is actually going to require  a GLP study or not, understanding that doing a GLP study in a horse for a year is probably far from trivial and I think there are probably three places in the country that can do it?  That's my first question.

            DR. McFARLAND:  Okay.  The answer is GLP studies are not necessarily required.  It's been a longstanding policy at the Office to understand that GLP studies may not -- number one, they're impractical for many of our types of products, simply because they're not always able to get the technical expertise to conduct the study in the GLP setting and GLP labs, and sometimes those are not completely overlapping subsets.

            So we certainly would accept preclinical data that's not GLP.  It needs to be -- they need to be robustly done, however, and there is a regulation that says that if you are going to say that a study is GLP, they expect for that entire study to be GLP, and if there are sections of a study which aren't, those need to be demarcated.

            So that's the general answer to the question.  We're really interested in getting the best data, regardless of where it comes from that's applicable to the product and the pharm-tox branch will frequently answer that question, as well, in our pre-IND interactions or with sponsors where they will typically have done some preliminary work, submit their plan for preclinical data and that's frequently a question that comes up as one of our standard comments.

            DR. ALLEN:  Okay.  So my second question then relates to efficacy and -- I noticed in the draft guidance again and obviously I was at the discussion back in 2005, but we place fairly strong emphasis on the fact that you could do essentially proof of principle, biological principles, in a small animal model.  But for the durability of response and the efficacy, a large animal model is preferred and desirable, and so I was struck yesterday in the meeting in the discussion about ES cells that we were not, I think, as stringent with respect to the large animal models and understanding there are problems with large animal models, with using autologous cells.

            I noticed in the guidance here for cartilage we allow latitude and we say that, for example, with large animal models where it's not feasible to use human cells because of issues of immunosuppression, that if you have an autologous or allogeneic product from that animal and it is being characterized with respect to the human situation that that would be accepted.

            So I guess I'm concerned that there are some inconsistencies between cell-based products and embryonic stem cells.

            And I guess that brings up my third question which is, if I have an embryonic stem cell and I differentiate it in vitro to the point of it being essentially a cartilage progenitor cell, then, which guidance do I go with.  I mean, can I take that cell and put it into this and say it's a product which now has to follow this guidance or am I constrained by the other, by the ES cell guidance?  And I just worry that we're placing an extra burden on ES and also, and most especially, we have a stringent requirement, I think, for demonstrating long-term efficacy and with that in those model's safety for cells like MSCs that are potentially less risky and yet we seem to be not so concerned.  We seem to just say it's hard to do in a large animal.  So we shouldn't worry.

            But I would be much more concerned potentially about the known and the unknown risks of ES cells and I would strongly urge the FDA to really reconsider as they formulate draft guidance, look at the importance of doing even allogeneic experiments long-term, one-year, let's say, large animal models.

            So I'm just trying to understand the science and to get coverage on this information because I think it's critically important.  I'm just -- I'm concerned there's just not consensus across these two documents, potentially.

            DR. McFARLAND:  I guess the only comment to that is, we've heard your comment and we'll take it under consideration.  I think -- I guess the other comment is, in these areas that are emerging, which is true for the cartilage and for the ES cell which would -- really, the indication, the general indications in general, a lot of these differences in risk assessment gets initially done in terms of interactions with individual sponsors, and it's frequently a question in our pre-submission interactions, which are similar to the concerns that you issued and that's how we initially gather information and gather information on risk assessment as things are just beginning.

            DR. GERSON:  I wonder if I could just ask for some clarification on what I view as sort of the guidance gap, if you will, and that is that, in the process of going from the formal regulation to the guidance documents and, in the process of going from the conceptualization of the need for a guidance, the developments of information gathering, sort of a discovery period, and then the development of a draft and you showed us the detail on the cartilage, to the final document which we've just seen the process of the earlier presentation on somatic cell therapy and the CMC for that recently issued, and your very last statement during your formal presentation, next-to-the-last statement, about the current thinking of the draft document.  So, okay, so now I'm an investigator, a research entity, a commercial entity, and I know there's a regulation and I know there's a guidance document that's some years old and now there's a lingering draft document and I want to do it right.  What am I supposed to do exactly, and how can the agency help that gap period between the old, former guidance, the new draft and the final guidance?  So how do you operate in that sphere of limbo?

            DR. McFARLAND:  The guidance gap, I kind of like that term.  Okay, there are multiple questions packed in.  Let me see if I can address them all and, if I miss some, let me know and I'll go back.  What are sponsors supposed to do in the situation that they have an old guidance, they have a draft guidance, which isn't formally the thinking of the agency or the field is moving and changing since the guidance?

            What an individual sponsor entity should do is, if they have those questions, direct them to us and in that specific way, either in a formal pre-IND session, pre-submission session, or in a more informal session if they're a little earlier in their development and that, I think, is what a specific sponsor should is come talk to us and put that on the table as a specific question.  I have X product.  You have X guidance.  It doesn't seem to fit in with where the science is right now, or ,we won't be able to tell you exactly where we are in terms of working on things, but we will be able to tell you what our current practice is in review specific to that product.

            The other thing that I think is helpful for sponsors to do is, we frequently give outreach presentations at scientific meetings, industry-type meetings, where we outline what our current thinking is in a particular area and topic, and those typically are helpful in filling that kind of gap in the general sense.  What are we doing to reduce the guidance gap, I suppose, is the implicit question behind it.

            At the agency level and at the Center level and at the office level, we are working on improving our processes for prioritization of guidances, of streamlining our processes in terms of generating the first draft of the guidance, which is sometimes a long haul when things aren't moving quickly or when we have had other, competing priorities as well as decreasing the time in the area of the guidance getting sign-off and the guidance at the various levels of administration throughout the Center, the office and the agency.  At all levels, we are working on some internal processes to do that.

            One of the things that Dr. Witten has done which we hope has helped is develop the Office of the Associate Director of Policy.  That is, all the product offices in the Center now have an associate directors of policy and one of our jobs is to work on decreasing the guidance gap, moving things forward, helping to facilitate guidance development by taking lessons learned from one guidance and bringing them back to review teams that are writing guidances.

            One of the things that happens is that any individual reviewer may have a limited number of experiences in their career writing guidances.  Some of the roadblocks that come up in writing the guidances are not unique to a specific guidance.  So one of the roles of the ADP and the regulatory policy staff at the Center level is to help the review teams understand where they're going to come up to roadblocks and help them get around those.

            The other thing that we do is meet at the Center level to coordinate policy development and to make each other aware of guidances in our individual offices, so that concerns that may arise in one office about a guidance that potentially slows things down, are incorporated early on.  I think the derivative of the guidance development in the center is positive right now, but it's an ongoing process.  I think it, in some way, reflects similar issues that it's happened in the research realm.

            DR. WITTEN:  Can I add something to what you said, Richard?

            DR. McFARLAND:  Sure.

            DR. WITTEN:  I just want to mention that Dr. McFarland has highlighted the role of the advisory committee in helping us with our guidance document development.  But it is also possible for outside individuals in organizations, not as members of the AC but in your other world or other people that you know to contribute in the following sense and one is that this guidance document agenda, I mean, people can propose topics.  They could comment to that guidance document agenda that's published with suggestions for where they think there are specific gap areas.

            In other words, Richard has gone over the way to comment to specific guidance documents to the public and comment to the docket when there's a draft published and provide feedback and input on a guidance document that we've put out either in draft or in final form.  And in addition anyone is free to make suggestions for guidance documents that they think would be worth developing and there's even a procedure for them to propose  background or information or even some type of draft.

            Now we can't work with an outside organization in developing a guidance document, but I think we can take nominations including some fairly substantive background.  If someone is interested in doing that, we would be glad to explain how to do that and we'd welcome that because our own agenda setting is based on what we see is our needs and the fields' needs.

            Putting a guidance document out is a nontrivial effort.  As Richard said, a lot of thought and time goes into it.  But I think there is a role for outside groups if they think carefully about it, what our needs are and what we would need.

            DR. TOMFORD:  Thank you.  I appreciate the amount of work that goes into a guidance document and the fact that the FDA works hard to make it fair and equitable.  My question involves -- I don't want to pick on this particular guidance document.  If you read it, it says preparation for products intended to repair/replace knee cartilage.  But the primary endpoint is not replacement of knee cartilage.  The primary endpoint is improvement in pain and improvement in physical function, two of which to me at least as an orthopedic surgeon are secondary endpoints.  The primary endpoint is what it says, replace knee cartilage.

            So I want to ask about this sort of deliberately vague concept because that seems pertinent here.  How is thst chosen?  I was thinking about the embryonic stem cells yesterday.  It would be unlikely that the FDA would approve a process where an embryonic stem cell that's replacing a cell in the retina isn't that cell.  It turns out to be a kidney cell or something.

            So I guess I'm concerned about this because this is a very controversial area in orthopedics as you know.  Why is this deliberately vague?  Why is not the title of the guidance document supported by the primary endpoint?

            DR. WITTEN:  Do you want me to answer that?

            DR. McFARLAND:  Well, if you want.  I don't care.  It doesn't matter to me.


            DR. WITTEN:  Yes.  I'd just say I wouldn't really focus on the title that much.  The titles of these generally describe what the product is, I mean, a lot of our guidances and I don't think any real deep reading of it is actually intended.  If somebody wants to develop one of these products, they'll know from the title that might be something useful to look for and I just wouldn't try to read any meaning into it.  I think that the titles are just supposed to tell somebody that this is a place to look.  So I don't think we have a deeper meaning to explain with that and the guidance document describes the kinds of endpoints we'd want to see for this type of product.

            CHAIR URBA:  Dr. Gunter.

            DR. GUNTER:  Thank you.

            DR. CHAPPELL:  Go ahead.

            DR. GUNTER:  Okay.  First of all, I don't want any of my comments to be perceived as critical because I think the guidance program the FDA has, that CBER has, that this office has, is actually really world class.  When you look in other regions of the world, there is virtually no guidance on especially this class of products.

            So the FDA and CBER should be commended for their efforts and achievements so far and I think Dr. Witten actually partially addressed my question already.  But I'll ask it anyway and that is I think stakeholders in the field would be interested in knowing what guidance documents are planned and he did mention an agenda of guidance documents and I know, Dr. McFarland, you've presented in some meetings what guidance documents were planned.

            So my first question is is there opportunity for stakeholders in the field to look to see what guidance documents you're planning and have input on that.  And then a second part to the question is have you ever considered some kind of formal survey of stakeholders as to what their needs for guidance documents are in a systematic way.

            DR. McFARLAND:  Okay.  The formal way to see what we've officially planned is the Biannual Guidance Agenda which it comes out roughly every two years and the last one was September 2006 and that is the formal vetted way for the agenda to look and, as Dr. Witten said, comment directly that and it will get to us if you have guidance documents that you think we should write.

            In terms of a formal way to do a survey, doing a survey raises lots of issues with OMB and paperwork and doing a survey from the Federal Government for that is not a trivial undertaking and I think to go through the process to do a formalized survey would actually take away resources that could better be used in developing the guidances.

            What we do do to use the term that came up in the research presentations, we do a lot of horizon scanning in concert with the research program and the regulatory program on things that we see in the future that might be issues.

            We take comments, informal comments, from every industry meeting.  Almost every time we do an outreach, someone is suggesting something that we should write on.  We take those all back and frequently, although not all the time, we are already sort of thinking about it.  I hope that answers your question.

            CHAIR URBA:  Dr. Allen and then Dr. Chappell.

            DR. ALLEN:  I just had a question really for clarification and I guess that is with respect to these guidance documents when public comment is invited do we, the Committee, or does the public, sponsors in the public at large, have access to those public comments.  I mean we can see the response to public comments, but are we seeing that the FDA is being responsive to those public comments in a specific way?  And I have no -- This is probably from a sense of ignorance, but I have no idea how many public comments, for example, would be garnered by a draft guidance document on IND.  I imagine a lot.  It may not be.  But could I just get a sense of the magnitude of a response to a typical document and whether that information is publicly available even after the finalized version has been produced?

            DR. WITTEN:  The public comments are public, although I have difficulty finding them on the web.  I mean I've been told you have to go in person to see them.

            DR. McFARLAND:  Yes, they're not particularly easy to find.

            DR. WITTEN:  Yes.

            DR. McFARLAND:  But we've just gone to a new eGovernment system across the government in terms of accepting comments and we're told that they'll be easier to access.

            In terms of how we have dealt with the comments when we issue a final guidance, we issue with it a notice of availability in the Federal Register where we discuss the comments, the number of comments, the depth of comments and what we have, in addition to changing the guidance, we have frequently specifically -- we have some guidance that suggests being issues with study endpoints or small animal use and these particular phrases and this is what we did with that.  So there is a formal process to get feedback on that.

            DR. CHAPPELL:  I just wanted to observe with regards to Dr. Tomford's comment that it relates to yesterday's repeated pleas for surrogate variables for early phase studies and that when we talk about endpoints, primary endpoints, we should always explicitly state for what phase of research we want those endpoints.

            For example, surely the eventual goal of cartilage knee replacement is to improve quality of life and minimize pain and a Phase III trial I would recommend that.  But also for early phase trials as we discussed yesterday, I think we want surrogate endpoints.  Yes, we want to know that the cells there are cartilage or cartilage progenitor cells or the eye example eventually I want to see better.  But my early goal is a surrogate one of just being assured that the appropriate cells are implanted into the retina.

            So my more general plea is to state primary endpoints and then say for which kinds of studies you think those primary endpoints are important and I say that because I've seen in the past statements that surrogate variables are inappropriate which was true at the time for Phase III trials at least in that context and yet it was applied to early phase trials and also visa versa.

            So when guidances recommend endpoints, I think they should be put in explicit context lest those reading them for one reason or another take them out of context and apply them to situations for which they were not intended.

            CHAIR URBA:  Other questions or comments?  Thank you.

            DR. GERSON:  Just a point of clarification.  These slides are very, very helpful.  Are they, since this isn't a public meeting, now -- Will they be on the web for general consumption?

            DR. McFARLAND:  Yes.

            MS. DAPOLITO:  Yes, but will they be easily accessible?


            CHAIR URBA:  They're in your package.

            MS. DAPOLITO:  Yes, they will be posted on the FDA Advisory Committee website and they should be easily accessible.

            CHAIR URBA:  Dr. Witten, do you have any final comments?

            DR. WITTEN:  I'd like to again thank the Advisory Committee for their participation today and a special thanks to you, Dr. Urba, for chairing this meeting.  I know this is your first foray and we really do appreciate it.  Thank you and thanks to all the FDA people who prepared for today as well.

            CHAIR URBA:  Thank you for your kind words and I want to thank Gail and all her staff for making the meeting run so smoothly and for all the Advisory Board members who took time out of their schedules to make this happen and for the FDA people who are working hard so that we can all do better things for our patients.  With that, we'll adjourn.  Thank you.

            (Whereupon, at 10:53 a.m., the above-entitled matter was concluded.)