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 103 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]