1

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES 
 
                       FOOD AND DRUG ADMINISTRATION 
 
               CENTER FOR BIOLOGICS AND EVALUATION RESEARCH





 
                        CBER STAKEHOLDERS MEETING 
 
                     COMMUNICATING WITH STAKEHOLDERS 
 
                               FDAMA 406(b)





                         Friday, August 14, 1998 
 
                                9:00 a.m.









 
 
                                 Room 800 
                         Hubert Humphrey Building 
                             Washington, D.C. 
                                                                  2 
 
                             C O N T E N T S 
 
       Opening Remarks and Welcome, 
          Kathryn C. Zoon, Ph.D., Director, CBER                  2 
 
       FDA Remarks, Linda Suydam, Associate Commissioner 
          for Strategic Management                                5 
 
       CBER Remarks, Kathryn G. Zoon, Ph.D.                      11 
 
       Panel A: 
 
          Alan Goldhammer, Ph.D., Executive Director, 
          Technical Affairs, Biotechnology Industry 
          Organization                                           24 
 
          Bert Spilker, M.D., Senior Vice President, 
          Science and Regulatory Affairs, Pharmaceutical 
          Research and Manufacturers of America                  31 
 
       Panel B: 
 
          Roger Brinser, Representing the Coalition 
          for Regulatory Reform                                  50 
 
          Emily Rossiter, Representing the Blood 
          Technology Companies                                   56 
 
          Sharon Leiser, QA, Regulatory Affairs 
          American Red Cross                                     64 
 
       Panel C: 
 
          Janice Bourque, Executive Director, 
          Massachusetts Biotechnology Council                    74 
 
          Jim Weston, Vice President, Government 
          Affairs and Strategic Policy, BIOPURE                  77 
 
          Janice Bourque, Executive Director, 
          Massachusetts Biotechnology Council                    80 
 
          Sheila Flaherty, Associate General Counsel, 
          Legal Department, Astra, USA                           87 
 
          Janice Bourque, Executive Director, 
          Massachusetts Biotechnology Council                    95 
 
       Open Microphone                                          100 
                                                                  3 
 
   1                      P R O C E E D I N G S

   2                   Opening Remarks and Welcome 
 
   3             DR. ZOON:  Good morning.  First of all, I would 
 
   4   like to welcome everyone to CBER's 406(b) meeting.  This is 
 
   5   the first of two meetings CBER is going to have for its 
 
   6   stakeholder.  This is part of our response to the FDAMA

   7   406(b) section, and we are delighted.  I think the spirit of 
 
   8   openness and listening to the needs of our constituents is 
 
   9   very, very important for us.  We will be having a sister 
 
  10   conference on the West Coast in two weeks, in Oakland.  For 
 
  11   those of you who did not have the opportunity to attend this

  12   one today, we hope that your colleagues will take the 
 
  13   opportunity to come to the West Coast and see us. 
 
  14             This is also a very difficult time, and I 
 
  15   appreciate everybody coming in the summer.  I know this is 
 
  16   prime vacation time so I want to tell everyone thank you for

  17   making the effort.  I know many of you who were not planning 
 
  18   to attend rearranged your schedules and made time to come, 
 
  19   and I want to thank all of you for that. 
 
  20             I also would like to thank Gail Sherman, Dennis 
 
  21   Strickland, Pat Kuntza and our OCMA staff for all their help

  22   and support for arranging this meeting today.  It has been a 
 
  23   lot, a lot of work for our staff, on short notice, to put 
 
  24   this together and, as you can see, they have done a 
 
  25   wonderful job and I appreciate that very much. 
                                                                  4 
 
   1             There is a cafeteria in this building, when we

   2   break for lunch, and there are bathrooms.  I won't attest to 
 
   3   the quality of the food but you certainly take advantage of 
 
   4   that. 
 
   5             We are going to have three panels this morning and 
 
   6   early this afternoon.  Each of you should have received a

   7   packet when you came in.  This includes a variety of 
 
   8   different pieces of information: an agenda, some information 
 
   9   on the Center for Biologics, as well as some statements that 
 
  10   have been prepared, and copies were available for those who 
 
  11   wished to do so.

  12             We will also have, after each of our panels, an 
 
  13   opportunity for an open mike where people can make comments.  
 
  14   If, in fact, we move a little bit faster than the agenda 
 
  15   suggests, and if some of the individuals coming from 
 
  16   Massachusetts are here earlier, we may be actually be able

  17   to finish a little bit earlier, but we will play that one as 
 
  18   we go along. 
 
  19             This activity, I believe, is something that we 
 
  20   have tried at various levels to reach our and talk to our 
 
  21   different constituents.  This is really the first time that

  22   we have opened it up to all constituents at the same time, 
 
  23   and I think it is very important, and I think it is 
 
  24   important for us to hear you.  I also think it will help for 
 
  25   you to hear each other, and look at the different issues and 
                                                                  5 
 
   1   concerns that each of you has, and it will give us an

   2   opportunity, at CBER, to present some of our initiatives, 
 
   3   some of our priorities and to get feedback from you on those 
 
   4   priorities. 
 
   5             For those of you that have not had a chance to 
 
   6   look at your packet yet, there is a docket for CBER for the

   7   406(b).  So, that docket will remain open, and we encourage 
 
   8   your input not only today but after the meeting.  If issues 
 
   9   come up, we would be delighted to hear from you. 
 
  10             My first pleasure this morning is to introduce 
 
  11   Linda Suydam.  Linda Suydam is the Associate Commissioner

  12   for Strategic Management in FDA, and she will be giving an 
 
  13   FDA presentation on the stakeholders' meeting.  So, thank 
 
  14   you.  Linda? 
 
  15                           FDA Remarks 
 
  16             MS. SUYDAM:  Thank you, Kathy.  Good morning, and

  17   welcome.  It is, indeed, a pleasure to welcome you to this 
 
  18   first of a series of stakeholders' meetings that the FDA is 
 
  19   having in the next few weeks in an attempt to meet the 
 
  20   requirements of Section 406(b). 
 
  21             [Slide]

  22             FDA has consistently in the past I think looked 
 
  23   for and asked for input into our processes, but never in 
 
  24   such a formalized way as this.  So, while Section 405(b) 
 
  25   mandates that we consult with the appropriate scientific and 
                                                                  6 
 
   1   academic experts, healthcare professionals, representatives

   2   of patient and consumer advocacy groups and the regulated 
 
   3   industry, we feel that there is more than just that mandate 
 
   4   of 406(b).  We want to have your input in understanding how 
 
   5   people view the agency in general, and how people view the 
 
   6   workload that we are facing in the next five to ten years.

   7             We plan to issue the 406(b) plan, as is required 
 
   8   by law, on November 21st, and that will be the result of the 
 
   9   stakeholders' meetings that we have been having and will 
 
  10   have with our various constituents throughout the country in 
 
  11   the next few weeks.

  12             This is a very intensive process.  Perhaps we are 
 
  13   starting it a little late this year in terms of the process 
 
  14   and having to have this finished by November, but we want to 
 
  15   remind people that we see this as an iterative process.  
 
  16   This is something that we intend to do in the future, and

  17   that we continue to get and ask for your feedback.  It will, 
 
  18   hopefully, be as formalized as this but also will allow you 
 
  19   the opportunity to provide us with your input over the year 
 
  20   and the next few years. 
 
  21             [Slide]

  22             Section 406(b) asks us to look in our plan at six 
 
  23   objectives, and the objectives are those that we would like 
 
  24   you to focus on as you are providing us input.  The first of 
 
  25   those objectives speaks to the kind of input and information 
                                                                  7 
 
   1   that the FDA provides to its constituents about the process

   2   for review of applications and submissions.  The second is 
 
   3   also an informational objective, and that is to maximize the 
 
   4   availability and clarity of information about new products 
 
   5   for both consumers and patients. 
 
   6             Both of those are obviously directives that we

   7   believe are important, that we want to get as much input in 
 
   8   as possible, and that we want to continue to hear about from 
 
   9   you over the next few months. 
 
  10             [Slide] 
 
  11             The next two objectives are to implement

  12   inspection and postmarket monitoring provisions of the Act, 
 
  13   and we are looking for input on how that can be done 
 
  14   creatively, effectively, and to meet the objectives of the 
 
  15   FDA as a consumer health protection agency. 
 
  16             We also want to ensure access to scientific and

  17   technical expertise.  That is why we continue to look for 
 
  18   input to our various processes and are hopeful that you will 
 
  19   give us new ways of maximizing that input over the next 
 
  20   year. 
 
  21             [Slide]

  22             The final two objectives are to establish 
 
  23   mechanisms for meeting the established time periods for 
 
  24   review of applications and submissions by July.  As you 
 
  25   know, FDA has statutory mandates, some of which we are 
                                                                  8 
 
   1   meeting and some of which we are not, and this objective is

   2   to encourage us to establish, as part of the plan, how we 
 
   3   will meet those objectives.  The final one is how we will 
 
   4   eliminate the backlog of applications and submissions by 
 
   5   January of the year 2000. 
 
   6             [Slide]

   7             In addition to the FDAMA six objectives, we are 
 
   8   also interested in having your input into what we are 
 
   9   calling the six areas of concern, issues of concern that we 
 
  10   have.  These are six areas that we are focusing on, and will 
 
  11   highlight in our 2000 budget to the Congress, and that we

  12   think require us to look at in terms of how we are doing 
 
  13   this activity, can we do it more efficiently, and can we do 
 
  14   it in a way that we are not doing now.  So, we are looking 
 
  15   for new ideas about adverse event and injury reporting. 
 
  16             As you know, there have been a number of articles

  17   that have talked about the issue of adverse events with 
 
  18   prescription drugs, and we believe that is just the tip of 
 
  19   the iceberg in terms of all of the products that FDA 
 
  20   regulates. 
 
  21             The agency is also very concerned about product

  22   safety assurance, and how we are meeting our obligations 
 
  23   under the law in terms of our inspectional and compliance 
 
  24   activities. 
 
  25             Product application review has been an area where 
                                                                  9 
 
   1   the agency has focused in the last few years, and where we

   2   have made significant progress but where we continue to need 
 
   3   to make progress, and we want to be able to do that activity 
 
   4   in the most efficient way, meeting consumer needs as well as 
 
   5   the industry's concerns.  We are looking for feedback on 
 
   6   that activity as well.

   7             [Slide] 
 
   8             Then, the final four areas that we are focusing on 
 
   9   are the President's initiative on food safety, which I think 
 
  10   most of you have read about.  Even though food is not the 
 
  11   area of concern today, it is one of the areas that we need

  12   to focus on, all of us, and we are putting additional 
 
  13   resources into that activity. 
 
  14             We also want to focus on our outreach activities 
 
  15   and make sure that we are connecting with our various 
 
  16   constituents, and that is why this process is so important

  17   to us. 
 
  18             We too believe that we are a scientific regulatory 
 
  19   agency and, as a result, we need to be very concerned about 
 
  20   the scientific infrastructure and the research activities of 
 
  21   this agency.

  22             Finally, is the issue of tobacco.  As you know, 
 
  23   the FDA has undertaken in the last few years a major 
 
  24   initiative in the area of eliminating the number of youths 
 
  25   who start smoking, and I think those efforts will continue 
                                                                 10 
 
   1   to be an important public health initiative.

   2             We are asking that you continue to send us 
 
   3   information.  The docket will be open for the next few 
 
   4   weeks.  We would like to have your input into both the 
 
   5   Biologics specific docket but also to the FDA docket as 
 
   6   well.

   7             [Slide] 
 
   8             We have three ways that you can comment.  We 
 
   9   believe that the information that is available on the web 
 
  10   pages is something that can give you the kind of background 
 
  11   that you need.  In addition, I would like to present some

  12   FTE numbers so that you can see the kind of resources that 
 
  13   the FDA has had over the last few years and, in fact, why we 
 
  14   feel pressured in terms of the ability to be able to meet 
 
  15   our statutory obligations. 
 
  16             [Slide]

  17             As you can see from the chart, the yellow, which 
 
  18   we are calling the "shrinking" FDA, shows you in constant 
 
  19   dollars what resources we have available for the basic 
 
  20   activities of the agency.  While our budget has increased 
 
  21   significantly, if you look at it in terms of actual dollars

  22   you will see that most of that increase is eaten up by 
 
  23   inflation, and also it is eaten up by the new programs that 
 
  24   are mandated and that have a specific dollar figure that is 
 
  25   mandated to those programs.  As a result, the real dollars 
                                                                 11 
 
   1   that the agency has to do its ongoing work have been

   2   decreasing over time.  So, as a result, there is a 
 
   3   tremendous amount of pressure. 
 
   4             [Slide] 
 
   5             This chart shows that a little bit more.  If you 
 
   6   look at it in terms of constant dollars with the increasing

   7   workload, you will see that this erosion of FDA's base is 
 
   8   something that concerns us, and certainly puts an added 
 
   9   constraint on how we can do our work in the future. 
 
  10             So, that is why we are looking at asking each of 
 
  11   you to help us in figuring out what the important activities

  12   of the agency are, and what the creative ways are that we 
 
  13   can go about in doing our job. 
 
  14             I am very happy to be here today, to be able to 
 
  15   have the input and listen to each of you during your 
 
  16   presentations, and I look forward to the next few weeks when

  17   we have these meetings across all of the agency's 
 
  18   constituents.  Thank you. 
 
  19                           CBER Remarks 
 
  20             DR. ZOON:  Thank you very much, Linda, for your 
 
  21   opening remarks.

  22             I thought while we are gathered together I would 
 
  23   introduce a few people to you, and I would like to first 
 
  24   introduce a number of the members of our CBER management 
 
  25   team.  If I could, I will start at the table.  We have Dave 
                                                                 12 
 
   1   Feigal, who is the Deputy Director for Medical at CBER; Mark

   2   Elengold, Deputy Director for Operations; Bill Egan, who is 
 
   3   the Deputy Director of the Office of Vaccines; Jerry Donlan, 
 
   4   who is the Deputy Director at the Compliance and Biologics 
 
   5   Quality.  I will get to you; I have special words for you!  
 
   6   Becky Devine, who is the Associate for Policy; Don Peterson,

   7   who is the head of our Office of Management; and Steve 
 
   8   Masiello, who is the head of the Office of Compliance and 
 
   9   Biologics Quality; and Mary Meyer, who is head of OCMA.  
 
  10   Thank you, Mary. 
 
  11             We also have some very special guests here.  Part

  12   of our initiatives would not be possible to accomplish 
 
  13   without the strong teamwork of CBER and our colleagues on 
 
  14   ORA.  I would like to take special notice of Mr. Ron 
 
  15   Chesemore.  Would you please stand up?  Ron is the head of 
 
  16   ORA.

  17             We also have two special guests.  We have here 
 
  18   Elaine Cole, who is the District Director in Baltimore; and 
 
  19   Diana Kalitis, who is the Regional Northeast Director. 
 
  20             So, thank you all very much for coming.  I think 
 
  21   this is a real effort among all of us to help and work

  22   together to get the many tasks that we need done, and I 
 
  23   thought it would be nice for you to have an opportunity to 
 
  24   actually see the folks who are responsible for all these 
 
  25   activities. 
                                                                 13 
 
   1             [Slide]

   2             What I would like to do in the next 20 minutes is 
 
   3   just give you a brief overview of some of the activities of 
 
   4   the Center for Biologic, and I would like to start out with 
 
   5   our mission statement.  This is very important, and it was a 
 
   6   fundamental part of the FDA Modernization Act.  Although

   7   CBER very much concurred with the revised FDA statement, we 
 
   8   actually revised ours several years before to reflect very 
 
   9   much the spirit that was stated.  
 
  10             Our mission statement says that our mission is to 
 
  11   protect and enhance the public health through the regulation

  12   of biological and related products including blood, 
 
  13   vaccines, and biological therapeutics according to statutory 
 
  14   authorities.  The regulation of these products is founded on 
 
  15   science and law to ensure their purity, potency, safety, 
 
  16   efficacy and availability.

  17             As all of you know, with the diversity of CBER's 
 
  18   products, this creates many challenges for us and we all 
 
  19   work together, both within CBER and ORA, and with the 
 
  20   industry and the consumer groups and others affected in 
 
  21   order to make sure that this actually happens.

  22             [Slide] 
 
  23             This overhead actually displays the types of 
 
  24   products that we regulated.  Those products are increasing 
 
  25   in their diversity over time because many of the new 
                                                                 14 
 
   1   technologies are being incorporated into CBER's portfolio. 

   2   These include our traditional products such as vaccines, 
 
   3   allergenic extracts, blood and blood components, blood 
 
   4   derivatives, and more recently tissues.  But it also 
 
   5   includes a number of the new biotechnology-derived products 
 
   6   including monoclonal antibodies, recombinant DNA-derived

   7   proteins, somatic cell and gene therapy and, more recently, 
 
   8   xenotransplantation. 
 
   9             These have been very important to CBER, and all 
 
  10   the products are important to our Center and we have to pay 
 
  11   attention to each of the types of classes.  This, in some

  12   ways, makes priority setting very challenging for CBER 
 
  13   because there are many different demands on our organization 
 
  14   and we strive to do all of these well. 
 
  15             [Slide] 
 
  16             We have had a number of successes in our Center,

  17   and I would just like to quickly go over those, in the past 
 
  18   five years predominantly.  These include the reinventing 
 
  19   government initiative.  Many of you are aware of this 
 
  20   administrative initiative, and many changes have occurred in 
 
  21   CBER even prior to the FDA Modernization Act.

  22             We have simplified manufacturing changes.  We have 
 
  23   eliminated the ELA for specified biotech products, as well 
 
  24   as lot release for specified biotech products. 
 
  25             We have developed the harmonized application form 
                                                                 15 
 
   1   for both NDAs and BLAs.

   2             As many of you have seen, we have been publishing 
 
   3   guidance documents on the chemistry, manufacturing and 
 
   4   control sections for all our products, and these will help 
 
   5   us prepare, as we are now, for the implementation of the new 
 
   6   provisions of the FDAMA.

   7             We have made great progress on the proposed rule 
 
   8   for a single biologics license, as recently issued.  Again, 
 
   9   we have worked very hard on a number of initiatives 
 
  10   regarding review of labeling and elimination of the pre- 
 
  11   approval labeling.  We have also been very aggressive at

  12   improving our IND oversight functions.  So, that has been an 
 
  13   active area. 
 
  14             The prescription drug user fee program, as Ms. 
 
  15   Suydam mentioned, actually has been a very successful 
 
  16   experiment, and we are now in phase two of that experiment. 

  17   CBER has met all the goals, and in many cases has exceeded 
 
  18   all the goals of the prescription drug user fee program, and 
 
  19   we are very proud of our accomplishments in that area.  As 
 
  20   you will see in the next few slides, that progress has not 
 
  21   been limited just to the user fee products.  We have put

  22   many of our management initiatives in place for our non-user 
 
  23   fee products, and have made great progress in the management 
 
  24   and time-lines of those particular product reviews. 
 
  25             We look forward to the PDUFA-II program.  I think 
                                                                 16 
 
   1   we, at CBER, believe that we can interact with you at the

   2   IND level and that is very important in getting products to 
 
   3   market sooner.  I think that interaction of scientific and 
 
   4   regulatory staff in dealing with the complex issues of 
 
   5   biological products is absolutely critical to meet the 
 
   6   public's needs for these safe and effective medicines.

   7             We have a strategic plan for our Center, and I 
 
   8   will discuss that with you.  It has been very successful in 
 
   9   moving forward a number of initiatives which I will outline. 
 
  10             The international conference on harmonization has 
 
  11   been very, very successful.  CBER has taken the lead on many

  12   documents, in particular in the area of biotechnology and in 
 
  13   the quality and safety aspects, but also has had enormous 
 
  14   input into the efficacy region of those documents.  We 
 
  15   believe the world is getting smaller and the efforts on 
 
  16   globalization are key to the success of the future of

  17   getting products that are safe and effective to the American 
 
  18   public. 
 
  19             This also applies to the WHO activities, the World 
 
  20   Health Organization.  Many of the products that are not 
 
  21   covered by ICH will be covered and harmonized using WHO as a

  22   vehicle for harmonization, and we believe this will be very 
 
  23   important in the areas of blood and vaccines. 
 
  24             With respect to cellular and gene therapy, a great 
 
  25   deal of progress has been made in this field.  CBER has 
                                                                 17 
 
   1   sponsored numerous conferences and workshops to assist this

   2   developing technology, and I think has achieved a fair 
 
   3   amount of success in providing the guidance that is 
 
   4   necessary to move these initiatives forward. 
 
   5             Our research program has recently been the first 
 
   6   to have a major external review.  Every program was looked

   7   at by a body of 26 distinguished scientists from academia, 
 
   8   industry and government.  This included six members of the 
 
   9   National Academy of Sciences.  There was a great deal of 
 
  10   support for the research program and its importance to the 
 
  11   ability of CBER to do its work in regulating biological

  12   products.  So, as you can see, there has been a lot of 
 
  13   activity at the Center, and we are very proud of the 
 
  14   successes. 
 
  15             [Slide] 
 
  16             Just to show some data regarding this, if you look

  17   at both our user fee and non-user fee approval times, you 
 
  18   can see that the processes, both the management processes 
 
  19   and the prescription drug user fee program, have had 
 
  20   enormous effect on the reduction in the time it takes to 
 
  21   approve safe and effective products.

  22             [Slide] 
 
  23             This overhead shows the same data for supplements.  
 
  24   Our workload is actually increasing at CBER, and this is 
 
  25   indicated in the next overhead. 
                                                                 18 
 
   1             [Slide]

   2             This shows you our IND workload.  Since 1997 we 
 
   3   have actually seen an increase in both our biotech and non- 
 
   4   biotech INDs for this year, and I think this is very much 
 
   5   stimulated by some of the changes made at CBER, as well as 
 
   6   it is going to be fostered by the FDA Modernization Act.

   7             [Slide] 
 
   8             This overhead describes the strategic goals of our 
 
   9   Center with respect to our strategic plan.  We put this plan 
 
  10   into place in 1995, and have been actively working on it and 
 
  11   we have made much progress in each of these areas.

  12             The first is a managed and integrated regulatory 
 
  13   program from discovery through postmarketing.  We have 
 
  14   mapped out the entire business processes of our Center.  We 
 
  15   put teams together.  They identified weaknesses and 
 
  16   bottlenecks.  They redesigned our business processes to

  17   create solutions.  We are now in the process of implementing 
 
  18   a newly designed, streamlined managed review process.  The 
 
  19   first step is to roll out this process beyond the review of 
 
  20   license applications and to focus now on the investigational 
 
  21   new drug phase of our processes.

  22             With respect to our research program, I talked 
 
  23   about our external review.  We are currently considering the 
 
  24   comments of the external review and are preparing a number 
 
  25   of initiatives to respond to that in the Center.  We are 
                                                                 19 
 
   1   also developing a coordinated model of research and I think

   2   this is going to be very key in really honing in on our 
 
   3   expertise as scientists, researchers and the regulatory 
 
   4   process through our researcher, reviewer, and regulatory 
 
   5   scientist models. 
 
   6             A high quality and diverse work force is very

   7   important.  Our people are our most important asset, and to 
 
   8   do the job we need highly skilled individuals that are good 
 
   9   listeners and work well with others. 
 
  10             Interactive information systems which are integral 
 
  11   to all our processes has been a major initiative at our

  12   Center.  It has been reaffirmed in PDUFA-II.  We have 
 
  13   dedicated an enormous amount of effort in this area.  We 
 
  14   have achieved desktop standardization in our Center.  We are 
 
  15   working very hard on electronic submissions, not only for 
 
  16   BLAs and NDAs but also for INDs.  We are implementing a

  17   docket management system, and our regulatory management 
 
  18   system is currently being developed so we have a single 
 
  19   corporate database for our entire center.  We have also 
 
  20   implemented electronic lot release. 
 
  21             Leveraging resources is an important part of our

  22   activities.  We recognize that resources will continue to be 
 
  23   limiting.  Developing strategic partnership to accomplish 
 
  24   our mission is key in CBER's initiatives. 
 
  25             [Slide] 
                                                                 20 
 
   1             Some of the major initiatives and action plans

   2   that are currently under way include the implementation of 
 
   3   the FDA Modernization Act, the implementation of the 
 
   4   Prescription Drug User Act-II, and continuing our activities 
 
   5   on the international conference on harmonization, 
 
   6   particularly with respect to the initiatives on GMP for

   7   active ingredients and pediatrics in a common technical 
 
   8   document. 
 
   9             Again, we are continuing to work on our strategic 
 
  10   plan, and completing the implementation of team biologics 
 
  11   which is a unique model of putting together product

  12   specialists and trained, skilled investigators from the 
 
  13   field to act as a highly trained core team of individuals to 
 
  14   inspect biologics manufacturers.  This also has an aspect of 
 
  15   streamlined processes within all forms of compliance, and I 
 
  16   think to date it has been a very successful initiative for

  17   postmarketing inspections. 
 
  18             We have also engaged in a tissue regulatory 
 
  19   framework.  Last February, in 1997, we published a 
 
  20   reinventing initiative on the regulation of human tissues.  
 
  21   This is a tiered risk-driven approach based on the

  22   regulatory variables and concerns that one might have about 
 
  23   tissues, and we are currently in the process of preparing 
 
  24   proposed rules for this particular initiative. 
 
  25             The blood action plan is a major initiative in 
                                                                 21 
 
   1   CBER.  We have accomplished a tremendous amount in this

   2   area.  You have seen guidances.  You will see a number of 
 
   3   proposed rules being issued -- very important areas.  I 
 
   4   think this will continue to be a major initiative over the 
 
   5   next two years.  It includes updating our regs. and new 
 
   6   regs.  It includes trying new approaches to the regulation

   7   of biological blood products, particularly using a monograph 
 
   8   system. 
 
   9             We are also looking at emerging infectious 
 
  10   diseases, and making this a priority in our blood area to 
 
  11   make sure that we are as vigilant as we can be with respect

  12   to our ability to identify and react to new infectious 
 
  13   diseases as they may affect blood and tissues. 
 
  14             The xenotransplantation action plan is a plan that 
 
  15   we put together at the Center to deal with the new 
 
  16   technology of xenotransplantation.  This will include

  17   xenotransplant patient regulations and guidelines.  It will 
 
  18   affect the issues of disclosure in this very sensitive and 
 
  19   important area. 
 
  20             [Slide] 
 
  21             Some of our challenges for the future are to

  22   successfully complete all that is on our plate, and this in 
 
  23   includes FDAMA, PDUFA-II, our international harmonization 
 
  24   efforts, being vigilant in the area of emerging infectious 
 
  25   diseases, including xenotransplantation and dealing with the 
                                                                 22 
 
   1   issue of human cloning and reproductive technologies.

   2             [Slide] 
 
   3             Some of the funding challenges that we face are 
 
   4   many, unfortunately.  These include funding initiatives for 
 
   5   tissues, xeno, blood, the implementation of the FDA 
 
   6   Modernization Act, the ICH processes, gene therapy, emerging

   7   infectious diseases, bioterrorism and our research programs.  
 
   8   Those are the challenges that we are working very hard on at 
 
   9   the moment. 
 
  10             [Slide] 
 
  11             There have been a number of significant

  12   legislations that have been passed that has impact on CBER's 
 
  13   daily activities.  Those are listed on this slide.  I am not 
 
  14   going to go through all of them.  A number of them have been 
 
  15   mentioned already, but each of these impacts on our daily 
 
  16   work and our daily considerations.  Many of these

  17   initiatives have been unfunded.  Clearly, the prescription 
 
  18   drug user fee program in its right was a funded initiative, 
 
  19   additive funds, for the review of new drugs and biologics. 
 
  20             [Slide] 
 
  21             In the last few minutes I would like to give you

  22   the state where CBER is right now with respect to our 
 
  23   operating budget and FTEs.  This shows you that in spite of 
 
  24   all the increasing responsibilities we have had our budge is 
 
  25   declining.  This is actually well seen in this graph.  Our 
                                                                 23 
 
   1   PDUFA dollars have actually increased.  To a large extent,

   2   this has been targeted for the review process, but also for 
 
   3   information management initiatives.  This negatively 
 
   4   affected the research programs because of some of the 
 
   5   reductions in the ability to use the PDUFA dollars for 
 
   6   research, but has been very helpful in the information

   7   technology area. 
 
   8             The biggest hit though is in our base funding.  As 
 
   9   you can see, those dollars have decreased dramatically over 
 
  10   the past five years. 
 
  11             [Slide]

  12             One of the hardest hit at CBER has been our 
 
  13   research budget, and this slide indicates the impact it has 
 
  14   had on CBER.  Because of the new initiatives, it has been 
 
  15   increasingly stressful on the organization to maintain the 
 
  16   level of research dollars that have been fairly stable in

  17   the early '90s. 
 
  18             [Slide] 
 
  19             This overhead shows you the FTEs.  While the FTEs 
 
  20   have been fairly stable over the past four years, as you can 
 
  21   see, we actually, even with the re-initiation of the

  22   prescription drug program, have had a decrease in the number 
 
  23   of FTEs allotted to the Center for Biologics. 
 
  24             [Slide] 
 
  25             The Modernization Act is very important to us.  We 
                                                                 24 
 
   1   are committed to its implementation.  This is just part of a

   2   very large initiative that our Center is very happy to 
 
   3   participate in.  We see this as a fundamental role of our 
 
   4   organization to serve the public, to serve our stakeholders, 
 
   5   and we appreciate the opportunity.  We look forward to 
 
   6   hearing from you today, and your comments today, as well as

   7   any comments you or your colleagues may have after today. 
 
   8             [Slide] 
 
   9             The docket number is listed on this slide, and 
 
  10   there are three ways to comment.  One is by mail; one is by 
 
  11   email and, finally online.

  12             I want to personally thank all of you for coming 
 
  13   today, and I very much look forward to hearing from you. 
 
  14             I would now like to ask our first two panelists to 
 
  15   please come up to the front.  Alan Goldhammer will be the 
 
  16   first to present.  Welcome, Alan.

  17                             Panel A 
 
  18               Biotechnology Industry Organization 
 
  19             DR. GOLDHAMMER:  Thank you very much, Kathy, and I 
 
  20   would also like to thank you for adjusting the schedule.  I 
 
  21   have another meeting that starts in about 25 minutes.  So, I

  22   will have to duck out shortly after my presentation here. 
 
  23             I am Alan Goldhammer, Executive Director for 
 
  24   Technical Affairs at the Biotechnology Industry 
 
  25   Organization.  We welcome the opportunity to address the 
                                                                 25 
 
   1   questions that were recently posed by the FDA in its July

   2   22nd message to the stakeholders. 
 
   3             In that message, FDA noted that its obligations 
 
   4   under Section 406(b) of FDAMA are to meet with interested 
 
   5   parties, with the goal of receiving input as to how the 
 
   6   agency can best meet its regulatory responsibilities.  This

   7   document was frank in its mention that innovations and 
 
   8   efficiencies alone may not be sufficient to deal with the 
 
   9   enormous growth in FDA's obligations that have been fueled 
 
  10   by rapid technological developments and increased complexity 
 
  11   of regulated products and mushrooming global trade.  I think

  12   you have already heard that from both Linda Suydam and Kathy 
 
  13   in their presentations this morning. 
 
  14             The agency goes on to identify a series of areas 
 
  15   that they believe are critical to the agency's public health 
 
  16   mission.  The agency notes that although we have shared

  17   areas where we have real concerns about our ability to meet 
 
  18   our statutory obligations, our stakeholders can be assured 
 
  19   that we are embarking on this consultation process with no 
 
  20   preconceived conclusions, and the agency sets forth again 
 
  21   the seven questions designed to assist in developing a plan

  22   for complying with FDAMA and these are the issues that are 
 
  23   before us today. 
 
  24             Before I address the specific points, I would like 
 
  25   to note the interconnecting thread that is implicit with 
                                                                 26 
 
   1   FDA's message to the stakeholders, as well as the questions

   2   that were posed.  This theme, in our mind, is the need for 
 
   3   adequate resources and I think you have just seen some 
 
   4   dramatic view-graphs documenting this. 
 
   5             Six years ago, the Prescription Drug User Fee Act 
 
   6   was passed in response to a specific crisis that there were

   7   insufficient resources within the FDA to review drugs and 
 
   8   biologics.  The agency was not able to meet its obligation 
 
   9   in reviewing drugs and biologics in a timely manner.  The 
 
  10   backlog of applications was growing out of control, and a 
 
  11   convincing case could and was made for the need to augment

  12   the agency's resources in a targeted manner, accompanied 
 
  13   with performance goals so that new priority products could 
 
  14   be reviewed and acted upon in six months, standard 
 
  15   applications in 12 months. 
 
  16             The success of this program was self-evident, and

  17   one of the critical sections of FDAMA was the 
 
  18   reauthorization of PDUFA with a new set of goals for an 
 
  19   additional five years.  Our thoughts are that the 
 
  20   performance enhancements can shorten drug development by 
 
  21   anywhere from 10-15 months.

  22             The success of PDUFA should not be taken as a sign 
 
  23   that the regulated industry only needs to give money to FDA 
 
  24   and that all the problems will be solved.  Our industry is 
 
  25   not FDA's only constituent.  Healthcare professionals, 
                                                                 27 
 
   1   patients who rely on new medical technologies, and the

   2   general public all have a vested stake in an FDA that is 
 
   3   fully funded so that it might carry out its responsibilities 
 
   4   for all the publics that it serves. 
 
   5             This means that FDA must have adequate 
 
   6   appropriated congressional funding.  It has been our

   7   experience that user fees can best be used to address 
 
   8   certain narrow programmatic problems.  However, the public 
 
   9   constituencies' overall interests about FDA's ability to 
 
  10   carry out its functions must continue to be addressed via 
 
  11   the appropriations process.  There is no question that

  12   recent efforts by both the administration and Congress to 
 
  13   see a balanced budget have had an impact on FDA's operating 
 
  14   budget.  Senior management at FDA must be prepared to 
 
  15   present its budgetary needs to both OMB and Congress in a 
 
  16   realistic and forceful manner.

  17             We would offer specific responses to three of the 
 
  18   seven questions, and these will be submitted in greater 
 
  19   length to the docket prior to its close. 
 
  20             On question one regarding FDA's explanation of the 
 
  21   submission review process, we have two comments.  Our

  22   industry has spent considerable resources trying to make the 
 
  23   drug development process more predictable.  FDAMA clarifies 
 
  24   many FDA responsibilities regarding its role in approving 
 
  25   the predictability of drug development.  However, FDA's 
                                                                 28 
 
   1   increasing reliance on advisory committees both to answer

   2   general questions about products during the development 
 
   3   process, and to review information as the penultimate step 
 
   4   prior to licensure, is oftentimes unpredictable.  Outcomes 
 
   5   of advisory committee decisions often surprise both the 
 
   6   sponsors and the FDA.

   7             There appear to be different internal practices 
 
   8   between different centers regarding the use of advisory 
 
   9   committees.  We believe it would be useful for the agency to 
 
  10   have a mechanism by which it can receive sound advice on 
 
  11   scientific questions.  The advisory committees are an

  12   appropriate vehicle here.  However, it may be appropriate to 
 
  13   convene a working group from the regulated industries to 
 
  14   review present agency use of advisory panels and make 
 
  15   recommendations as to how the process might be improved to 
 
  16   maximize their utility to the FDA.  We will be submitting

  17   some more thoughts on this to the docket. 
 
  18             The second point is that oftentimes agency actions 
 
  19   highlight an outdated or vague regulation or guidance that 
 
  20   is in need of revision.  In such cases, these should be 
 
  21   identified as early as possible, and the FDA should reach

  22   out to stakeholders for discussion of these issues. 
 
  23             An example of this are definitions of the same 
 
  24   versus different for orphan drugs.  This has particular 
 
  25   application for the biotechnology industry because chemical 
                                                                 29 
 
   1   structures or monoclonal antibodies and recombinant proteins

   2   are very complicated and sometimes fall into grey areas as 
 
   3   to whether they are the same or whether they are different.  
 
   4   If a product is not the same, then it can receive a separate 
 
   5   orphan drug designation.  However, if not, then clinical 
 
   6   superiority or reduction in adverse reactions must be

   7   demonstrated.  Would demonstration of a major improvement in 
 
   8   patient care, that is, combination of such factors as higher 
 
   9   effective dose or ease of administration qualify under this 
 
  10   provision?  It would be useful to consider developing a 
 
  11   guidance document or revising the regulation to address

  12   these issues. 
 
  13             The second question that we would like to address 
 
  14   is assuring product quality and safety.  The issue of 
 
  15   product quality and safety is one that is never compromised 
 
  16   within our industry.  Our products are mostly large

  17   molecular weight proteins.  The manufacturing processes and 
 
  18   purification procedures are complex.  Much time and effort 
 
  19   is spent during the development process, as well as FDA's 
 
  20   review of the license application, to design manufacturing 
 
  21   process controls and a quality assurance process and program

  22   that will lead to a final product of the highest possible 
 
  23   quality and consistency.  We would also note that FDA has in 
 
  24   place regulations that the reporting of adverse reactions, 
 
  25   another area that they have identified as a critical issue. 
                                                                 30 
 
   1             One of the key agreements reached during the

   2   renegotiation of the Prescription Drug User Fee Act 18 
 
   3   months ago was to provide FDA with extra funding to move it 
 
   4   towards a fully electronic filing environment over the next 
 
   5   five years.  One of the areas noted which would fall in to 
 
   6   this area was adverse event reporting.  This should

   7   streamline reporting and data analysis, and we are prepared 
 
   8   to work with FDA and other stakeholders on this matter as 
 
   9   issues are identified. 
 
  10             The third major point that I would like to 
 
  11   address, and one which is very important and is identified

  12   as a priority of our board is that of the FDA science 
 
  13   infrastructure.  We believe that there needs to be a 
 
  14   continuing strong commitment within the Food and Drug 
 
  15   Administration towards maintaining an appropriate scientific 
 
  16   base.  Regulatory decisions, including the development of

  17   guidance documents and regulations, must be made on the best 
 
  18   available science.  It has been the experience of our member 
 
  19   companies, with numerous examples relating to both clinical 
 
  20   development and complex manufacturing issues, that these 
 
  21   were speedily resolved because of the scientific expertise

  22   within the Center for Biologics.  The recent FDA science 
 
  23   board review of CBER activities was positive in this regard.  
 
  24   There needs to be a closer tie with industry in identifying 
 
  25   research areas and reviewing ongoing programs, and I think 
                                                                 31 
 
   1   we can work towards this goal.  Our board of directors has

   2   identified this as another major priority.  We are carefully 
 
   3   examining this issue and expect to file specific comments on 
 
   4   the docket. 
 
   5             Thank you. 
 
   6             DR. ZOON:  Thank you very much, Alan.  Are there

   7   any questions?  Since Alan has to go, I will take the 
 
   8   opportunity to ask if there are any clarifications or 
 
   9   questions?  No?  Thank you very much. 
 
  10             DR. GOLDHAMMER:  Thank you. 
 
  11             DR. ZOON:  I would now like to introduce Bert

  12   Spilker.  He is senior vice president, science and 
 
  13   regulatory affairs of PhRMA. 
 
  14       Pharmaceutical Research and Manufacturers of America 
 
  15             DR. SPILKER:  Thank you, Kathy. 
 
  16             Good morning, members of CBER, ladies and

  17   gentlemen.  I am Dr. Bert Spilker, senior VP of 
 
  18   Pharmaceutical Research and Manufacturers of America.  My 
 
  19   comments this morning must of necessity be condensed in 
 
  20   order to fit the allotted time.  Further details and 
 
  21   substantiation will be submitted to the docket.

  22             PhRMA appreciates the opportunity to provide input 
 
  23   as FDA considers how best to achieve compliance with the 
 
  24   agency's various statutory obligations.  It is important to 
 
  25   underscore, however, that consultation with stakeholders 
                                                                 32 
 
   1   like PhRMA does not relieve FDA from the ultimate

   2   responsibility to manage and, as necessary, reallocate its 
 
   3   resources to achieve the statutory time-lines and other 
 
   4   goals of the FD&C Act in a timely manner. 
 
   5             I will address the questions in order.  Question 
 
   6   one on agency explanations:  We wish to make three points. 

   7   The first point is that it is important for FDA to make its 
 
   8   procedures more transparent, particularly in terms of good 
 
   9   review practices, also known as GRPs. 
 
  10             The second point, copies of GRPs, as well as CBER 
 
  11   and CDER reviewer handbooks plus MAPPS, which are mainly

  12   CDER, for NDA and IND reviews should be provided to the 
 
  13   industry and other stakeholders even though these documents 
 
  14   may still be in draft form.  This step would provide 
 
  15   industry with a better understanding of how these groups 
 
  16   operate, and also enable industry to bring out procedures

  17   into conformity with FDA.  This action is intended in the 
 
  18   spirit of openness to foster improved collaboration.  This 
 
  19   action is also part of Section 119 of FDAMA. 
 
  20             The third point, allow more time for companies to 
 
  21   respond to FDA proposed labeling changes near the end of the

  22   review period.  At present, companies often have less than 
 
  23   24 hours to decide whether or not to accept FDA changes or 
 
  24   get an approvable letter with FDA language that is not in 
 
  25   the company's interest. 
                                                                 33 
 
   1             Second question on clarity of information:  We

   2   wish to make two points.  First, we appreciate that FDA is 
 
   3   putting information about new drugs on the Internet.  This 
 
   4   is extremely positive.  This practice should be followed for 
 
   5   all products at the time of approval. 
 
   6             Second point, the FDA should allow companies and

   7   other groups to provide well documented information on 
 
   8   marketed drugs using market forces. 
 
   9             On the third question we wish to make five points.  
 
  10   The first, there is nothing that is more important to the 
 
  11   pharmaceutical industry than the safety of our products. 

  12   Every day, worldwide, our companies are monitoring the 
 
  13   safety of their products.  We have extensive systems in 
 
  14   place today to collect safety data and we report to the FDA 
 
  15   all adverse reactions according to regulations. 
 
  16             The second point, the FDA should stress to

  17   Congress, the press and the public that the current safety 
 
  18   standards for new drug approval are significantly higher 
 
  19   than they were in the past.  For example, in 1980 there were 
 
  20   an average of 1500 patients studied in 34 clinical trials in 
 
  21   the average NDA.  These numbers have risen to over 4000

  22   patients in 68 clinical trials today.  The amount of safety 
 
  23   data is related to the number of patients exposed to a new 
 
  24   drug. 
 
  25             Third point, we support the views of 21 patient 
                                                                 34 
 
   1   organizations who wrote to USA Today last week to emphasize,

   2   and I quote, "the FDA has not compromised its world-class 
 
   3   standards for the safety and effectiveness of new 
 
   4   medicines."  Another quote is, "fear that in overreaction to 
 
   5   a small number of recent drug withdrawals, policy makers may 
 
   6   decide to slow down the drug approval process.  This would

   7   hurt public health and harm the patients we represent by 
 
   8   denying them the new treatments and cures they are so 
 
   9   anxious to receive." 
 
  10             The fourth point we wish to make is that both FDA 
 
  11   and the pharmaceutical industry must educate Congress, the

  12   press and the public about the vast amount of safety 
 
  13   activities already  in place.  Recent drug withdrawals 
 
  14   demonstrate that the systems are basically working, not that 
 
  15   they are broken. 
 
  16             The last point, to the extent that the system for

  17   monitoring the safety of medicines after they are on the 
 
  18   market can be improved, the pharmaceutical industry s eager 
 
  19   to work with the FDA, with patients, with doctors, 
 
  20   pharmacists, hospitals, Congress, and anyone else to achieve 
 
  21   that goal.

  22             The fourth question is on FDA access to scientific 
 
  23   and technical expertise, and we wish to make six points. 
 
  24             First, we support FDA conducting targeted research 
 
  25   on regulatory policy, particularly if planned 
                                                                 35 
 
   1   collaboratively with industry.

   2             Two, we support in-service training that supports 
 
   3   the skills of staff to conduct reviews of marketing 
 
   4   applications. 
 
   5             Three, we support training of field staff, partly 
 
   6   within pharmaceutical companies.

   7             Four, we support increased collaboration with 
 
   8   other regulatory agencies worldwide.  That is, collaboration 
 
   9   of CBER with other regulatory agencies worldwide. 
 
  10             Fifth, we support the establishment of periodic 
 
  11   meetings for division directors in both CBER and CDER with

  12   up to four industry representatives on a bimonthly or 
 
  13   quarterly basis.  The purpose of these sort of informal 
 
  14   meetings is to share scientific and technical information, 
 
  15   management ideas, overall approaches, and creative thinking. 
 
  16             Six, we support increased efficiency in the use of

  17   current resources within CBER. 
 
  18             Question five is on review of non-user fee 
 
  19   products.  The point we want to make is that the current 
 
  20   level of full-time support staff paid through user fees 
 
  21   should not be diminished.

  22             Question six is on ideas to eliminate backlogs.  
 
  23   Here, our comments will be made to the docket only. 
 
  24             The last question is on other objectives beyond 
 
  25   the six.  Here, we wish to make three additional comments. 
                                                                 36 
 
   1             First, it would be valuable for reviewers to have

   2   brief sabbaticals in the regulated industries.  This will 
 
   3   increase their knowledge of the industry, its procedures and 
 
   4   its perspectives.  Thus, they will better understand the 
 
   5   industry they are regulating.  It should be noted that CDER 
 
   6   chemists currently have such sabbaticals in place.

   7             Second point, the agency should educate the public 
 
   8   about benefit-to-risk ratios and the fact that medical 
 
   9   interventions such as surgery, medicines, devices, and even 
 
  10   diagnostics and foods are not totally without risks. 
 
  11             The last point, there is a need for external

  12   advisory panels to advise FDA on efficient administrative 
 
  13   policies and activities. 
 
  14             Thank you for the opportunity afforded me to 
 
  15   address you this morning. 
 
  16             DR. ZOON:  Thank you very much.  This statement is

  17   now open for questions by any of the panel members. 
 
  18             MS. SUYDAM:  Dr. Spilker, I have a question about 
 
  19   making agency's procedures more transparent.  You had, 
 
  20   obviously, one suggestion which is that we provide reviewer 
 
  21   handbooks.  Are there other things that you think we should

  22   be doing that we are not doing? 
 
  23             DR. SPILKER:  One other point that was mentioned 
 
  24   today was to initiate meetings on a periodic basis between 
 
  25   division directors and industry representatives.  We are not 
                                                                 37 
 
   1   talking about the sessions that currently take place

   2   sometimes every five years and sometimes eight years.  
 
   3   Recently one director said he felt that every eight years 
 
   4   was more than enough. 
 
   5             [Laughter] 
 
   6             But those are more formal and larger meetings.  We

   7   are talking about more informal ones, not to talk about 
 
   8   specific drugs or anything but just policies, ideas, ways of 
 
   9   working together more collaboratively and better.  I think 
 
  10   that Alan Goldhammer mentioned something about getting 
 
  11   together with industry ahead of time to talk about

  12   guidances.  That, in a sense, may not just be making what 
 
  13   you do more transparent but I think the key word from 
 
  14   industry's perspective is that we would like to collaborate 
 
  15   as much as possible.  We recognize that you will make 
 
  16   decisions but at least you will have input.  I think that

  17   there are some examples, which I will be discussing on 
 
  18   Monday, of some guidances that were issued without industry 
 
  19   input and led to a number, from our point of view, problems 
 
  20   which had to be addressed.  I think we can forestall these 
 
  21   and prevent these by having more meetings ahead of time,

  22   such as the types of meetings that I have mentioned and 
 
  23   others that you are aware of. 
 
  24             MS. SUYDAM:  Thank you. 
 
  25             MR. ELENGOLD:  I would like to follow up on 
                                                                 38 
 
   1   Linda's question.  In these, which you described as small,

   2   informal meetings with four representatives, what occurs to 
 
   3   me, in my mind, in how to implement that -- have you 
 
   4   considered what the impact of the Federal Advisory Committee 
 
   5   Act would be on our implementing that?  That is the first 
 
   6   thought that crosses my mind.  Once we seek advice on

   7   guidances, we pretty much are locked into making it an open 
 
   8   public meeting, which tends to be large. 
 
   9             DR. SPILKER:  Thank you for asking that.  Those 
 
  10   are really two separate issues totally in my mind.  What I 
 
  11   was talking about was meetings with division directors and

  12   it was not to be talking about guidances at all but just 
 
  13   ways in which industry interacts with the division 
 
  14   directors.  For the guidances I quite understand your point. 
 
  15             MR. ELENGOLD:  I think though even in ways of 
 
  16   doing business that could be construed as seeking advice

  17   and, at least in my mind, would trigger a need to get some 
 
  18   kind of legal opinion on whether that would constitute 
 
  19   advice seeking.  You yourself said giving advice on how to 
 
  20   better handle things.  Once you go to more than one 
 
  21   organization or group it may trigger that.

  22             DR. SPILKER:  Well, I think this could be explored 
 
  23   though. 
 
  24             MR. ELENGOLD:  We can explore it but, you know, 
 
  25   you should be thinking along those lines as well. 
                                                                 39 
 
   1             DR. SPILKER:  Fair enough.

   2             DR. FEIGAL:  I have a question or maybe it is more 
 
   3   of a comment because I am not sure it is answerable, but one 
 
   4   of the phenomena that sort of interested many of us was 
 
   5   seeing the steady increase over the first five years of the 
 
   6   user fee of the number of new molecular entities coming in

   7   or the number of supplements.  One of the speculations, and 
 
   8   it relates to some of your comments about withdrawals, was 
 
   9   that the shortened review time and the more predictable part 
 
  10   of the process, the fact that there was also a shift towards 
 
  11   more first cycle approvals, had actually changed the

  12   economics of drug approval and had actually made some things 
 
  13   which in the past would have taken so long to approve that 
 
  14   they wouldn't have been pursued, and the issue is where are 
 
  15   all these extra products coming from, and were these, in 
 
  16   fact, innovations or were we scraping the bottom of the

  17   barrel, so to speak, of things that were sort of marginal 
 
  18   either for economic reasons or other reasons? 
 
  19             I was just wondering whether you have any thoughts 
 
  20   on the more rapid review time.  Initially, when you look at 
 
  21   an improvement of 10-15 months, that is not all that

  22   impressive although you realize how much work that is, to do 
 
  23   that.  But are these things all related to each other, and 
 
  24   do you have any comments on those sorts of musings? 
 
  25             DR. SPILKER:  Those are excellent points.  The 
                                                                 40 
 
   1   first point I do want to take slight exception to, that

   2   improvement of 10-15 months is not that great.  
 
   3   Proportionally, if you think of drug development as 10-15 
 
   4   years, which I think is still fairly accurate, I would tend 
 
   5   to agree proportionally.  If you think about the about the 
 
   6   patent life of a drug, and also you think about the revenues

   7   that a drug will bring to a pharmaceutical or biotechnology 
 
   8   company, I think that 10-15 days would be deemed very 
 
   9   important, and I guarantee you that that is the mind set 
 
  10   inside these companies and they will do anything within 
 
  11   their power to gain an additional 10-15 days, let alone

  12   months.  That wasn't the main question but I did want to 
 
  13   make that comment. 
 
  14             It is difficult for me to answer without doing a 
 
  15   total survey of the industry which, to my knowledge, has not 
 
  16   been done.  I think what I would suggest the agency could do

  17   to answer that question is to see how many INDs there were 
 
  18   in the pipeline beforehand.  You may have had a lot of INDs 
 
  19   in the pipeline so that a lot of supplements and NDAs, PLAs, 
 
  20   BLAs etc. were submitted afterwards to make up the numbers 
 
  21   but the impetus was really growing.

  22             I can tell you from personal experience at 
 
  23   Burroughs-Wellcome where I spent 14 years that in the 
 
  24   antiviral area, talking about Zovirax in particular of 
 
  25   acyclovir, that the very first application we had was for an 
                                                                 41 
 
   1   ophthalmic.  We held that to put in an IV form.  We then had

   2   one for herpes encephalitis, and we were told by the agency, 
 
   3   during the '80s, that they would only review one antiviral 
 
   4   from the company at a time, and they were very nice to ask 
 
   5   us which one we wanted them to review.  So, we had multiple 
 
   6   dosage forms, most of which were sitting on the shelf inside

   7   the company and were not submitted to the agency.  When we 
 
   8   asked questions, we said you have taken literally six years; 
 
   9   we have not had an approval on herpes encephalitis; why is 
 
  10   that?  And, the answer came back it is the state-of-the-art 
 
  11   to use the drug; it would be malpractice not to use it.  We

  12   don't need to approve it right now since we are working on 
 
  13   others -- all of which was true because Vira A, or it could 
 
  14   have been C, was the only other drug available, which is not 
 
  15   nearly as good. 
 
  16             So, the point was that there were cases that I can

  17   attest to where we were holding back these, and they were 
 
  18   sitting on the shelf.  I don't know it that was true for 
 
  19   other companies or how widely spread that was. 
 
  20             DR. FEIGAL:  I particularly appreciate hearing 
 
  21   CDER examples.

  22             [Laughter] 
 
  23             DR. ZOON:  I have clarifications, if I could. 
 
  24             DR. SPILKER:  Certainly. 
 
  25             DR. ZOON:  The first is when you stated you 
                                                                 42 
 
   1   support increased collaboration with other regulatory

   2   agencies worldwide for CBER, did you have any specific in 
 
   3   mind because there are a lot of regulatory agencies out 
 
   4   there and I don't think we could do all of them? 
 
   5             DR. SPILKER:  No, not at all.  I would say that we 
 
   6   will be talking to the companies more and I can try to get

   7   any clarifications and submit that information to the 
 
   8   docket. 
 
   9             DR. ZOON:  That would be very helpful because we 
 
  10   want to hear from you where you think the issues are, and we 
 
  11   can certainly take that under advisement in our

  12   consideration. 
 
  13             The second is that you said there is a need for an 
 
  14   external advisory panel to advise FDA on efficient 
 
  15   administrative policies and activities, and I was wondering 
 
  16   if you could just talk a little bit about what you think

  17   this advisory panel should look like and the activities 
 
  18   which it should undertake. 
 
  19             DR. SPILKER:  I can speak more to the second 
 
  20   point, and this was a result, as you can imagine, of some 
 
  21   brainstorming within different groups of the industry

  22   representatives.  The key word here is administration.  We 
 
  23   are not talking about science.  We may not even necessarily 
 
  24   be talking about reviews.  But we do have a large 
 
  25   organization, although it is all relative of course, and 
                                                                 43 
 
   1   there are many administrative questions that come up

   2   especially as you change, you grow, you move into different 
 
   3   areas with different responsibilities.  We feel that a 
 
   4   modern management consulting type of approach, whether it 
 
   5   was one organization to turn to or a group of management 
 
   6   consultants who were independent, might advise you on ways

   7   to structure some of the administrative changes that you are 
 
   8   considering.  There were no specifics given except that in 
 
   9   general, and this again, I stress, was more of your internal 
 
  10   management and not to tell you anything but a group for you 
 
  11   to turn to, and it is certainly not going to be industry

  12   people.  They would be independent people who would be your 
 
  13   own advisors. 
 
  14             DR. ZOON:  Okay, thank you.  That is very helpful.  
 
  15   The other question I have for you is that on your first 
 
  16   point in question one you said you supported FDA doing

  17   targeted research.  Does this include the scientific 
 
  18   infrastructure of the organization? 
 
  19             DR. SPILKER:  We were mainly focusing on the part 
 
  20   that you didn't read, which has to do with research on 
 
  21   regulatory policies.  One good example, which we have

  22   already spoken about when we visited with you, was the topic 
 
  23   of bovine spongiform encephalitis, or BSE, and the European 
 
  24   initiative that is still on the books for January 1, '99, 
 
  25   new products containing bovine products can be imported into 
                                                                 44 
 
   1   Europe, which includes gelatin in all capsules.  So, you can

   2   imagine the implications that this has for the 
 
   3   pharmaceutical industry, and there are questions of variance 
 
   4   of Jakob-Creutzfeldt disease in these products, etc. -- not 
 
   5   to get into the science, but this is indicative of the area 
 
   6   that we place the highest priority on, and I would like to

   7   answer it and say that our priorities in terms of research 
 
   8   focus primarily on issues such as those where we see a great 
 
   9   need and you, at CBER and FDA in general, are in a much 
 
  10   better position I think than the industry is to conduct that 
 
  11   research and to have some impact on a very important issue.

  12             DR. ZOON:  Thank you.  The last clarification is 
 
  13   in your question seven, other objectives  You listed that 
 
  14   reviewers from CDER have been on brief sabbaticals in the 
 
  15   regulated industry.  I would just like to ask what 
 
  16   precautions are taken in order to prevent conflict of

  17   interest? 
 
  18             DR. SPILKER:  A very relevant question, and that 
 
  19   goes both ways of course.  I think that that is a question 
 
  20   that can be best addressed by speaking with the appropriate 
 
  21   people within CDER and seeing also whether they think it is

  22   a successful program.  If you feel that it does have 
 
  23   applicability, we are raising this as something for your 
 
  24   consideration and saying that if you find that it does have 
 
  25   merit, then we would be open to discussing ways in which it 
                                                                 45 
 
   1   could be implemented.  But that would only be if you felt

   2   that it was appropriate. 
 
   3             DR. ZOON:  Thank you very much.  That is very 
 
   4   helpful. 
 
   5             MR. ELENGOLD:  I have one more.  In this 
 
   6   relatively brief statement, there are two points in here

   7   where you allude to further quicker disclosures of 
 
   8   information -- the posting of approval information and 
 
   9   reviewed immediately and the wider dissemination of internal 
 
  10   procedures.  To me, both of those in today's modern age 
 
  11   relate to putting stuff up on the Internet very fast.  One

  12   of the challenges that I know we, in CBER, have faced 
 
  13   repeatedly is the matter of priority and competing for both 
 
  14   general resources and ADP resources in particular, we have 
 
  15   to make some choices.  Since it applies here in two places, 
 
  16   does the industry believe that this is a high enough

  17   priority that it does deserve specific funding and, in fact, 
 
  18   specific funding of Internet initiatives for dissemination 
 
  19   of this under PDUFA? 
 
  20             DR. SPILKER:  Thank you, Mark.  The two, in my 
 
  21   mind, are very different.  The putting of some information

  22   on the Internet, which I did specifically refer to although 
 
  23   whether I mentioned the name Internet or not I am not sure, 
 
  24   is for a new drug at the time of approval.  That, I don't 
 
  25   believe, would require additional resources.  It was done 
                                                                 46 
 
   1   with Viagra; it was done with a couple of others.  But if

   2   you feel there are other ways -- you could put it in the 
 
   3   Federal Register and we can wait. 
 
   4             The other issue of the reviewer handbooks, GRPs, 
 
   5   etc., etc., I would suggest not putting those on the 
 
   6   Internet and just making them available in hard copy.  If

   7   you were to sell those at X dollars per copy to cover all 
 
   8   costs, we would be delighted to pay that and even some 
 
   9   administrative fees in there too. 
 
  10             Really, I am a pretty old fashioned guy when it 
 
  11   comes to documents, and anything I see on my screen I have

  12   to printout anyway to read.  I don't know if you are like me 
 
  13   but I certainly think that we are not asking -- and I am 
 
  14   really serious -- we are not asking for that to be on the 
 
  15   Internet. 
 
  16             MR. ELENGOLD:  There are two issues on that.  For

  17   the posting of approval immediately, and other than saying 
 
  18   it is approved and the press release, that is an extremely 
 
  19   resource-intensive initiative.  Faced with a 150-plus 
 
  20   review, getting it electronically converted, and redacting 
 
  21   it if appropriate to remove manufacturing methods is both an

  22   ADP and technical/scientific intensive resource.  And, that 
 
  23   has been a problem that we have faced and are facing right 
 
  24   now. 
 
  25             The second problem, no matter how technologically 
                                                                 47 
 
   1   phobic one is, is that under the Electronic Freedom of

   2   Information Act Amendments, as soon as we make a document 
 
   3   available in hard copy any person -- and I see Mr. Weitzman 
 
   4   here, and he would be the first to immediately insist that 
 
   5   we make it available in electronic form at the same time in 
 
   6   a format that is usable.

   7             So, they are completely intertwined and I can tell 
 
   8   you specifically that the CBER SOPP manual is not available 
 
   9   and posted on our Internet site specifically because of a 
 
  10   resource issue.  So, they are intertwined whether we like it 
 
  11   or not.

  12             DR. SPILKER:  Let me clarify our position a little 
 
  13   further then.  Of the two issues, the one that is much more 
 
  14   important to the industry is the second one, that of having 
 
  15   some understanding of GRPs, the reviewer handbooks etc.  The 
 
  16   other one is not nearly as important and, in fact, we can

  17   almost dispense with it.  I do see, since we are talking 
 
  18   about speed there, that it is a question of the Internet 
 
  19   resources etc.  I would hope that you could talk to your 
 
  20   attorneys within FDA to see if there is any way in which 
 
  21   these could be made available in hard copy, even charging

  22   for them, and not for the electronic version.  Possibly you 
 
  23   could just charge a lot more for an electronic version, 
 
  24   which might cover it, or just perhaps -- we shouldn't get 
 
  25   into it any further. 
                                                                 48 
 
   1             DR. ZOON:  No.

   2             MR. ELENGOLD:  No, I don't want to get into 
 
   3   details. 
 
   4             DR. SPILKER:  Let me just leave it there.  I hope 
 
   5   I have at least clarified our position on that. 
 
   6             DR. ZOON:  Thank you.  Are there any other

   7   questions?  A question from the audience?  Mr. Chesemore, if 
 
   8   you would use the microphone, please? 
 
   9             DR. CHESEMORE:  Dr. Spilker, you mentioned under 
 
  10   question four that you support training of field staff 
 
  11   partly within pharmaceutical companies.  This is an area

  12   that I think many of us in the agency support, but when we 
 
  13   bring it up sometimes in other products regulated by FDA, 
 
  14   not just pharmaceuticals, some people feel that it is 
 
  15   inappropriate for the agency to participate in training with 
 
  16   the industry, and I just wondered if you could expand on

  17   that a little. 
 
  18             DR. SPILKER:  Yes, if it is deemed inappropriate 
 
  19   for field staff to be trained within the industry, then I 
 
  20   would like to see as a fall back, if that is considered 
 
  21   unacceptable, that industry has an opportunity to try to

  22   present its viewpoints and its perspectives to the field 
 
  23   staff.  I think one of the major issues that does exist 
 
  24   today is when field staff, and I think it is also true 
 
  25   within the agency, here in the District, but let's just talk 
                                                                 49 
 
   1   about field staff for the moment but I don't want to exclude

   2   it, do not have a good understanding of what the regulated 
 
   3   industry is that they are dealing with.  I think that the 
 
   4   industry should have, even if it is at a separate site, not 
 
   5   within the industry, an opportunity to just present its 
 
   6   views because there are occasions when inspectors come to a

   7   company when it is quite clear that their understanding f 
 
   8   industry's perspective or their understanding of how 
 
   9   industry operates, its goals, etc., are not really fully 
 
  10   understood.  I think having such an opportunity would 
 
  11   benefit both sides because really the goal of this entire

  12   exercise is understanding so that both sides can do their 
 
  13   job.  In this case, the field staff can do their job more 
 
  14   effectively for the agency. 
 
  15             DR. ZOON:  Thank you very much.  Are there any 
 
  16   other questions, clarifications?  If not, I want to thank

  17   you, Bert, very much for your comments and answering the 
 
  18   myriad of questions, and we will take a 15-minute break.  
 
  19   Thank you. 
 
  20             [Brief recess] 
 
  21             DR. ZOON:  Let me ask the next panelists to please

  22   come up to the table.  We are now starting our next panel, 
 
  23   and this panel primarily is going to be focusing on blood 
 
  24   and related products. 
 
  25             I would like to introduce Mary Gustafson, from 
                                                                 50 
 
   1   CBER, who is head of the Division of Blood Applications, who

   2   is here from the Office of Blood Research and Review to 
 
   3   clarify any issue that may be raised from that group. 
 
   4             I would like to first ask Roger Brinser, who is 
 
   5   representing the Coalition for Regulatory Reform, to please 
 
   6   make his comments.  Thank you.

   7                             Panel B 
 
   8                 Coalition for Regulatory Reform 
 
   9             MR. BRINSER:  Thank you, Dr. Zoon. 
 
  10             Good morning.  My name is Roger Brinser.  I am the 
 
  11   Director of Regulatory Affairs for Sera-Tec Biologicals, LP,

  12   a source plasma collection company.  Today I am speaking to 
 
  13   you as a co-chair for the Coalition for Regulatory Reform. 
 
  14             CFRR was formed in 1994, at the request of FDA, to 
 
  15   bring the blood and plasma industries together to jointly 
 
  16   explore ideas for a more efficient regulatory system for

  17   blood and plasma products.  The CFRR is composed of the 
 
  18   American Association of Blood Banks, which includes the  
 
  19   American Red Cross and the Armed Services Blood Program 
 
  20   Office, America's Blood Centers, and the American Blood 
 
  21   Resources Association.  This organization represents the

  22   entire spectrum of blood and plasma collection and 
 
  23   transfusion interests.  We appreciate the opportunity to 
 
  24   comment on the important topics outlined in Section 406(b) 
 
  25   of the Food and Drug Administration Modernization  Act. 
                                                                 51 
 
   1             Agency communication -- recently, FDA's

   2   communication with industry has improved greatly.  The 
 
   3   agency has published proposed rules in a timely fashion, 
 
   4   given industry an adequate opportunity to comment, 
 
   5   disseminated draft guidance early in the process, and 
 
   6   conducted more frequent agency workshops to address

   7   important regulatory changes.  CFRR applauds FDA's improved 
 
   8   communication and encourages further steps in this regard.  
 
   9   Foremost, CFRR encourages FDA to strictly adhere to its good 
 
  10   guidance practices document and broaden the document's scope 
 
  11   of application.  The greatest effect in terms of regulatory

  12   efficiency is seen when industry is given an opportunity to 
 
  13   meaningfully participate in the regulatory process.  Groups 
 
  14   like CFRR and others stand ready to work with FDA in 
 
  15   developing even initial drafts of agency guidelines. 
 
  16             Improve the review process -- in the last year the

  17   Center for  Biologics Evaluation and Research has made great 
 
  18   strides toward improving the licensure process.  The 
 
  19   proposed rule to replace the product license application and 
 
  20   establishment license application, of PLA/ELA, has been 
 
  21   published and the biologics license application, of BLA,

  22   process shows great promise.  The guidance document that 
 
  23   implements the BLA, the so-called CMC guidance, also was 
 
  24   recently published.  CFRR strongly encourages CBER to ensure 
 
  25   that the paperwork reduction and regulatory efficiency goals 
                                                                 52 
 
   1   of the BLA are maximized with its implementation.

   2             In addition, FDA has a host of new tools for 
 
   3   effecting modifications or changes to approved applications.  
 
   4   These include the prior approval supplements, or PAS, the 
 
   5   changes being effected, or CBE30, and annual report 
 
   6   submissions.  These are important milestones. However, much

   7   work remains to be done in the area of biologics 
 
   8   applications.  FDA should utilize these tools to the 
 
   9   greatest possible extent.  The onerous PAS process should be 
 
  10   used only for novel products or for a first-time request to 
 
  11   license an establishment or product.

  12             Areas where the agency has promised guidance and 
 
  13   which industry desperately needs, include guidance specific 
 
  14   to blood and plasma for CBE30 and, in particular, annual 
 
  15   reports and comparability protocols.  These are tools that 
 
  16   may yield the greatest regulatory efficiencies but remain

  17   untapped.  Many companies already have been required to 
 
  18   submit annual reports without clear guidance on what the 
 
  19   reports are supposed to contain, or how the agency will use 
 
  20   this information. 
 
  21             Comparability protocols offer the promise of a

  22   standardized method for effecting certain application 
 
  23   changes without the need for prior agency approval, but the 
 
  24   scope of eligible changes and protocol contents remain 
 
  25   undefined.  These tools and others, if used as intended, can 
                                                                 53 
 
   1   relieve the agency's application review burden for non-user

   2   fee industries. 
 
   3             The blood action plan -- the blood action plan 
 
   4   holds promise for better communication of agency product 
 
   5   quality expectations to industry.  Based on FDA's public 
 
   6   statements, the blood action plan calls for a rewrite of the

   7   blood and plasma regulations.  This includes formalizing 
 
   8   requirements published through guidance and memoranda into 
 
   9   regulations.  CFRR applauds these efforts and hopes to work 
 
  10   with the agency in achieving these goals. 
 
  11             It is important to note, however, that no publicly

  12   available documents currently exist to describe the blood 
 
  13   action plan. Time frames for achieving the plan objectives 
 
  14   have not been publicly announced, and industry input has not 
 
  15   been sought.  One initiative of the plan is to develop a 
 
  16   pilot program for approval of certain blood and plasma

  17   products through a monograph system.  While this program 
 
  18   holds promise for both the FDA and industry in terms of the 
 
  19   application process, without an industry-FDA dialogue this 
 
  20   program may never get off the ground and an important 
 
  21   opportunity may be lost.

  22             Product quality -- although  GMPs are the 
 
  23   cornerstone of quality products, the blood and plasma 
 
  24   industries have lacked clear GMPs.  Instead, the current 
 
  25   GMPs contain many references to biologics that often do not 
                                                                 54 
 
   1   directly bear on the blood and plasma industries.  The

   2   current GMPs applicable to blood and plasma products span 
 
   3   three sections of the Code of Federal Regulations, that is, 
 
   4   the 200 series, 600 series and 800 series.  A comprehensive 
 
   5   rewrite of the GMPs is needed to incorporate these important 
 
   6   requirements into one set of unified regulations for blood

   7   and plasma products. 
 
   8             Other regulatory requirements that bear on product 
 
   9   quality include error and accident reporting, adverse event 
 
  10   reporting, and product recalls and withdrawals.  These tools 
 
  11   are under-utilized.  Although industry expends vast

  12   resources submitting error and accident reports, FDA has 
 
  13   failed to use this information as a quality assurance tool.  
 
  14   Quarterly reports of errors and accidents are published but 
 
  15   no meaningful analysis or trend reporting of submitted 
 
  16   errors and accidents has ever been made publicly available. 

  17   This is a missed opportunity.  FDA can help industry better 
 
  18   itself by making this kind of information available.  
 
  19   Furthermore, error and accident reporting should not be 
 
  20   extended to other industry segments without careful 
 
  21   consideration.

  22             Recalls and withdrawals are intended to help 
 
  23   ensure that only quality products reach patients.  However, 
 
  24   the current recall regulations are not appropriate for blood 
 
  25   and plasma products.  Many, if not most, blood and plasma 
                                                                 55 
 
   1   recalls involve only hypothetical risks, expired products or

   2   already transfused products  Other tools such as recipient 
 
   3   notification may be more appropriate in such circumstances.  
 
   4   A more rational recall and withdrawal policy would save 
 
   5   agency resources and permit industry to concentrate its 
 
   6   resources on delivering high quality products.

   7             In closing, I would like to say that CFRR 
 
   8   recognizes the magnitude of FDA's task -- ensuring that only 
 
   9   safe and effective products are made available to consumers.  
 
  10   Without adequate funding CBER cannot carry out this mandate.  
 
  11   Furthermore, this important mandate requires that the agency

  12   retain individuals with extensive skills and technical 
 
  13   expertise.  As such, CFRR fully supports CBER-based research 
 
  14   needed to maintain an appropriate scientific infrastructure. 
 
  15             Thank you for the opportunity to comment.  CFRR 
 
  16   looks forward to working with the agency on current and

  17   future regulatory initiatives.  There is a copy of this 
 
  18   available as you exit.  Thank you. 
 
  19             DR. ZOON:  Thank you very much.  This statement is 
 
  20   now open for questions or clarifications.  Mary? 
 
  21             DR. GUSTAFSON:  Roger, you mentioned that you

  22   would like to see the GGP parameters broadened.  Do you have 
 
  23   ideas on how that should be done?  You indicated that you 
 
  24   encourage us to adhere to our good guidance practices and 
 
  25   you would also like to broaden the document's scope of 
                                                                 56 
 
   1   application.

   2             MR. BRINSER:  I don't have anything specific at 
 
   3   this point in time, but that is something we could include 
 
   4   in a further response. 
 
   5             DR. ZOON:  Thank you very much.  We very much 
 
   6   appreciate your comments.  The next speaker is Emily

   7   Rossiter, representing the Blood Technology Companies. 
 
   8                    Blood Technology Companies 
 
   9             MS. ROSSITER:  When I sent the agenda I put Blood 
 
  10   Technology Companies, not "the" Blood Technology Companies.  
 
  11   Let's treat this rather generically.

  12             My name is Emily Rossiter, and I have been working 
 
  13   in the field of blood banking for over 25 years, first with 
 
  14   the American Red Cross and then as an independent consultant 
 
  15   for the last 15 years.  I have never worked for FDA but I 
 
  16   have continuously been working with FDA on this side of the

  17   table.  Today, I appreciate the opportunity to act as 
 
  18   consultant to CBER on reform and reinvention. 
 
  19             [Slide] 
 
  20             I am joined in these comments today by the six 
 
  21   firms listed on this first slide, Haemonetics Corp., COBE

  22   BCT, Inc., Terumo Medical Corp., Fall Corp., Genetic Testing 
 
  23   Institute, Inc., Gamma Biologicals, Inc., and six other 
 
  24   diagnostics, software and blood solutions manufacturers.  
 
  25   These companies all support these comments.  These last six 
                                                                 57 
 
   1   firms specifically asked that their names be withheld.

   2             [Laughter] 
 
   3             Some are clients, and I am sure that will trigger 
 
   4   a follow-up question.  All support quicker patient access to 
 
   5   improved blood products and technologies through shorter 
 
   6   review times at FDA, and more constructive dialogue with

   7   CBER policy staff.  These companies make blood banking and 
 
   8   plasma related products, drugs, devices and in vitro 
 
   9   diagnostics that are reviewed by CBER and have been outside 
 
  10   user fee and fast track channels. 
 
  11             They are basically at the end of the line.  They

  12   do not make licensed biological products so their review 
 
  13   times are not covered in the licensed product review time 
 
  14   data that I think we have seen thus far.  They have been 
 
  15   living in an environment in which their customers are under 
 
  16   extreme pressures to hoe the line on the cost of providing

  17   blood for transfusion.  I can speak personally for myself, 
 
  18   as well as them, when it comes to trying to work smarter in 
 
  19   an era of cost restrictions.  We "feel your pain," FDA. 
 
  20             [Slide] 
 
  21             I would like to highlight four areas today

  22   specifically for the CBER blood applications audience as you 
 
  23   brainstorm further ways to improve performance and meet 
 
  24   obligations under the new reform legislation.  These areas 
 
  25   are review and response timetables, the extend and detail in 
                                                                 58 
 
   1   reports and submissions, the integration of related

   2   submissions, and regulatory harmonization. 
 
   3             Most of the suggestions can be implemented at a 
 
   4   policy level without changes to regulation.  They stem from 
 
   5   a philosophy that the quality of information coming in to 
 
   6   FDA is more important than the quantity; that time and

   7   predictability, as I think Alan Goldhammer mentioned that 
 
   8   term, predictability, mean everything to companies in the 
 
   9   blood bank field as well; and that faced with limited 
 
  10   resources, further priority setting by CBER could redirect 
 
  11   staff time and efforts in constructive ways.

  12             [Slide] 
 
  13             First and most importantly, review times for 
 
  14   blood-related drugs, devices and products need to be reduced 
 
  15   significantly across the board if we are to get them to the 
 
  16   patient.  Six months should be the outside limit for any

  17   review cycle, not just fast track products.  Taking more 
 
  18   than six months in a field as dynamic as blood banking 
 
  19   creates a self-perpetuating problem -- the information is 
 
  20   out of date before it gets reviewed.  This leads to 
 
  21   amendments, review letters and further response cycles and

  22   further evolution of technology and FDA policy.  The best 
 
  23   way out of this loop is to shorten turnaround so that 
 
  24   expectations and technology can be synchronized. 
 
  25             Review times for responses to warning letters or 
                                                                 59 
 
   1   other enforcement topics need goals too.  If circumstances

   2   warrant an FDA enforcement letter or action, calling for a 
 
   3   prompt response of, say, 10-30 days from industry, then 
 
   4   review by FDA within 2-3 months would be reasonable so that 
 
   5   customers and patients who could benefit are not left in 
 
   6   limbo.

   7             [Slide] 
 
   8             Second, there are many areas of detail and 
 
   9   tradition that will come up for scrutiny during your 
 
  10   reinvention sessions, and I have listed some of my favorites 
 
  11   on this slide.

  12             Let me first emphasize that I do not mean we 
 
  13   should reduce the level of detail available to FDA on site 
 
  14   or upon request.  These suggestions affect the amount of 
 
  15   detail sent to FDA routinely for placing into a queue 
 
  16   somewhere review, response, and management.  For example,

  17   blood or plasma recalls -- all recalls are not equal.  Many 
 
  18   blood or plasma recalls involving only hypothetical risks, 
 
  19   technical deviations or small numbers of expired products 
 
  20   could be relegated to market withdrawal status. 
 
  21             Error and accident reporting -- this program is

  22   unique in its implementation in blood establishments, and is 
 
  23   over 20 years old I think.  FDA has proposed extending error 
 
  24   and accident reporting to hospital-based transfusion 
 
  25   services, and recently highlighted its applicability to 
                                                                 60 
 
   1   licensed in vitro diagnostic manufacturers.

   2             Before extending it, let's critically examine the 
 
   3   historical experience with the current program.  Has it 
 
   4   served a critical need in the past years?  We may find that 
 
   5   the more surveillance programs such as Medical Device 
 
   6   Reporting and the MedWatch Program, plus the existence of

   7   industry-based quality programs for tracking and trending 
 
   8   may provide more modernized methods of getting useful 
 
   9   information. 
 
  10             "Me too" sites and products are another good area 
 
  11   to reduce paperwork without reducing safety for blood donors

  12   or recipients.  The addition of new apheresis collection 
 
  13   sites, or adding sites to make already approved blood 
 
  14   components in an organization that has already proved itself 
 
  15   should not be a major task for FDA review. 
 
  16             Similarly, the addition of modified blood products

  17   such as irradiated or leukocyte-reduced products should not 
 
  18   be a major exercise, and by major exercise I mean prior 
 
  19   approval supplements for each location, pre-approval 
 
  20   inspections, and the like. 
 
  21             CBER staff have embraced the concept of report

  22   simplification and reduction, trying to ease the process by 
 
  23   which changes can be made to existing products.  But more is 
 
  24   needed.  More downgrading of changes to 30-day notice and 
 
  25   annual report is both possible and necessary to allow CBER 
                                                                 61 
 
   1   staff to focus on larger, more critical issues.

   2             [Slide] 
 
   3             Third, the integration of approval processes for 
 
   4   new blood product license supplements with drug and device 
 
   5   clearances would speed technology to improve patients.  The 
 
   6   slide behind me explains, hopefully -- or helps to explain

   7   what I mean by this. 
 
   8             The top three boxes on this slide represent 
 
   9   technologies used to collect or process blood or plasma from 
 
  10   donors.  Several companies make blood processing solutions 
 
  11   and disposable, single-use plastic bag sets which are used

  12   along with filters and separators and expressers, which I am 
 
  13   generically calling instruments, to make blood products for 
 
  14   transfusion, depicted on the bottom three boxes. 
 
  15             Typically, the storage solution, in the upper left 
 
  16   of the slide, undergoes a drug approval process in the U.S.,

  17   that is, a new drug application or abbreviated new drug 
 
  18   application, and the processing containers along with any 
 
  19   related instruments undergo device clearance, either a 
 
  20   510(k) or premarket approval.  A pre-approval inspection may 
 
  21   also be required.

  22             Obtaining premarket clearance for these 
 
  23   technologies in the top three boxes in recent times has 
 
  24   taken anywhere from two to over ten years whether they are 
 
  25   new generations of technologies, "me too" or modest 
                                                                 62 
 
   1   improvements.  If these solutions and devices are destined

   2   for use directly in patient care or in unlicensed blood 
 
   3   banks, these clearances are the only ones needed from FDA, 
 
   4   but if the same solutions or sets are to be used in a 
 
   5   licensed blood center, and the blood products are shipped in 
 
   6   interstate commerce, we are only half way there.  Another

   7   premarket approval and pre-license inspection cycle is often 
 
   8   required, sometimes for each of the products on the lower 
 
   9   slide and for each location or facility.  This adds another 
 
  10   few years of delay to the availability of the resulting 
 
  11   blood product interstate.  This means that patients served

  12   by unlicensed intrastate blood banks can benefit from newer 
 
  13   technologies several years before patients served by 
 
  14   licensed facilities, which is the majority of patients. 
 
  15             Over the years, FDA has used guidance documents 
 
  16   and notifications to facilitate licensed blood center use of

  17   new technologies.  For example, in infectious disease marker 
 
  18   testing.  There is room to expand this practice where 
 
  19   technology has a proven track record for man years, or where 
 
  20   the benefits clearly outweigh the risks. 
 
  21             [Slide]

  22             Finally, further harmonization will help blood 
 
  23   technology improvements reach the patient.  Areas where 
 
  24   CBER, CDRH or CDER regulates similar technologies for 
 
  25   similar uses should be analyzed, and the lowest common 
                                                                 63 
 
   1   denominators found for a more unified approach to regulatory

   2   policy and enforcement.  These areas include parenteral 
 
   3   solutions, instruments in vitro diagnostics, single-use 
 
   4   disposable products, and computer software programs.  
 
   5   Differences among the regulatory policies for these projects 
 
   6   should be held to scrutiny, perhaps by external advisory

   7   groups, and the differences eliminated unless they can 
 
   8   adequately be defended by science, not emotion. 
 
   9             FDA's ongoing efforts at international 
 
  10   harmonization are encouraging.  In the area of blood 
 
  11   banking, an analysis of the risks and benefits of the

  12   European Community's policy toward blood processing 
 
  13   solutions as device accessories, versus FDA's drug approach, 
 
  14   might reveal some useful information during the reinvention 
 
  15   deliberations. 
 
  16             Ultimately, international harmonization efforts

  17   should continue until a single global dossier is recognized 
 
  18   for all blood and plasma products, related drugs and 
 
  19   devices. 
 
  20             [Slide] 
 
  21             Before closing, I want to recognize some of the

  22   recent successes of FDA and CBER.  First, the FDA Home Page 
 
  23   and Internet sites have greatly improved industry's ability 
 
  24   to stay up to date and monitor developments in a timely 
 
  25   fashion.  Continuing efforts to enhance the information, 
                                                                 64 
 
   1   adding search capability and better links and organizations

   2   should continue. 
 
   3             Second, to CBER blood staff, the open door and 
 
   4   open telephone policies that you have consistently tried to 
 
   5   maintain are absolutely essential to progress and a safe 
 
   6   blood supply.  It has been difficult to accommodate the

   7   mounting requests that have resulted from your current 
 
   8   workload, but it is important that you know that each 
 
   9   personal contact with industry is regarded as a precious 
 
  10   investment in the future. 
 
  11             Thank you.

  12             DR. ZOON:  Thank you very much.  Are there any 
 
  13   questions or clarifications?  No?  Thank you very much.  Our 
 
  14   last speaker in this panel is Sharon Leiser, QA, Regulatory 
 
  15   Affairs, American Red Cross. 
 
  16                        American Red Cross

  17             MS. LEISER:  Good morning Dr. Zoon, Ms. Suydam, 
 
  18   FDA staff, and fellow members of the regulated community.  
 
  19   My name is Sharon Leiser, and I am here speaking on behalf 
 
  20   of the American Red Cross which supplies approximately one- 
 
  21   half of the nation's supply of transfusable blood

  22   components, approximately 20 percent of the nation's plasma 
 
  23   derivatives, approximately 20 percent of the nation's tissue 
 
  24   for transplantation purposes, and which is supporting the 
 
  25   agency's current effort for the provision of stem and cord 
                                                                 65 
 
   1   cells.  Thank you for providing us with the opportunity to

   2   speak today. 
 
   3             As a member of the Coalition for Regulatory 
 
   4   Reform, the American Red Cross fully supports and agrees 
 
   5   with the points made today by Mr. Brinser, the 
 
   6   representative for the CFRR.  American Red Cross also wants

   7   to emphasize several points about the implementation of the 
 
   8   FDA Modernization Act that I will be touching on today.  The 
 
   9   American Red Cross will also provide written comments which 
 
  10   will expand on some of these points. 
 
  11             We wish to commend you, FDA, on your efforts to

  12   date.  First, we have seen, for example, a substantial 
 
  13   improvement in the blood licensure submission review 
 
  14   process.  The review of ARC submissions has been reduced 
 
  15   from a backlog of over 900 open cases in 1995 to a current 
 
  16   open caseload of only a few dozen.  In addition, the review

  17   period for submissions has decreased approximately 50 
 
  18   percent in only a two-year time period.  These improvements 
 
  19   benefit the public by increasing our ability to manufacture 
 
  20   better and more efficacious blood components and plasma 
 
  21   derivatives and supply them to those in need.

  22             Second, we are encouraged by the information 
 
  23   recently presented on the blood action plan.  We see this 
 
  24   plan as the start of a potentially beneficial program for 
 
  25   the agency, for the regulated community, and for the public 
                                                                 66 
 
   1   which relies on us and on the FDA to provide the safest

   2   blood in the world.  We are particularly excited by the 
 
   3   agency's initiatives to update the regulations and guidances 
 
   4   for blood and blood products.  We eagerly await publication 
 
   5   of the blood action plan and our opportunities for further 
 
   6   participation in the plan's development.

   7             The American Red Cross strongly endorses efforts 
 
   8   towards open communication between the FDA, consumer groups, 
 
   9   industry, and professional societies such as AABB.  There 
 
  10   has been considerable headway in this arena, particularly 
 
  11   with the increased use of the Web and other electronic

  12   communication mechanisms.  We also encourage the FDA to 
 
  13   expand an effective communication policy to all levels of 
 
  14   FDA and CBER by reexamining the current practices for 
 
  15   working with the regulated community and other groups. 
 
  16             For example, both the regulated community and the

  17   FDA need to work in a more open style of addressing issues 
 
  18   by directing our approaches toward resolution as partners.  
 
  19   We encourage continued interaction between the FDA and work 
 
  20   groups such as the CFRR to seek resolution of outstanding 
 
  21   issues such as those relating to adverse reactions, errors

  22   and accidents and product retrievals.  We also suggest 
 
  23   reevaluation of the requirements for participation, as 
 
  24   appropriate, by national FDA staff in professional meetings 
 
  25   that are sponsored by the regulated community or other non- 
                                                                 67 
 
   1   government entities to allow for more participation.

   2             I would like to turn now to some of FDA's specific 
 
   3   questions listed in "A Message to FDA Stakeholders."  The 
 
   4   agency asked what could be done to improve the submission 
 
   5   review processes, to sustain an effective, timely, and 
 
   6   science-based postmarketing surveillance system, to

   7   adequately meet increasing demands, and to eliminate 
 
   8   backlogs in the review process.  As noted earlier, we have 
 
   9   already seen vast improvements in these processes. 
 
  10             One of the innovations about which we are most 
 
  11   encouraged is CBER's implementation of the new comparability

  12   protocol process which will be used in conjunction with the 
 
  13   revised system of ranking and grading licensure submissions.  
 
  14   This system is the first step in creating a review process 
 
  15   which will meet the needs of both the biologics industry and 
 
  16   the public's health and safety in the 21st century.

  17             We encourage the rapid development and completion 
 
  18   of this and other initiatives.  In particular,  we would 
 
  19   like to see clear guidelines for the use of the 
 
  20   comparability protocol process.  We also encourage the FDA 
 
  21   to think even more innovatively in addressing the following:

  22             providing clear guidance about the requirements 
 
  23   for the new annual report process; 
 
  24             improving the ranking and grading of specific 
 
  25   blood and blood products as the foundation of the blood 
                                                                 68 
 
   1   licensure review process;

   2             without compromising the public input process, 
 
   3   creating a system for making quick changes to guidances as 
 
   4   scientific and technical knowledge expands; 
 
   5             expanding the regulations to directly reference 
 
   6   blood and blood products instead of trying to fit them into

   7   a system with which they do not harmonize; and, 
 
   8             creating an innovative staff incentive/reward 
 
   9   system that will foster new ideas and speedier reviews 
 
  10   without compromising quality and effectiveness. 
 
  11             I want to specifically talk about improving the

  12   ranking and grading of products.  First, the agency should 
 
  13   define what information is necessary to evaluate the 
 
  14   licensure submission reviews.  Second, the submissions and 
 
  15   reviews should be tiered based on hazard and impact.  We 
 
  16   believe that, in following this approach, the demands on the

  17   agency will be reduced thereby increasing FDA's ability to 
 
  18   focus resources on new products.  For example, there are 
 
  19   many blood products, like red blood cells, platelets, 
 
  20   platelet pheresis, which have been in the public arena for a 
 
  21   long time.  Their qualities, including efficacy and

  22   manufacturing specifications, are well known.  It is 
 
  23   reasonable that licensure submission requirements for these 
 
  24   well-known products could be placed on the lowest review 
 
  25   tier, and compliance confirmation could be based on post- 
                                                                 69 
 
   1   licensure sampling audits instead of licensure.  The

   2   greatest amount of resources could them be transferred to 
 
   3   completely new products like red blood cells pheresis.  
 
   4   Then, as these new products become mainstream, their ranking 
 
   5   and tier of review could be lowered to allow for other new 
 
   6   products to absorb review resources.

   7             On the FDA question about what approach the agency 
 
   8   should use to assure an appropriate scientific 
 
   9   infrastructure, we want to emphasize that we, as well as the 
 
  10   rest of the regulated community, wish to work with FDA 
 
  11   regarding creative and innovative ways to use scientific

  12   expertise.  We recommend that there be staff exchange 
 
  13   programs with academia, other government agencies such as 
 
  14   NIH, CDC, and the National Science Foundation, and industry 
 
  15   research organizations, to share staff, expertise, and 
 
  16   research results.  The idea is that by fostering better

  17   understanding of applicable science in a cross-cultural 
 
  18   setting, we can simultaneously assure an appropriate 
 
  19   scientific infrastructure which utilizes the most current 
 
  20   knowledge and also promotes staff development. 
 
  21             I would like to briefly touch upon a point I

  22   mentioned earlier concerning approaches to improving error 
 
  23   and accident reporting.  This is an example of a regulatory 
 
  24   program which might benefit from expanded public input 
 
  25   beyond the regulated community.  American Red Cross, in 
                                                                 70 
 
   1   developing its own program, consulted with Hal Kaplan from

   2   the University of Texas, Southwestern Medical Center at 
 
   3   Dallas.  Dr. Kaplan has suggested a system modeled after a 
 
   4   classification for causal factors with multiple applications 
 
   5   including transportation, nuclear power, and the 
 
   6   petrochemical industry.  Information would be submitted to

   7   an independent agency and shared among the regulated 
 
   8   community for the mutual benefit of its members and the FDA.  
 
   9   We also encourage, as part of its implementation of the 
 
  10   Modernization Act, that you search out ideas an innovations 
 
  11   from other fields which might be applicable to the FDA

  12   system. 
 
  13             We believe the FDA's initial efforts in meeting 
 
  14   the requirements and demands contained within the FDA 
 
  15   Modernization Act merit considerable recognition and praise.  
 
  16   Thank you again for this opportunity to participate, and we

  17   look forward to future efforts to partner and build a new 
 
  18   system together. 
 
  19             DR. ZOON:  Thank you very, very much.  Are there 
 
  20   any questions or clarifications?  Becky? 
 
  21             MS. DEVINE:  You had mentioned adding blood to

  22   some specific regulations, that they didn't fit in certain 
 
  23   places.  Could you expand on what areas you were thinking 
 
  24   about in that regard? 
 
  25             MS. LEISER:  One big area is recalls.  An example 
                                                                 71 
 
   1   is stock recovery.  The definition says that you can only

   2   perform one if none of a lot has been released.  Well, a lot 
 
   3   is an entire blood unit and we have different expiration 
 
   4   dates for different components.  So, under that definition 
 
   5   we can never perform a stock recovery. 
 
   6             Otherwise, we will further expand upon this in our

   7   response to the docket.  Roger also mentioned, when he 
 
   8   talked about three sections that are used for blood and, 
 
   9   yet, really do not apply to blood. 
 
  10             DR. ZOON:  This will be very helpful.  We look 
 
  11   forward to your additional comments to the docket.  Mark?

  12             MR. ELENGOLD:  I have one question.  In the next 
 
  13   to the last paragraph, in the discussion of an alternative 
 
  14   system where reports would go to an independent agency, an 
 
  15   independent group for classification as to causal subjects, 
 
  16   would that replace the error and accident reporting to FDA

  17   or be in addition to it? 
 
  18             MS. LEISER:  We are looking at it as a 
 
  19   replacement. 
 
  20             MR. ELENGOLD:  Well, in the cases where an error 
 
  21   or accident led to a violative product, we use those for

  22   leads to potential recalls or other actions.  What would the 
 
  23   link be to us for following up on violative product in the 
 
  24   marketplace? 
 
  25             MS. LEISER:  I think it would be the same link as 
                                                                 72 
 
   1   now.  This would be like contracting out a service.  It

   2   would not be an agency that is blind to FDA.  FDA would have 
 
   3   access to any information as with any other regulated 
 
   4   biologics manufacturer.  For more information though, we 
 
   5   will submit more to the docket.  I am not totally cognizant 
 
   6   of this area.

   7             MR. ELENGOLD:  I was just curious because it would 
 
   8   look like that if it went to a third party that would lead 
 
   9   to a delay of triage and reporting to another triage and 
 
  10   reporting system within the agency.  Very often these 
 
  11   reports do lead to out ability to monitor withdrawal of

  12   violative products.  So, I would be interested in seeing 
 
  13   that submitted as well.  Thank you. 
 
  14             DR. ZOON:  Thank you.  Mr. Chesemore? 
 
  15             MR. CHESEMORE:  I was wondering if you could 
 
  16   expand on your comment, on page three, with respect to

  17   reevaluation of the requirements for participation by 
 
  18   national FDA staff in professional meetings sponsored by the 
 
  19   community to allow for more participation.  What do you see 
 
  20   as some areas there, and what are you hoping for? 
 
  21             MS. LEISER:  Well, there may be budgetary

  22   barriers, but we find that national staff is not always 
 
  23   permitted to travel long distances to participate in 
 
  24   meetings.  When we say participate we mean presentations.  
 
  25   There was a large meeting, sponsored by various sectors of 
                                                                 73 
 
   1   the regulated community, last January in New Orleans.  We

   2   did have FDA participation but there was a lot of red tape 
 
   3   that had to be gone through to get that participation.  So, 
 
   4   we feel that we can't learn from you if we can't get you. 
 
   5             DR. ZOON:  There is a question in the back.  
 
   6   Please identify yourself.

   7             MR. BINION:  Steve Binion, with the Femwal 
 
   8   Division, Baxter Healthcare Corp.  Actually, I just have two 
 
   9   quick comments and a clarification, referring back to 
 
  10   Emily's presentation. 
 
  11             On behalf of Femwal, I would like to commend CBER

  12   on the extensive use of Internet communication tools.  I 
 
  13   would also indicate that we too generally favor moves toward 
 
  14   global regulation of blood and blood technology products.  
 
  15   We will be making separate comments to the docket. 
 
  16             Then, just in case there was any suspense element

  17   involved, Baxter was not one of the six -- 
 
  18             [Laughter] 
 
  19             Thank  you. 
 
  20             DR. ZOON:  Thank you very much.  Are there any 
 
  21   other comments?  If not, I wish to thank you very, very

  22   much.  I appreciate those very thoughtful comments.  I am 
 
  23   actually going to proceed with the next panel.  So, I would 
 
  24   like to thank our current panelists very much and invite the 
 
  25   next set of panelists to the table. 
                                                                 74 
 
   1             I would also like to take this opportunity to

   2   introduce Jay Seigal.  He is the Director of the Office of 
 
   3   Therapeutics Research and Review. 
 
   4             Are you ready to begin or do you need a little 
 
   5   more time?  No?  Well, we have our next panel that 
 
   6   represents a number of biotech companies, and I would like

   7   to first introduce Janice Bourque, Executive Director of 
 
   8   Massachusetts Biotechnology Council. 
 
   9               Massachusetts Biotechnology Council 
 
  10             MS. BOURQUE:  Thank you.  Thank you for letting us 
 
  11   attend and have this public session so we could speak.

  12             [Slide] 
 
  13             As she mentioned, I represent the Massachusetts 
 
  14   Biotechnology Council, and I have with me today Jim Easton, 
 
  15   who is Vice President of Government Affairs and Strategic 
 
  16   Policy from one of our member companies, BIOPURE, as well as

  17   Sheila Flaherty, who is Associate General Counsel of the 
 
  18   Legal Department of Astra USA.  We speak collectively on 
 
  19   behalf of our members, and the comments we have were drawn 
 
  20   not specifically from any individual company per safety and 
 
  21   efficacy but as a collective response.

  22             [Slide] 
 
  23             For those of you who don't know, the Massachusetts 
 
  24   Biotechnology Council has been around for about 13 years, 
 
  25   and we have worked very hard in trying to ensure that the 
                                                                 75 
 
   1   biotech companies in Massachusetts have a way to reach their

   2   full potential, and often we represent them in a number of 
 
   3   different ways and this is one of them. 
 
   4             We have approximately over 200 companies, and most 
 
   5   of them are small to mid size.  We have several large ones 
 
   6   that most of you are aware of, and most of them have

   7   products that run from early stage development to 
 
   8   commercialized products. 
 
   9             [Slide] 
 
  10             The MBS supports the FDA in its FDAMA mission to 
 
  11   realize the prompt approval of safe and effective new drugs

  12   and other therapies.  Obviously, the main goal for both of 
 
  13   us is to get these products as quickly as possible to 
 
  14   patients because that is really what our aim is, to try and 
 
  15   alleviate any type of suffering that they might have. 
 
  16             [Slide]

  17             I won't spend any time on the FDAMA objectives.  
 
  18   That was already done earlier this morning by Linda.  But 
 
  19   these are the six that she covered well. 
 
  20             [Slide] 
 
  21             So you can understand the process of what we did

  22   with these 200 member companies, we have excellent resources 
 
  23   in terms of regulatory experts who live and breathe this 
 
  24   type of work every day, and they came together and tried to 
 
  25   identify collective concerns, common concerns that they 
                                                                 76 
 
   1   thought we could bring with us today, and to propose some

   2   recommendations. 
 
   3             [Slide] 
 
   4             Specifically, there were five areas that we wanted 
 
   5   to address: the performance goals, user fees and meetings, 
 
   6   manufacturing changes, fast track issues, off-label uses and

   7   pharmacoeconomics.  On a more global, over-arching 
 
   8   mechanism, we wanted to address the issue of harmonization 
 
   9   consistency within the agency, increased transparency, and 
 
  10   the enhancement of the role of the ombudsman in cooperation 
 
  11   with the FDA and the industry.

  12             [Slide] 
 
  13             The result of which was a White Paper that we 
 
  14   developed and submitted to the FDA, and there are specific 
 
  15   areas that were identified by the FDA of individuals who 
 
  16   were responsible for helping implement the five areas that

  17   we are addressing and this document was submitted to them as 
 
  18   well.  It was broken into points to consider documents, as 
 
  19   well as recommendations on our common concerns. 
 
  20             [Slide] 
 
  21             Today, what we would like to do is to address

  22   these specific five areas, and Jim, myself and Sheila will 
 
  23   do that in sort of a panel format.  We won't individually 
 
  24   stand up here and speak; we are going to speak from a panel 
 
  25   over here. 
                                                                 77 
 
   1             The first two sections, 119 and 116 for meetings,

   2   performance goals and manufacturing changes, will be 
 
   3   addressed by Jim Weston.  I will then address fast track and 
 
   4   Sheila will address off-label use and healthcare economic 
 
   5   information.  Then, I will close with some of the over- 
 
   6   arching concerns that we have and recommendations.  So, I

   7   will turn it over now to Jim. 
 
   8             [Slide] 
 
   9             MR. WESTON:  As Janice mentioned, each of these 
 
  10   working groups picked a specific section of FDAMA to 
 
  11   address, and in addressing each of these sections we took a

  12   look at specifically what we were trying to accomplish by 
 
  13   addressing the section.  Starting with the meetings and 
 
  14   performance goals, Section 119, we had a key objective of 
 
  15   being able to look overall at how we could improve the 
 
  16   process which would provide delivery of breakthrough

  17   products to patients in a time-sensitive manner. 
 
  18             Specifically, we are addressing how we could 
 
  19   establish agreements on the design of clinical trials and 
 
  20   preclinical studies in meetings; how to resolve any issues 
 
  21   that occurred in a timely manner; and also how to maintain

  22   consistency in the review process.  These were specific 
 
  23   agreements which we provided in our document to be able to 
 
  24   do that with the resource limitations of the agency. 
 
  25             [Slide] 
                                                                 78 
 
   1             In coming out of that then, we had some specific

   2   guidance documents in our points to consider.  Specifically, 
 
   3   we talked about the ability to have obligations of both the 
 
   4   sponsor and the FDA regarding setting up meetings.  For 
 
   5   example, in setting up meetings we used the classification 
 
   6   of the A, B and C meeting types of setting defined time-

   7   lines of either 30, 60 or 75 days to have a meeting after it 
 
   8   has been requested.  Specifically, though, in the whole 
 
   9   concept of fast track, which we will talk about later, a 
 
  10   fast track product, we requested that those in all cases 
 
  11   have a 30-day  limitation because of the priority of doing

  12   it. 
 
  13             In terms of holding meetings, one of the key 
 
  14   provisions is the ability to have common minutes from 
 
  15   meetings.  FDA has been requested to provide minutes of 
 
  16   meetings within 30 days, but also then the sponsor will be

  17   given 10 days to be able to review and comment on those 
 
  18   meetings as necessary. 
 
  19             In terms of the types of meetings, we agreed that 
 
  20   there ought to be a classification for different types and, 
 
  21   specifically for fast track, those meetings should always go

  22   to the higher standard in all cases. 
 
  23             For performance goals also we looked at the 
 
  24   ability to have feedback from the specific meeting type of 
 
  25   information, and specifically having monthly updates on a 
                                                                 79 
 
   1   progress report of a submission, specifically a fast track

   2   submission. 
 
   3             [Slide] 
 
   4             We also looked at the section dealing with 
 
   5   manufacturing changes.  This is Section 116.  Here, our goal 
 
   6   was to be able to clarify certainly the major and minor

   7   changes, and be able to have uniformity of change 
 
   8   classification throughout many of the documents, and to be 
 
   9   able to provide a guidance document, not necessarily a 
 
  10   regulation but a guidance document. 
 
  11             Historically, there have been many types of

  12   approaches to this in existing guidance documents.  The 
 
  13   three-tier approach appears to be the most common one going 
 
  14   forward. 
 
  15             [Slide] 
 
  16             We basically embodied that by going forward with

  17   the three-tier approach, and compliment CBER on their 
 
  18   ability to have this in many of their existing documents.  
 
  19   But dealing basically with changes, a substantial change 
 
  20   will require pre-approval for it; a moderate change to a 
 
  21   product, which is a supplement with a notice, typically a

  22   30-day review period; and a minimal change, which is 
 
  23   obviously notice in an annual report. 
 
  24             The concept of a comparability protocol is also a 
 
  25   very important concept which we embody and need to have 
                                                                 80 
 
   1   defined.  We proposed specific guidance in our document

   2   dealing with tests and acceptance criteria in the process 
 
   3   for a comparability protocol. 
 
   4             Obviously, in terms of changes, we are embodying 
 
   5   many of the existing CBER regulations dealing with label 
 
   6   changes.

   7             [Slide] 
 
   8             MS. BOURQUE:  With regards to the fast track 
 
   9   section, we would like to suggest that the PDUFA-II 
 
  10   performance goals that have been stated would be first 
 
  11   applied to fast track, the point being that if you have a 60

  12   percent performance goal requirement, perhaps 90 percent of 
 
  13   that 60 percent could be comprised of fast track approvals 
 
  14   and review, the point being that obviously when you address 
 
  15   fast track we are talking about serious and life-threatening 
 
  16   issues or unmet medical needs.

  17             [Slide] 
 
  18             Obviously, give the resources that you might have, 
 
  19   we would always challenge and encourage FDA to exceed that 
 
  20   goal when it came to fast track items. 
 
  21             [Slide]

  22             In terms of definitions, there are two types of 
 
  23   definitions that would need further clarification and 
 
  24   development, one being serious and life-threatening 
 
  25   conditions.  In the 1992 Federal Register notice, and again 
                                                                 81 
 
   1   reiterated in FDAMA, there was a broad and flexible

   2   interpretation of just what that would be.  We would like to 
 
   3   recommend that those broad and flexible interpretations be 
 
   4   adopted throughout the agency, with a consistent use in all 
 
   5   the divisions, primarily because there have been comments 
 
   6   that have been made that perhaps only AIDS and cancer are

   7   considered serious and life-threatening and we would like to 
 
   8   suggest that perhaps there are other diseases that might fit 
 
   9   that as well. 
 
  10             Secondly, with regards to the definition of the 
 
  11   potential to address unmet medical needs, obviously if there

  12   is no treatment there is an unmet medical need.  We would 
 
  13   like to suggest and recommend that perhaps there is an unmet 
 
  14   medical need for diseases that already may have an imperfect 
 
  15   though existing treatment.  I would like to give you a 
 
  16   couple of examples.

  17             Let's suppose that an existing treatment can offer 
 
  18   a patient temporary clinical benefit but the new treatment 
 
  19   might be able to provide a longer term clinical benefit.  
 
  20   Or, suppose that perhaps the existing treatment only 
 
  21   alleviates the symptoms of a disease but that the new

  22   treatment would, in fact, be able to address the underlying 
 
  23   pathology of that disease.  Perhaps there are great side 
 
  24   effects and risks associated with an existing treatment and 
 
  25   the new product would be able to provide a safer or more 
                                                                 82 
 
   1   tolerable treatment for the patient.

   2             Another example might be perhaps an existing 
 
   3   treatment comes from products that are human or animal based 
 
   4   and perhaps a recombinant product might provide a safer 
 
   5   mechanism of product where you don't have the possible 
 
   6   transmission of virus issues.

   7             This, obviously, is not a complete list but it is 
 
   8   suggestions and ideas that we have on how you might be able 
 
   9   to define unmet medical needs. 
 
  10             [Slide] 
 
  11             With regards to endpoints, specifically surrogate

  12   endpoints, obviously there are two types of endpoints that a 
 
  13   sponsor can utilize in trying to demonstrate an effect.  One 
 
  14   would be on an unvalidated surrogate endpoint, and the 
 
  15   second would be on a clinical or validated endpoint. 
 
  16             With regards to fast track, we would like to

  17   suggest that perhaps if a sponsor is utilizing an 
 
  18   unvalidated surrogate endpoint that, in fact, is reasonably 
 
  19   likely to predict clinical benefit, this particular type of 
 
  20   program would be subject to the post-approval requirements, 
 
  21   and that those post-approval requirements actually would be

  22   those of subsection (b)(2), and these subsection 
 
  23   requirements would apply to fast track and not create a new 
 
  24   grouping of post-approval requirements. 
 
  25             Secondly, if the sponsor is using a clinical or 
                                                                 83 
 
   1   validated clinical endpoint, in fact, they should be able to

   2   receive regular approval and not be subject to the post- 
 
   3   approval requirements of subsection (b)(2).  So, essentially 
 
   4   what we are recommending -- and I believe, PhRMA at an 
 
   5   earlier point had suggested sort of a two-track system 
 
   6   whereby the sponsors who are using clinical endpoints can

   7   obtain fast track benefits without sacrificing the benefits 
 
   8   of a regular approval. 
 
   9             We also recommend that the guidance documents 
 
  10   should include discussion about the various items I will 
 
  11   speak about.  The selection and recommendations to the

  12   sponsor and the selection process of surrogate endpoints -- 
 
  13   perhaps what could happen, there could be quarterly 
 
  14   conferences in which the industry could actually propose 
 
  15   what these surrogate endpoints could be and introduce them 
 
  16   and discuss them with the FDA.

  17             More specifically, we would like to recommend that 
 
  18   there are two specific areas that might require some 
 
  19   attention.  One would be those for chronic or degenerative 
 
  20   type diseases which, obviously, require longer or larger 
 
  21   clinical trials.  The second would be for those surrogate

  22   endpoints that have broader applicability to a class of 
 
  23   technologies such as with gene or cell therapies. 
 
  24             This guidance document that is going to be 
 
  25   developed also should give recommendations and guidance to 
                                                                 84 
 
   1   the sponsor and the use of professional societies and

   2   academic resources with regards to quality of life scales as 
 
   3   perhaps the primary clinical endpoint and with regards to 
 
   4   dissemination of information of surrogate endpoints. 
 
   5             In terms of the designation of a product for fast 
 
   6   track, we would recommend that this designation would be by

   7   the directors of the review divisions.  We feel that they 
 
   8   have the most hands on and direct knowledge, and would be 
 
   9   able to make very good decisions with regards to which 
 
  10   products should be tracked in a fast track program. 
 
  11             We would also suggest that withdrawal of this

  12   designation would be based on two circumstances.  One 
 
  13   circumstance would be whereby the sponsor would demonstrate, 
 
  14   via a pivotal clinical trial design, that it is no longer 
 
  15   pursuing an indication for a serious or life-threatening 
 
  16   disease.  The second circumstance for withdrawal would be

  17   after an advisory panel meeting and a complete review of the 
 
  18   NDA or BLA that the FDA determines that a product does not 
 
  19   meet an unmet medical need. 
 
  20             We would recommend that prior to any type of 
 
  21   withdrawal of the fast track designation that they give the

  22   opportunity to first notify the sponsor of that desire, and 
 
  23   that the sponsor have an opportunity to meet informally with 
 
  24   the FDA prior to that final notification. 
 
  25             Obviously, as was brought up earlier with regards 
                                                                 85 
 
   1   to the IND with the fast track, you have the opportunity to

   2   request fast track designation whether you are filing your 
 
   3   IND or throughout the process or at your NDA or BLA status.  
 
   4   We would recommend that with regards to the IND process that 
 
   5   once fast track status is designated that the sponsor and 
 
   6   the FDA meet within the first 60 days to really begin the

   7   dialogue and the process of understanding what all the 
 
   8   requirements would be. 
 
   9             We would suggest that they develop a general 
 
  10   schedule with major action dates and milestones so that both 
 
  11   parties are very clear on what is expected.  We have also

  12   offered time-lines in terms of should either party not be 
 
  13   able to respond within that general schedule. 
 
  14             Additionally, we are asking that the sponsors try 
 
  15   to seek early approval on the protocol and agreement on the 
 
  16   protocol.  Often some of our companies have experienced

  17   situations whereby a protocol was agreed upon.  There was a 
 
  18   change in reviewers, for whatever reason, and then suddenly 
 
  19   the company is faced with that protocol no longer being 
 
  20   acceptable.  So, we would like to get that up front and 
 
  21   early.

  22             With regards to fast track and the NDA and BLA 
 
  23   submissions, the nice mechanism triggers this rolling review 
 
  24   opportunity.  What that means is that companies have the 
 
  25   ability, obviously, to submit portions of their application 
                                                                 86 
 
   1   to the FDA so that they can get decisions made on those

   2   facets of them.  We feel that is a great way to maximize the 
 
   3   utilization up front and minimize the time at the final end 
 
   4   when you come to final approval. 
 
   5             We would also recommend, however, that there be 
 
   6   some kind of information system or tracking system so that

   7   the companies are able to track the status of their NDA and 
 
   8   BLA through the process and would know at any point in time 
 
   9   where exactly they are. 
 
  10             [Slide] 
 
  11             With regards to alternative standards for

  12   marketing, this really pertains to subsection (b)(2) where 
 
  13   the products are approved on the basis of their clinical or 
 
  14   surrogate endpoint that is reasonably likely to predict 
 
  15   clinical benefit.  We believe it was the congressional 
 
  16   intent that this would apply to unvalidated data regardless

  17   of whether it was a surrogate or clinical endpoint. 
 
  18             Let me give you an example.  Let's suppose a 
 
  19   product was able to demonstrate it had a 93 percent 
 
  20   confidence interval.  The current standards require a 95 
 
  21   percent confidence interval.  Well, 93 percent, we believe,

  22   would qualify for reasonably likely to predict clinical 
 
  23   benefit. 
 
  24             The subsection (b) approval would require, 
 
  25   obviously, a post-approval study to validate that efficacy 
                                                                 87 
 
   1   and we feel that would be appropriate.

   2             I guess our point here -- and this was well stated 
 
   3   in the earlier FDA subpart (e) regulation whereby perhaps a 
 
   4   90 percent chance of effectiveness is always better than 
 
   5   none at all.  So, the issue comes to whether the standard of 
 
   6   95 percent in terms of safety and efficacy in trying to

   7   determine reasonably likely to predict clinical benefit, 
 
   8   that there might be other things that may be taken into 
 
   9   consideration there when it doesn't meet the 95 percent 
 
  10   standard. 
 
  11             With regards to post-approval requirements, again,

  12   this has to do with subsection (e).  The FDA may, but it is 
 
  13   not mandated to require Phase IV studies or for the pre- 
 
  14   approval of the marketing literature -- we feel that with 
 
  15   the pre-approval of the marketing literature, the pre- 
 
  16   approval process should be terminated six months after the

  17   product has been approved unless, of course, the sponsor is 
 
  18   demonstrating somehow a pattern of inappropriate promotional 
 
  19   activity. 
 
  20             [Slide] 
 
  21             MS. FLAHERTY:  I would like to talk to  you very

  22   briefly today about two further sections of FDAMA, and give 
 
  23   some of the Mass. Biotech. Council's recommendations to the 
 
  24   FDA for implementation of those two areas. 
 
  25             Both sections deal with the dissemination of 
                                                                 88 
 
   1   information by industry to healthcare providers and to

   2   formulary committees.  The first area is Section 401 which 
 
   3   deals with off-label use. 
 
   4             The key objective, as we understand the statute, 
 
   5   of Section 401 is to provide healthcare professionals with 
 
   6   the best information available to treat patients and to make

   7   informed healthcare decisions. 
 
   8             [Slide] 
 
   9             We submitted comments to the FDA on their proposed 
 
  10   regs. that they have already promulgated to implement this 
 
  11   section, and our comments on those regs. were submitted on

  12   July 23, 1998.  Today, I will give you just a few brief 
 
  13   highlights. 
 
  14             MBC feels that the criteria for acceptable journal 
 
  15   article and reference texts under the proposed regs. is too 
 
  16   restrictive in comparison to the criteria outlined in the

  17   statute itself.  The statute requires that the article to be 
 
  18   disseminated should be about a clinical investigation that 
 
  19   would be considered scientifically sound by experts. 
 
  20             MBC does not have any problems with this 
 
  21   recommendation or requirement under the statute, however,

  22   the proposed rule requires an additional level of detail 
 
  23   beyond that which is usually included in published reports.  
 
  24   So, we are afraid that certain articles that are, indeed, 
 
  25   about clinical investigations that aren't considered 
                                                                 89 
 
   1   scientifically sound by the experts would not be eligible

   2   for distribution under this proposed rule. 
 
   3             The second portion of the proposed rule that we 
 
   4   would like to comment on is the requirements for mandatory 
 
   5   disclosures.  The proposed rule sets forth a specific 
 
   6   mandatory disclosure requirement that must be included on

   7   every journal article, regardless of the content of that 
 
   8   journal article.  While the statute itself does require 
 
   9   disclosures, and the MBC is not opposed to including 
 
  10   disclosures, we feel that industry should have a little bit 
 
  11   of discretion to tailor those disclosures to appropriately

  12   give the healthcare professional the information about what 
 
  13   the specific limitations are, or the specific problems, or 
 
  14   information in the article that is dealing with off-label 
 
  15   uses. 
 
  16             The second disclosure provision of the proposed

  17   regulation requires that with any additional information the 
 
  18   FDA requires the manufacturer to include that information, 
 
  19   including bibliographic statements, other articles or 
 
  20   specific statements by the FDA to be attached on the front 
 
  21   of the article.  We think those specific attachment

  22   requirements are too restrictive in the sense that they 
 
  23   could potentially mean that the information that the 
 
  24   manufacturer is trying to get out to physicians is at the 
 
  25   bottom of a pile that the physician will never get to. 
                                                                 90 
 
   1             What we would propose is that if we are required

   2   to submit this information along with the article we are 
 
   3   wanting to distribute, we are happy to do that but we think 
 
   4   the FDA should leave it to the industry to just ensure that 
 
   5   we include that information and not have specific 
 
   6   requirements as to where and how that information should be

   7   attached or presented. 
 
   8             A third issue with the proposed rule is the 
 
   9   definition of economically prohibitive.  The statute 
 
  10   provides for an exception in instances where it would be 
 
  11   economically prohibitive for a manufacturer to actually

  12   submit an SNDA for the proposed off-label use. 
 
  13             While we acknowledge that that limitation or 
 
  14   exception in the statute is, indeed, a very limited 
 
  15   exception, the proposed reg. itself effectively eliminates 
 
  16   any such exception.  In other words, if a manufacturer is

  17   not going to submit an SNDA they would not be able to 
 
  18   disseminate information under Section 401. 
 
  19             The next point that we have is the narrow 
 
  20   definition of unapproved uses.  We are concerned that the 
 
  21   definition of unapproved uses in the regulation tends to say

  22   that you can only talk about uses that are explicitly in 
 
  23   your labeling, otherwise it is an unapproved use.  In many 
 
  24   instances specified dosages for other information is 
 
  25   included in pivotal studies and is submitted to the FDA but, 
                                                                 91 
 
   1   as we are negotiating the labeling of that particular

   2   product, we may or may not include everything in those 
 
   3   pivotal studies.  We would suggest that the unapproved use 
 
   4   definition be expanded to include information from our 
 
   5   pivotal studies that were the basis for our approval in the 
 
   6   first place.

   7             Finally, we would ask that the FDA consider 
 
   8   permitting Internet reporting for some of the reporting 
 
   9   requirements under the statute.  The industry will be 
 
  10   required to keep a list of who they disseminated the 
 
  11   information to and what specific information was

  12   disseminated.  We would request that the FDA permit us to 
 
  13   either submit that electronically to them over the Internet 
 
  14   or, alternatively, that we be permitted to post that 
 
  15   information on our Internet site. 
 
  16             We would also like to suggest to the FDA one means

  17   of getting around the potentially burdensome problem of 
 
  18   distributing numerous disclaimers, other articles or FDA 
 
  19   statements.  We would be willing, or we would suggest that 
 
  20   you permit industry, on the reprint, to include our Web site 
 
  21   address and indicate that there is, you know, further

  22   information included on our Web site, in much the same way 
 
  23   as direct consumer advertising permits the use of the Web 
 
  24   site address to direct the consumer to additional 
 
  25   information. 
                                                                 92 
 
   1             Finally, PhRMA submitted separate comments on this

   2   regulation to the industry which we, in the MBC and our 
 
   3   working groups, reviewed carefully.  We would just like to 
 
   4   urge the FDA to adopt as many of PhRMA's proposals as they 
 
   5   find acceptable because we endorse them wholeheartedly. 
 
   6             [Slide]

   7             The second section dealing with dissemination of 
 
   8   information in FDAMA that we would like to talk to you about 
 
   9   today is Section 114, which deals with the dissemination of 
 
  10   healthcare economic information. 
 
  11             The key objective of the statute, as MBC sees it,

  12   is that the congressional intent was to provide economic 
 
  13   data to support managed care organizations, integrated 
 
  14   delivery systems, and other organizations in their drug 
 
  15   selection decisions.  Basically, these managed care 
 
  16   organizations and other delivery systems and hospital buying

  17   groups ask industry for this information on economic data 
 
  18   all the time.  They are making their decisions based on 
 
  19   economic information anyway, whether we give it to them or 
 
  20   not, and sometimes that economic information is anecdotal 
 
  21   rather than scientific based.  That is why Congress included

  22   this provision. 
 
  23             [Slide] 
 
  24             The FDA is in the process, I believe, right now of 
 
  25   drafting a guidance to implement this provision, and MBC 
                                                                 93 
 
   1   would urge that that guidance follows the intent of the

   2   statute and I will just highlight a few of the points. 
 
   3             The statute now changes the standard for 
 
   4   substantiating healthcare economic information to a 
 
   5   competent and reliable scientific evidence standard.  What 
 
   6   that means is basically that no longer do you need to submit

   7   two adequate and well-controlled studies to support your 
 
   8   healthcare economic data.  If you have competent and 
 
   9   reliable scientific evidence, which could be one  well- 
 
  10   controlled study or another adequate other type of study 
 
  11   instead of a head-to-head clinical study, you should be able

  12   to support your healthcare economic claims. 
 
  13             There are certain limitations on Section 114 that 
 
  14   permit the use of this lowered standard.  Those limitations 
 
  15   are that you are only allowed to talk about healthcare 
 
  16   economic information that is directly related to an approved

  17   indication -- in other words, no off-label discussions, or 
 
  18   you can't use healthcare economic information, or you can't 
 
  19   provide it on off-label uses. 
 
  20             The second is the permitted audience, a very 
 
  21   restricted audience that would be eligible to receive this

  22   information from the manufacturer.  There would be formulary 
 
  23   committees or other managed care organizations or healthcare 
 
  24   buying groups who would be making those decisions.  In other 
 
  25   words, you couldn't provide that information to single 
                                                                 94 
 
   1   physicians who are prescribing directly to patients or to

   2   consumers of the products themselves. 
 
   3             We would also urge the FDA to adopt a definition 
 
   4   of healthcare economic information that includes all forms 
 
   5   of that information where that information is intended to 
 
   6   facilitate decision-making at the formulary level.  That

   7   would include cost analysis, cost effective analysis, and 
 
   8   cost benefit analyses. 
 
   9             We would urge the FDA to permit manufacturers to 
 
  10   use reasonable assumptions with the healthcare economic 
 
  11   consequences derived from the approved indication, rather

  12   than just clinical endpoints. 
 
  13             [Slide] 
 
  14             We would also urge that healthcare economic 
 
  15   information could be supported by clinical outcomes that 
 
  16   would include many different areas, such as the physiologic,

  17   anatomic, biologic endpoints as well as health status, 
 
  18   quality of life measures, life expectancy, patient 
 
  19   performance, patient satisfaction, compliance, and other 
 
  20   such measures that are relevant to these formulary committee 
 
  21   members and others when they are making decisions of what

  22   drugs to put on their formularies. 
 
  23             I would also recommend that the FDA permit us to 
 
  24   disseminate information in many different ways, using both 
 
  25   printed material, computer-based material, interactive 
                                                                 95 
 
   1   software, etc.

   2             Finally, MBC would urge the FDA to use experts to 
 
   3   evaluate the substantiation, the information, whether it is 
 
   4   modeling, meta-analysis.  Healthcare economics is a vital 
 
   5   new area of study and we would urge the FDA to use experts 
 
   6   in the field when they are evaluating healthcare economic

   7   claims. 
 
   8             Finally, I would just like to also say in this 
 
   9   regard that PhRMA has submitted a guidance for industry to 
 
  10   the FDA for their consideration in drafting the guidance 
 
  11   and, again, we support and urge you to endorse PhRMA's

  12   recommendations. 
 
  13             [Slide] 
 
  14             MS. BOURQUE:  In closing, there were three over- 
 
  15   arching general concerns that the industry had with regards 
 
  16   to recommendations to the FDA, and those three I mentioned

  17   earlier were the harmonization and consistency of the 
 
  18   handling of drugs and biologics; the second, the increased 
 
  19   transparency and accountability within FDA, and the 
 
  20   cooperation between the FDA and industry. 
 
  21             [Slide]

  22             With regards to harmonization and consistency, we 
 
  23   are really talking about within the agency and we would like 
 
  24   to cite CBER as the model.  We have noticed that CBER 
 
  25   utilizes science as the basis for pulling together guidance 
                                                                 96 
 
   1   documents and regulations, and it is that model that we

   2   would like to see carried out through the agency, which 
 
   3   currently is not. 
 
   4             We would also recommend regarding changes 
 
   5   associated with FDAMA that there be a uniform personnel 
 
   6   training program.  We are finding that there are some

   7   reviewers who are knowledgeable about some of these changes 
 
   8   and some that are not, and also in terms of the 
 
   9   understanding and the handling of these types of changes so 
 
  10   the industry has a consistent response from whoever they are 
 
  11   dealing with at the agency.

  12             [Slide] 
 
  13             With regards to subset analysis, that is where the 
 
  14   industry and the sponsor have to provide more information 
 
  15   and, obviously, analyses with regards to age, gender, or 
 
  16   race.  We would strongly recommend that there be, again, a

  17   uniform and consistent acceptance of the expectation of what 
 
  18   that would look like from the industry so that there are not 
 
  19   differences between this type of analysis being provided in 
 
  20   one division versus another division.  Actually, in the 
 
  21   February 11, 1998 final rule regarding this in the Federal

  22   Register, we would suggest you adopt that rule because we 
 
  23   think it is a very good approach. 
 
  24             With regards to transparency, we are really 
 
  25   talking about how, again, can the industry and FDA work more 
                                                                 97 
 
   1   closely together so that we all are fully apprised of what

   2   our concerns are with regards to the product that is being 
 
   3   developed. 
 
   4             Specifically again, I would like to cite CBER as 
 
   5   having a protocol that we think is very good, whereby CBER 
 
   6   actually submits a copy of the draft submission document to

   7   the sponsor prior to submitting it to the advisory panel.  
 
   8   What this allows is for the sponsor to actually develop 
 
   9   responsive documents with regards to, and it also allows the 
 
  10   sponsor to develop clarifications in case there is confusion 
 
  11   or some concern that can be clarified.  At times, it also

  12   can improve the accuracy of the contents of that document.  
 
  13   Currently, that is not carried out agency-wide, and we think 
 
  14   that that really is a fine representation of working closely 
 
  15   so that the document that the advisory panel receives is the 
 
  16   best it possibly can be from both the FDA's side and the

  17   sponsor's side. 
 
  18             Additionally, we would like to suggest in terms of 
 
  19   accountability that perhaps there be mechanisms put in place 
 
  20   in terms of more self-reviewing or self-policing mechanisms 
 
  21   such as, again, defining and developing more uniform

  22   timetables agency-wide that would be adhered to.  The agency 
 
  23   has been good at starting to publish performance results and 
 
  24   we would like to see that continued on a more regular basis 
 
  25   rather than perhaps periodically, but measure themselves and 
                                                                 98 
 
   1   let the public be able to scrutinize and the industry on how

   2   well they are doing.  It is a great form of information, as 
 
   3   well as the point I am going to get into, the expansion of 
 
   4   the ombudsman's rule. 
 
   5             [Slide] 
 
   6             It would be, we think, advantageous if the

   7   ombudsman's rule could be expanded perhaps.  Currently, 
 
   8   there is a preference to handle things on a center level.  
 
   9   We would really like the ombudsman's rule to be able to have 
 
  10   the jurisdiction to go agency-wide.  As an industry, we 
 
  11   would like to be able to provide maybe collectively

  12   concerns.  As people were mentioning whose name or whose 
 
  13   name was included in certain lists -- companies often are 
 
  14   reluctant to bring a problem that they are having with a 
 
  15   particular reviewer, whether it is with management of time 
 
  16   or timetables, or whatever, for fear that there will be

  17   repercussions and that somehow they will be penalized for 
 
  18   addressing this. 
 
  19             We thought that perhaps if there was a more 
 
  20   proactive position that the ombudsman's role could take in 
 
  21   terms of hosting forums on some general issues we are having

  22   so the industry could collectively response.  But even more 
 
  23   specifically, if the industry or the sponsor is having a 
 
  24   difficulty with a reviewer, again whether it is on policy 
 
  25   challenges or whether it is something more specific, the 
                                                                 99 
 
   1   sponsor would be able to go immediately to the ombudsman and

   2   be able to raise the issue outside of the center, not that 
 
   3   it wouldn't at some point include the center but certainly 
 
   4   would raise it to a different level so they would sort of 
 
   5   have an independent third-party person to really go to and 
 
   6   feel that they could do this at any point, not that they

   7   would want to make this overly burdensome and constantly go 
 
   8   without working through the issues, but really give them a 
 
   9   place where they can go to resolve this where there are no 
 
  10   repercussions for their raising these issues to help them 
 
  11   work through this.

  12             Maybe another recommendation would be in terms of 
 
  13   revising the complaint review procedure.  It is our 
 
  14   understanding that when a complaint is issued against a 
 
  15   particular reviewer it goes in their personnel files and no 
 
  16   one else is really aware of it.  We would like to perhaps

  17   suggest a mechanism where this could be raised to higher 
 
  18   visibility and scrutiny, and where there would be a 
 
  19   mechanism so that these types of complaints and issues could 
 
  20   somehow be put in a collective manner and be available to 
 
  21   the industry so people, as well as the agency, would be able

  22   to see issues that may be occurring with a particular 
 
  23   reviewer, or issues in general that seem to be recurring. 
 
  24             [Slide] 
 
  25             Finally, we obviously have submitted this document 
                                                                100 
 
   1   and we would recommend that you go through the more specific

   2   aspects of this document.  We want to let you know that our 
 
   3   working group is available.  There are subgroups that worked 
 
   4   on these areas, and we would be glad to spend more time 
 
   5   addressing some of the concerns or specific recommendations 
 
   6   that we made in this document, and in the spirit of FDAMA,

   7   we want to thank you for hosting this meeting and say that 
 
   8   we are here and available to continue the dialogue.  So, 
 
   9   thank you. 
 
  10             DR. ZOON:  Thank you very much.  You have given us 
 
  11   a lot to consider and we appreciate that.  I think the

  12   thought that went into the development of such 
 
  13   recommendations will clearly be very much considered by the 
 
  14   center.  So, thank you very much -- and I am sure by the 
 
  15   agency as well. 
 
  16             Are there any clarifications?  Questions?  Wow!

  17             [Laughter] 
 
  18             Well, I would like to thank you very much, and I 
 
  19   appreciate the effort of you coming here and the work that 
 
  20   you put into this.  So, thank you very much. 
 
  21             I would now like to open the floor for any

  22   additional comments that anyone may wish to make, if there 
 
  23   are any.  If you will raise your hand, I will recognize you, 
 
  24   and if you can identify yourself. 
 
  25                         Open Microphone 
                                                                101 
 
   1             MS. O'DAY:  My name is Miriam O'day, and I am Vice

   2   President of the Immune Deficiency Foundation.  I do have a 
 
   3   prepared statement, if you are accepting those. 
 
   4             DR. ZOON:  Yes, come up here. 
 
   5             MS. O'DAY:  I would like to say that we support 
 
   6   all of the recommendations that the regulated industry has

   7   made for improved communication with the agency.  I would 
 
   8   also like to note that we had short notice to make a public 
 
   9   statement today, and that we will make formal comments to 
 
  10   the docket.  We may do that individually, and we may also do 
 
  11   that as the Plasma Users Coalition.

  12             IDF is a member of the Plasma Users Coalition, 
 
  13   along with the National Hemophilia Foundation, the Committee 
 
  14   of 10,000, and the Alpha-1 Foundation, and the Alpha-1 
 
  15   National Organization. 
 
  16             Safe products in quantities that meet the needs of

  17   the affected patient population are common goals of 
 
  18   consumers, manufacturers and the FDA.  The frequent plasma 
 
  19   user communities require safe products, and depend on the 
 
  20   FDA to regulate the plasma industry accordingly.  However, 
 
  21   we also note that regulatory decisions cannot be made in a

  22   vacuum due to the current problems with availability of 
 
  23   plasma derivative products that are essential and life- 
 
  24   sustaining for the patients that consume them. 
 
  25             Addressing product shortages and availability has 
                                                                102 
 
   1   been difficult for patients, physicians, manufacturers and

   2   regulators.  During the current and ongoing shortage of 
 
   3   IGIV, the IDF was able to quantify the effects of the 
 
   4   shortage from the patient and physician perspective through 
 
   5   a survey sent to our constituents.  The FDA, industry and 
 
   6   consumers were taken by surprise by the shortage of IGIV and

   7   had enormous difficulty quantifying the effects of the 
 
   8   shortage. 
 
   9             It would seem that the FDA, as the regulatory 
 
  10   agency in control of lot release, recalls and withdrawals, 
 
  11   and enforcement of regulatory actions regarding GMP

  12   problems, would have the ability to access information to 
 
  13   quantify and predict near-term trends.  It was surprising to 
 
  14   us and others the difficult FDA had in determining 
 
  15   distribution and supply in the marketplace. 
 
  16             We would like to ask if the FDA has engaged in

  17   data collection concerning supply as recommended by the HHS 
 
  18   Advisory Committee on Blood Safety and Availability in 
 
  19   April, and will an ongoing effort be made by the FDA to 
 
  20   continue to consider supply while ensuring that the 
 
  21   manufacturers are in compliance with GMPs.

  22             We support the FDA's "dear doctor" letter and the 
 
  23   fact that the FDA instituted expedited IGIV lot release when 
 
  24   they became aware of the shortage.  However, we would 
 
  25   recommend staggered inspections and a regulatory environment 
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   1   that keeps an eye on supply.

   2             IDF is concerned with anecdotal reports that even 
 
   3   today several fractionators are not releasing product, or 
 
   4   are releasing limited amounts of product due to activities 
 
   5   relating to addressing GMP issues.  Are inspections phased 
 
   6   in and can manufacturing and lot release continue while

   7   improvements are made?  We recommend that the FDA remain 
 
   8   keenly aware of the small number of manufacturers currently 
 
   9   producing pooled-plasma derivatives and, in the case of the 
 
  10   Alpha-1 community that they are serviced by a sole supplier. 
 
  11             The shortages have highlighted a need for

  12   community outreach which is a difficult challenge.  The FDA 
 
  13   Office of Consumer Affairs could manage solutions to patient 
 
  14   and physician outreach and coordination of information.  We 
 
  15   would like to encourage OCA to work in conjunction with CBER 
 
  16   in the arena of plasma derivatives.  The American public

  17   feels invested in blood safety and media reports are often 
 
  18   misleading when dealing with scientific stories.  Media 
 
  19   events occur which affect the products regulated by CBER and 
 
  20   the American public at large.  As an example I would use the 
 
  21   outbreak of stories linking mad cow disease to CJD.  OCA

  22   could be the agency positioned to give public responses much 
 
  23   in the same way that they handled the situation with breast 
 
  24   implants. 
 
  25             Oftentimes consumer advocacy groups reach out to 
                                                                104 
 
   1   Congress or the White House if they feel the governmental

   2   agency they are dealing with is unresponsive.  Ultimately 
 
   3   the original agency of complaint falls under undue scrutiny 
 
   4   as the result of advocacy efforts, rather than responding 
 
   5   appropriately to the original concern.  To address this type 
 
   6   of issue, the NIH is establishing a public liaison office to

   7   listen and respond to constituencies.  The new NIH office 
 
   8   will be a repository of information equipped with the 
 
   9   ability to respond to concerns with information on existing 
 
  10   programs. 
 
  11             IDF endorses advisory committees with consumer

  12   representatives as an essential component in the FDA 
 
  13   regulatory process, and we support continued use of consumer 
 
  14   advisors.  We applaud the reduction of paperwork suggested 
 
  15   in the FDAMA plan, and specifically commend the institution 
 
  16   of BLAs.

  17             We would further recommend that the FDA improve 
 
  18   internal communications to assist companies designing 
 
  19   clinical trial study protocols for products already on the 
 
  20   marketplace.  We have heard from biotechnology companies 
 
  21   that established study parameters are often open-ended and

  22   guidance from the FDA would expedite the review process. 
 
  23             In closing, any recommendations or complaints that 
 
  24   consumers may have need to be placed in the context of the 
 
  25   FDA operating with diminished resources.  It is unacceptable 
                                                                105 
 
   1   to us that the regulatory body responsible for ensuring

   2   safety in the plasma industry should be operating without 
 
   3   the necessary staff.  Consumer groups like ours consider FDA 
 
   4   budget constraints devastating, and will continue to urge 
 
   5   Congress to adapt increased FDA budgets. 
 
   6             Thank you.

   7             DR. ZOON:  Thank you very much.  Are there any 
 
   8   clarifications, questions?  If not, thank you.  Any other 
 
   9   comments?  Please identify yourself. 
 
  10             MR. WALSH:  John Walsh, President of Alpha-1 
 
  11   Foundation and also a founding member of the Plasma Users

  12   Coalition, and a blood derivative consumer with weekly 
 
  13   infusion of alpha-1 antiprotease inhibitor product called 
 
  14   prolastin. 
 
  15             Firstly, I am even later than Miriam with respect 
 
  16   to notification of this meeting.  So, I don't have a

  17   prepared statement but we will certainly add to the docket a 
 
  18   more formal statement, both from the Plasma Users Coalition 
 
  19   as well as Alpha-1 Foundation. 
 
  20             I would like to start with a kudos for the FDA 
 
  21   including, you know, open door policy.  I think at CBER

  22   especially we have experienced ongoing or increasingly more 
 
  23   interest by Drs. Feigal, Epstein, Weinstein, as well as you, 
 
  24   Dr. Zoon, and we appreciate that. 
 
  25             The Internet access has helped us a lot to 
                                                                106 
 
   1   understand the process and how we can input better. 

   2   Specifically, the information on the Internet for this 
 
   3   meeting was very helpful.  We downloaded it and read it on 
 
   4   the way to the plane. 
 
   5             [Laughter] 
 
   6             Your support for the notification of withdrawals

   7   and recalls was very helpful.  I think as everybody in this 
 
   8   room understands, the IPPIA, Novartis and Red Cross have 
 
   9   joined forces with consumer groups to be able to support a 
 
  10   national notification plan.  We ask that the FDA make 
 
  11   certain that that is implemented to the extent that you can,

  12   and again we appreciate the partnership established between 
 
  13   community, government and consumer groups. 
 
  14             The advisory committee role is critical not only 
 
  15   to exchange information but to have continued input from the 
 
  16   consumer perspective.  A lot of the times we are the last

  17   ones on the bus, and we are certainly the most seriously 
 
  18   affected.  We expect to have an opportunity to present our 
 
  19   positions, and we appreciate our positions on the advisory 
 
  20   committees and, hopefully, FDA will have an advantage from 
 
  21   that recommendation.

  22             Access to scientific resources -- advisory 
 
  23   committees are certainly one part of that.  Each of our 
 
  24   organizations in the Plasma Users Coalition also has our own 
 
  25   MASACs, medical and scientific advisory committees, that 
                                                                107 
 
   1   have made recommendations with respect to current clinical

   2   trial evaluations or review and other issues related to 
 
   3   product development for our communities.  We would ask that 
 
   4   you use those resources.  They are open and available to you 
 
   5   at no cost, and we would ask that you use those. 
 
   6             Shortage strategies -- I haven't heard anybody

   7   talk about shortages.  I know there is a dilemma with the 
 
   8   FDA as to how much control you have over how much product 
 
   9   the industry manufactures.  We, as a consumer community, 
 
  10   certainly ask you to address that and try to understand the 
 
  11   impact of a consent decree or warning letter as it relates

  12   to supply of product.  We have had instances in both the 
 
  13   IGIV communities and the alpha-1 community over the last few 
 
  14   months that have been highly publicized that have affected 
 
  15   us with life-saving therapies. 
 
  16             Right now we have a current shortage of alpha-1

  17   protease inhibitor in the form of prolastin -- one 
 
  18   manufacturer, as Miriam indicated, and we have INDs by 
 
  19   companies being reviewed by FDA, and a very strong statement 
 
  20   that BPAC as well as the Advisory Committee on Blood Safety 
 
  21   and Availability, which I participate on, recommending that

  22   availability be the balance, and the focus, and the 
 
  23   priority.  Yet, it is understood by us -- I know we can't 
 
  24   discuss IND details, and we don't have access to details, 
 
  25   that they are requiring use of 1 kilo of a product that is 
                                                                108 
 
   1   in short supply, and we will have allocation until another

   2   product comes on the market, or an IND request for product 
 
   3   evaluation.  One kilo of product out of a patient community 
 
   4   that is only getting 50 percent, just increased in August to 
 
   5   80 percent of what we need to infuse on a weekly basis makes 
 
   6   no sense to us.  It is going to detract from the current

   7   supply available.  So, we ask that that be considered so you 
 
   8   are more sensitive to the IND process, and listen to our 
 
   9   needs, if you will. 
 
  10             That is all I have to say.  I have a lot more to 
 
  11   say but I just brought some notes down.  We appreciate the

  12   opportunity to present in an open forum.  We will welcome 
 
  13   participation, and want very much to give input to the FDA.  
 
  14   Thank you for the forum. 
 
  15             DR. ZOON:  Thank you very much.  Are there any 
 
  16   other comments, statements, questions?

  17             MS. SCOTT:  Amy Scott, from Smith Kline-Beecham.  
 
  18   Kathy asked me to please make a comment.  So, I will. 
 
  19             Actually, I have been thinking all morning after 
 
  20   hearing everybody talk about the different ways to get more 
 
  21   communication going between the agency and the industry. 

  22   There have been a lot of proposals made for a lot of formal 
 
  23   type of situations with quarterly meetings, and things like 
 
  24   that. 
 
  25             I would like to bring it down just to the level of 
                                                                109 
 
   1   the review process, and remind everybody that one of the

   2   great strengths, I think, of CBER as a regulatory body has 
 
   3   been the ability to collaborate with the industry, and to 
 
   4   work through the review process together, and have very 
 
   5   open, maybe less formal communication throughout the review 
 
   6   process.

   7             I think part of the problems of all of the 
 
   8   additional pressures that are being put on the agency at 
 
   9   this point is that there is a concern in the industry and 
 
  10   probably among yourself also that that is going to go away, 
 
  11   that things are going to become more formalized.  So, I

  12   would encourage the folks at the agency to figure out ways 
 
  13   to preserve that type of an approach to the regulatory 
 
  14   process because I think it is very important and it really 
 
  15   does help to facilitate things in the long run. 
 
  16             I jotted down a few ideas while I was sitting

  17   there about the ways that you might internally think of 
 
  18   preserving this.  One of the things is to just make sure 
 
  19   that your reviewers and your staff, especially the newer 
 
  20   folks, really understand the importance of that type of open 
 
  21   communication and how it really can facilitate things in the

  22   end. 
 
  23             Somebody from the Massachusetts Biotechnical 
 
  24   Council mentioned the need for training of the folks on your 
 
  25   staff, especially in terms of all this regulatory reform and 
                                                                110 
 
   1   the Modernization Act and all of the initiatives that are

   2   taking place to make sure that they are not only aware of 
 
   3   these things, but they really understand the implications of 
 
   4   these things so that when industry comes to them to use 
 
   5   particular tools that are being afforded and they really 
 
   6   know how to work through those, and use those tools.

   7             I think also it might be useful for the industry 
 
   8   if you could think about it and give us some helpful hints 
 
   9   or some guidance on how you see we could help you preserve 
 
  10   that type of collaborative interaction; what we can do as a 
 
  11   company or as an industry to give you better heads-up on

  12   questions and issues that we might find necessary to discuss 
 
  13   so that you could then get back to us and give us feedback 
 
  14   in a timely fashion. 
 
  15             Also, I think with so much that is happening with 
 
  16   all this regulatory reform, one of the big concerns is the

  17   logistical aspects of it all.  So, that is another reason to 
 
  18   maintain this open communication so that the industry can 
 
  19   call and talk to you about, "gosh, how do we do this? how do 
 
  20   we do that?"  If there are decisions that come out of some 
 
  21   of this back and forth logistical discussion that aren't

  22   necessarily in a guidance document or aren't in the 
 
  23   regulations, if you make a decision for a particular company 
 
  24   that is then a generic type decision that could be applied 
 
  25   to other situations that other companies may have, that you 
                                                                111 
 
   1   go ahead and communicate that in maybe a policy memorandum

   2   or something like that as just kind of building upon the 
 
   3   guidance documents that exist, without having to go through 
 
   4   all sorts of other formal processes for getting documents 
 
   5   out there. 
 
   6             So, those are just some thoughts.

   7             DR. ZOON:  Thank you very much.  Are there any 
 
   8   other comments?  Yes? 
 
   9             MR. KLAMRZYNSKI:  Matt Klamrzynski, Abbott 
 
  10   Laboratories.  I have submitted submissions over the last 15 
 
  11   years to CBER, and the notable points that have been made

  12   here in trying to implement FDAMA are all very good.  The 
 
  13   one that I just wanted to focus on now is in support of the 
 
  14   last speaker and also MBC on the highly interactive process 
 
  15   that is necessary to help CBER meet their mission of 
 
  16   enhancing public health by bringing new, innovative products

  17   to the marketplace and to patients. 
 
  18             What enhances it the most in industry is to have 
 
  19   as much feedback as possible from CBER in the earliest time 
 
  20   frame because many of the questions that are generated will 
 
  21   result in long-term experiments or clinical trials.  That is

  22   why the predetermination meetings and the agreement meetings 
 
  23   are going to be very, very significant to industry.  
 
  24   Guidances are going to be necessary.  But also during the 
 
  25   review process itself, you have set up a very professional, 
                                                                112 
 
   1   business-like management review process over the years, but

   2   we have to make it work better and in a more timely fashion.  
 
   3   And, I think the guidances and the working groups that maybe 
 
   4   come out of these meetings will help in that regard. 
 
   5             Thank you. 
 
   6             DR. ZOON:  Thank you very much.  Any other

   7   additional comments? 
 
   8             MR. ELENGOLD:  Since I am supposed to be the 
 
   9   operational guy, can I ask the last four speakers, before 
 
  10   you leave to stop over at this table and give the 
 
  11   transcriber and the minute-taker the names and affiliations

  12   just so when we get the transcript out they will appear 
 
  13   correctly?  Thank you. 
 
  14             MR. WALSH:  I don't mean to belabor it but I have 
 
  15   one more issue with respect to shortages.  We have 
 
  16   cooperated extensively with CBER with respect to the

  17   prolastin shortage, and in the immediate exchange, when we 
 
  18   determined from patients in Germany and clinicians in 
 
  19   Germany that there was a shortage of prolastin, we asked 
 
  20   CBER for information on that.  Once they determined exactly 
 
  21   what the problem was, they were forthcoming and cooperative. 

  22   In the meantime, the leadership of our community agreed to 
 
  23   basically discourage calls into the Office of Compliance 
 
  24   regarding shortage issues.  In the process, over the last 
 
  25   few months, in three different testimonies before Congress, 
                                                                113 
 
   1   the BPAC and the HHS Advisory Committee on Blood Safety and

   2   Availability, the FDA reported that because of the decrease 
 
   3   in calls, that must correlate to a decrease in the shortage 
 
   4   situation, and that is just not true. 
 
   5             We need to work out a system.  Right now, if I 
 
   6   call the Office of Compliance, inevitably what they will

   7   tell me is that there is not a prolastin shortage.  Well, 
 
   8   Bayer is never going to be able to satisfy demand.  Our 
 
   9   community is always going to have a shortage and will 
 
  10   effectively be on allocation because over 400 to 600 people 
 
  11   can't get product that need product until another

  12   manufacturer comes on line.  So, we need to work a system 
 
  13   out whether, as Miriam said, it is to change it over to 
 
  14   consumer affairs or whether it is to say to the FDA we can't 
 
  15   comment because we don't have any control, but we need as 
 
  16   accurate information as possible.  If CBER's measure of a

  17   shortage is call-ins, then we can give you call-ins. 
 
  18             [Laughter] 
 
  19             But that is counter-productive and we understand 
 
  20   that.  So, we need to work out a system, whether it is to 
 
  21   get a working group together to do that or not, that should

  22   be considered in a shortage and allocation strategy. 
 
  23             DR. ZOON:  Thank you very much.  Any other 
 
  24   comments or issues?  Don't be shy! 
 
  25             I want to thank all the speakers today, both the 
                                                                114 
 
   1   formal and informal speakers, for their well thought out

   2   comments, and we appreciate them, and also look forward very 
 
   3   much to the written comments to the docket.  Many of the 
 
   4   ideas presented are very, very worthwhile and good.  Some of 
 
   5   these we will implement as soon as possible because it just 
 
   6   makes so much sense to do so.  So, I think just based on

   7   what we heard today, we will do some things relatively 
 
   8   quickly. 
 
   9             The docket will remain open and available for your 
 
  10   review and comment, and don't forget the meeting, August 
 
  11   28th, in Oakland and the overall FDA meeting which is

  12   scheduled in mid-September. 
 
  13             I want to thank you for CBER and, Linda, would you 
 
  14   like to make any last comments for the agency? 
 
  15             MS. SUYDAM:  Well, I thank you all also.  It was a 
 
  16   very productive meeting and it was what we had hoped these

  17   meetings would be.  I think if this is a sign of what the 
 
  18   rest are going to be like, I am very encouraged about this 
 
  19   process. 
 
  20             DR. ZOON:  Thank you.  Thank you all. 
 
  21             [Whereupon, at 12:20 p.m., the proceedings were

  22   adjourned] 