> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> SCIENCE BOARD MEETING
>
> 9:10 a.m.
>
> Friday, November 16, 2001
>
> Conference Room 1066
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> PARTICIPANTS
>
> [Science Board Members]{.underline}
>
> Marion W. Anders, D.V.M., Ph.D.
>
> Michael P. Doyle, Ph.D.
>
> Owen Fennema, Ph.D.
>
> Robert S. Langer, Sc.D., Chair
>
> Robert M. Nerem, Ph.D.
>
> Cecil M. Pickett, Ph.D.
>
> Jose Principe, Ph.D.
>
> [FDA Participants]{.underline}
>
> Norris E. Alderson, Ph.D., Acting Senior Advisor for Science, FDA
>
> Dennis Baker, Associate Commissioner for Regulatory Affairs, FDA
>
> Celeste F. Bove, CCC-A, Acting Executive Secretary, Office of
> Coordination and Communication
>
> David W. Feigal, Jr., M.D., M.P.H., Director, Center for Devices and
> Radiological Health (CDRH)
>
> Ajaz Hussain, Ph.D., Deputy Director, Office of
>
> Pharmaceutical Science, CDER
>
> David Lepay, M.D., Senior Advisor for Clinical Science, FDA
>
> Joe Levitt, Director, Center for Food Safety and Nutrition (CFSAN)
>
> Bernard Schwetz, D.V.M., Ph.D., Acting Principal Deputy Commissioner,
> FDA
>
> Steven Sundlof, Director, Center for Veterinary Medicine (CVM)
>
> Linda Suydam, D.P.A., Senior Associate Commissioner for Communications
> and Constituent Relations
>
> Janet Woodcock, M.D., Director, Center for Drug Evaluation and
> Research (CDER)
>
> Kathryn Zoon, Ph.D., Director, Center for Biologics
>
> Evaluation and Research (CBER)
>
> [Invited Guests and Speakers]{.underline}
>
> Frances Bruttin, PrincewaterhouseCoopers, Pharmaceutical Sector Team
>
> Alexa I. Canady, M.D., Co-Chair, CDRH External Science Review
> Committee
>
> Doug Dean, Ph.D., PricewaterhouseCoopers, Pharmaceutical Sector Team
>
> Steve Hammond, Manager, Process Analytical Group, Pfizer
>
> G.K. Raju, Ph.D., Executive Director, MIT Pharmaceutical Manufacturing
> Initiative
>
> Norman Winskill, Ph.D., Vice President, Manufacturing, Pfizer, Inc.
>
> [Public Comment Speakers]{.underline}
>
> Robert Chisolm, International Technology Manager,
>
> AstraZeneca
>
> Gideon Kantor, Ph.D., personal statement
>
> Nouna Kettaneh-Wold, Umetrics
>
> Gabi Levin, Ph.D., Brimrose Corporation of America
>
> Scott C. Ratzan, M.D., M.P.H., M.A., Editor, Journal of Health
> Communication
>
> Svante Wold, Ph.D., Umetrics
>
> AGENDA
>
> Page
>
> **Call to Order**
>
> Robert S. Langer, Sc.D., Chair 5
>
> **Introductory Remarks**
>
> Bernard A. Schwetz, D.V.M., Ph.D. 7
>
> **Update on Action from April 2001 Meeting**
>
> Norris E. Alderson, Ph.D. 22
>
> **Emerging Science Issues: Pharmaceutical Manufacturing**
>
> Janet Woodcock, M.D. 28
>
> Doug Dean, Ph.D. 46
>
> Frances Bruttin 57
>
> G.K. Raju, Ph.D. 74
>
> Norman Winskill, Ph.D. 111
>
> Steve Hammond 123
>
> Ajaz Hussain, Ph.D. 149
>
> **Discussion**
>
> FDA Science Board 166
>
> **Open Public Comment**
>
> Nouna Kettaneh-Wold 194
>
> Gideon Kantor, Ph.D. 198
>
> Scott C. Ratzan, M.D., M.P.H., M.A. 205
>
> Gabi Levin, Ph.D. 221
>
> Robert Chisolm 230
>
> **Update on CDRH External Science Review**
>
> Robert M. Nerem, Ph.D. 241
>
> **Response to Update**
>
> David W. Feigal, Jr., M.D., M.P.H. 260
>
> **Discussion**
>
> FDA Science Board 286
>
> **Emerging Issues in FDA\'s Oversight of**
>
> **Clinical Research**
>
> David A. Lepay, M.D. 298
>
> **Discussion**
>
> Science Board 324
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> CHAIRMAN LANGER: Good morning. I would like to call the meeting to
> order. My name is Bob Langer. I wanted to do two things. First, my
> major task is to remind all the Board members to pay Donna \$8 for
> lunch during the break. And, secondly, I thought we could just maybe
> go around the table and introduce everyone just briefly.
>
> DR. PRINCIPE: My name is Jose Principe. I am Professor of Electrical
> Engineering. My expertise is biosignal processing. I work at the
> University of Florida.
>
> DR. PICKETT: I am Cecil Pickett. I am Executive Vice President of
> Research and Development at Schering-Plough Research Institute.
>
> DR. FENNEMA: Owen Fennema, Emeritus Professor of Food Chemistry,
> University of Wisconsin.
>
> DR. NEREM: Bob Nerem from Georgia Institute of Technology. I am
> Professor of Mechanical Engineering and Biomedial Engineering.
>
> DR. CANADY: I am Alexa Canady. I am not on the Science Board but was
> on the Review Committee, Co-Chair, and I am Professor of Neurosurgery
> at Wayne State University.
>
> DR. DOYLE: I am Mike Doyle. I am Director of the Center for Food
> Safety at the University of Georgia.
>
> DR. ANDERS: Greg Anders, now a Professor Emeritus of Pharmacology and
> Physiology at the University of Rochester.
>
> DR. SUYDAM: I am Linda Suydam, FDA Senior Associate Commissioner for
> Communications and Constituent Relations.
>
> DR. SCHWETZ: Bern Schwetz, Acting Commissioner of the FDA.
>
> CHAIRMAN LANGER: I am Bob Langer. I am Chair of the Science Board and
> a Professor at MIT in Chemical and Biomedical Engineering.
>
> DR. ALDERSON: I am Norris Alderson. I am the Senior Acting
> Director\--I am Acting Senior Advisor for Science. I\'ll get it right.
> It\'s a good job.
>
> \[Laughter.\]
>
> MS. BOVE: I am Celeste Bove. I\'m the Acting Exec. Sec. in the Office
> of Science.
>
> MR. BAKER: I am Dennis Baker. I\'m the Associate Commissioner for
> Regulatory Affairs.
>
> MR. SUNDLOF: I am Steve Sundlof. I am the Director of the Center for
> Veterinary Medicine.
>
> DR. WOODCOCK: Janet Woodcock, Director, Center for Drugs.
>
> CHAIRMAN LANGER: Okay, so now I would like to turn this over to Bern
> Schwetz, who is the Acting Principal Deputy Commissioner, to make some
> introductory remarks.
>
> DR. SCHWETZ: Thank you, Bob. I\'m in the precarious spot of beginning
> to talk and my notes are still in my office over in the other
> building, which is a position I try not to get caught in very often.
>
> Let me follow up from where Norris was going with his title. When the
> Science Board met last time, Liz Jacobson was still with us as the
> Acting Senior Advisor for Science, and in the meantime Liz has
> retired, and is still helping us in some ways. But she is no longer in
> the position that she was in when we met last time, and instead Norris
> has agreed to come in and help in this regard.
>
> Norris has spent many years in the Center for Veterinary Medicine, and
> in his most recent position\--recent in the last 15, 16, 17
> years\--has been the Director of the Office of Research within the
> Center for Veterinary Medicine. And in consultation with Steve, who
> reluctantly agreed to let Norris out of CVM for a while, Norris agreed
> to come and fill this position as the Acting Senior Advisor for
> Science, and I am very happy to have Norris helping me in that regard.
>
> There is another change that has been made within my immediate Office
> of the Commissioner that I want to update you on. Dr. Mac Lumpkin is
> now serving as the Acting Deputy Commissioner of the agency. Mac was
> in the Center for Drugs with Janet for many years, and more recently
> has served as the senior medical advisor to me during this time when I
> have been the Acting Commissioner.
>
> So we have now given Mac a more permanent title, if you will, of the
> Acting Deputy Commissioner, so I am glad to have his help. It helps to
> have, when you\'re not a physician in charge of the agency, it\'s nice
> to have a physician as a right-hand person helping with the day-to-day
> running of the agency.
>
> I also want to thank our two new members of the Science Board. Dr.
> Cecil Pickett, as he has already identified himself, is from
> Schering-Plough Research Institute, the Executive Vice President of
> Discovery Research, a cell biologist by training, and was on the
> Science Advisory Board of NCTR. And I had a conversation, a couple of
> conversations with Dan Casciano about the possibility of having Cecil
> work on the Science Board at this time, instead of on the NCTR Science
> Advisory Board, and Dan agreed. So, Cecil, we\'re very happy to have
> you with us.
>
> And Dr. Principe is also new. We welcome both of you to the Board. A
> professor of electrical engineering, has an interest in something that
> is important to a lot of us, computational neuroengineering. That is
> something that a lot of us have talked about in one way or another as
> it relates to drug research or a new approach for looking at the
> nervous system function. That is something that I\'m hoping we will be
> talking about more as we go. So welcome to both of you.
>
> I have in my notes to talk about where we are from the standpoint of a
> new Commissioner, not that I can bring you information, but in hopes
> that maybe you have some information.
>
> \[Laughter.\]
>
> Because while I don\'t think we\'re in a different position that we
> were several months ago, where names were being mentioned but there
> isn\'t any specific action. So as far as I am in this position, the
> agency is still stuck with me, and for how long we don\'t know. But at
> any rate, things continue as they have been.
>
> I want to talk a bit about counter-terrorism and the impact of the
> recent two months on the priorities and the operation and the
> activities of the agency. Everybody says things aren\'t the way they
> used to be. Things haven\'t gone back to normal. I can assure you that
> things haven\'t been very normal in the agency since then. And I\'m
> not going to go into detail on anyone of these things, but I just want
> to kind of give you a flavor of the kinds of day-to-day issues that
> we\'ve had and what has been consuming our time and energies at a time
> when we\'re trying to keep the usual business of the agency flowing.
>
> We have very thoroughly reviewed the emergency preparedness plans that
> we have within each of the Centers, because they all have them, for
> dealing with emergencies that relate to the products that are in the
> domain of that particular Center. We have certainly spent a lot of
> time backing up the rest of the department and the other agencies from
> the standpoint of the availability of vaccines and drugs and medical
> devices, because whether it was the terrorist actions in New York City
> or anthrax since then, we needed to have everything from blood to
> skin, drugs, vaccines.
>
> Many of our products were out there and of concern in one way or
> another, so we spent a lot of time reviewing product security, and how
> would we know if our products were the subject of some terrorist
> action or not? To say nothing of the fact that we have an adequate
> supply in the event that they are needed in case of some action. So
> product security has been reviewed.
>
> Food security has been a big issue, and a lot of us have spent time
> talking to the press, talking to the public, talking to the industry,
> communicating about where we are on food security as a possible means
> of terrorist action.
>
> The threat of anthrax in our mail rooms had a major impact. It\'s one
> thing to talk about having drugs available for those other people who
> might be exposed to anthrax, but when we have anthrax that
> supposedly\--we had the presumptive positives in five of our mail
> rooms. After routine sampling and culturing, the word came back that
> we had presumptive positives, and then there were many days before it
> was confirmed negative.
>
> Well, in the meantime our people, like others, were put on
> antibiotics, and thousands of questions, many hours spent in front of
> our employees trying to provide perspective and answer questions, and
> hope that we wouldn\'t get positive confirmed results back, and what
> were we going to do in the event that they did? So I think that was
> another test of our ability to deal with an internal emergency that
> certainly had ramifications on the outside, as well.
>
> Again, the expertise that we have that comes into play at times like
> this, an example is the recent interest in the irradiation of mail as
> a way of getting rid of anthrax or some other organisms through the
> mail. And in the Center for Devices and Radiological Health we have
> the expertise to be able to help answer those questions. So our people
> have been in there with the Postal Service and the others on a daily
> basis trying to figure out, is that an effective and safe way, and
> what kind of operating conditions would you have to have? What are the
> capabilities? Is it just flat surface letters, or is it boxes? How
> thick can something be?
>
> Another wrinkle to this is, if we go into the irradiation of mail
> aspect, what about things, products that we regulate that are shipped
> in the mail? And that\'s everything from drugs to biologics to devices
> to food, a number of other things that end up going in the mail, that
> if it was irradiated, wouldn\'t be effective if you used it. So there
> are a whole bunch of other questions.
>
> So then do we have to go back to the manufacturers and say, \"In the
> event that your product is shipped in the mail, is it stable under
> these conditions?\" And what do you have to tell the consumer to worry
> about? So it\'s amazing how many ripples come out of this kind of
> thing.
>
> Some of this has translated into a supplemental budget that we have
> put in, and from the standpoint of the money that has been requested
> by the administration, of that \$20 billion that is earmarked so far,
> we have a request for \$106 million. \$61 million of that would be
> used to help protect us against things that would be imported, so a
> lot of this would go to the field.
>
> A lot of it has to do with food security, but Joe Levitt isn\'t
> getting it hands-on. It\'s really going to the field operations, so
> Dennis Baker and his people are the ones who will get a lot of this to
> help improve our presence at the border, as well as our presence, our
> capacity behind the border for doing the laboratory work that is
> increased in the event that we have activities at the border and have
> to do a lot of sampling. Or the domestic side of it, where in the
> event that we have to do a lot of sampling because of questions that
> have arisen from domestic supplies, that we need the capacity to be
> able to do the lab work that this kind of increased action drives.
>
> So that\'s \$61 of the \$106 million, and the rest of it has to do
> with other parts of the agency where we\'re trying to increase the
> stockpiles, make sure we have the materials that are needed in the
> stockpiles that CDC manages and the rest of the department manages for
> emergencies.
>
> We have spent a lot of time in the product centers\--we, I mean
> generously, the people who are in the product centers have spent a
> huge amount of time communicating with the manufacturers to be sure
> that products that are critical are in fact not only available but in
> a supply that would be sufficient to meet the needs that we might
> anticipate under emergency conditions, antibiotics and vaccines in
> particular, and the possibility that we would develop new capacity for
> producing vaccines. There have been a lot of discussions with the
> industry that hasn\'t been manufacturing vaccines, or at least the
> ones that we need for anthrax, smallpox, and so on.
>
> So there has been a lot of discussion, and the pressure that we get to
> get out there and make it tomorrow and have it ready is one that is
> very difficult for us, because the last thing we want to do is to
> approve a vaccine that\'s coming from a new source, that isn\'t safe
> or isn\'t effective, and to build up hopes only to find out that it
> wasn\'t what we thought and we may have created a worse problem than
> we hoped to solve.
>
> So at a time when everybody wants to be protected right now and have
> everything in place, we are trying to make sure that in the event that
> we increase the capabilities for manufacturing or developing new
> products, that when they are made available, they are safe, but do it
> as fast as we can so that we are not seen as \"business as usual\" and
> there\'s an emergency and we stood in the way.
>
> We of course have continued to raise attention to the fact that we
> have some pathogens in laboratories of ours, and so does the industry
> that we regulate that\'s developing vaccines and other products, and
> to get out and find out the security of all of those pathogens that
> could be of interest to somebody else. So that has been a focus of
> ours, and part of this money that I\'m talking about goes to increase
> our own internal security.
>
> And of course the amount of coordination with other agencies, inside
> and outside the department, has consumed hours per day of a lot of us,
> just talking and being sure that we keep the Secretary informed, or
> other members of our department who are out in the press informed, or
> to be sure that as decisions are made on how we should deal with these
> kinds of issues, that the best thoughts are put on the table to help
> focus the discussion and make some of these decisions.
>
> One of the things that we have developed internally as a result of
> this is what we\'re referring to, and the name isn\'t necessarily
> nailed down yet, but a new Crisis Management Center. Dr. Woodcock has
> agreed to help pull this together for us, so for now, Janet is
> detailed to the Office of the Commissioner and Dr. Steve Galson, who
> is her new deputy, is helping to run the Center from day to day, but
> Janet is nearby. But Janet is helping us develop a plan to have a
> Crisis Management Center.
>
> The agency has decades of experience in dealing with emergencies. That
> is one thing that has been part of our menu all along, because we have
> an average of two to three tampering incidents per week, and those
> tamperings might be anything from a hoax, some of them have been real,
> some of them have been not only real but very serious. And the
> possibility now on our mind is that you never know when a
> tampering\--this has been true before, but especially true now\--when
> one of those tampering incidents might be the beginning of a terrorist
> activity.
>
> And because we see a lot of these on a day-to-day basis and the
> Centers are well-prepared to deal with food poisoning issues and other
> product tamperings, there is a threshold of that at which we need to
> engage as a whole agency, as we have for the anthrax, as opposed to
> the Center for Foods dealing with a food crisis that they have dealt
> with in a normal way all along and it doesn\'t come to the attention
> of the whole agency.
>
> So this management center will help to keep us communicating and help
> to sort out those more routine variety of emergencies that the Centers
> take care of all the time, as opposed to one that could rise to the
> level that the whole agency needs to deal with it and be prepared to
> work with CDC and maybe the USDA and EPA and other agencies. So we
> appreciate that Janet has agreed to help bring this center to
> fruition.
>
> Let me switch gears now. We end up spending a lot of our time talking
> about terrorism and preparedness for it, but I want to talk about some
> other things, too.
>
> Peer review. The CDRH peer review has been completed to the stage
> where Bob and Alexa are going to comment on the review that has been
> done of CDRH. We are happy to see that this has been a productive
> process, and Dr. Feigal is going to respond to the comments that will
> be made.
>
> We continue to talk to Dennis in the Office of Regulatory Affairs,
> with the expectation that a review of ORA\--because of the science
> within the field operation\--would be the next peer review, and then
> CVM and CDER will follow, so one-by-one we keep moving on this.
>
> Just a very small comment on budgets from the standpoint of the 2002
> budget. We are under continuing resolution. Both the House and the
> Senate have passed conference reports, and the agency is doing pretty
> well for 2002.
>
> And we are pleased to know that we are receiving the pay increase, the
> salary increases as an item this year, as opposed to in past years
> having to take the required pay increases of our employees out of our
> operating budget. Well, this year the operating budget is there and,
> in addition, there is money for the pay increases, so that is a
> significant step forward. And if we had had that for the last five or
> six years, we wouldn\'t have been in the trouble we were
> programatically.
>
> In addition, I mentioned the supplemental budget request of \$106
> million. That will help. One of the things that we realize is that
> while we have spent a lot of money on the food safety initiative in
> the last three or four years, a lot of the investment that we\'ve made
> in food safety is very important from the standpoint of food security,
> so it has been a good investment.
>
> And it goes the other way, as well, so that as we get money for people
> at the borders, as we get more money to help with vaccines and drugs
> and what not, that helps, the security money helps safety surveillance
> and maintenance as well. So it isn\'t that we are investing in
> something that has a use only under those peculiar circumstances, so
> that\'s good for us.
>
> We\'re working on the 2003 budget, but that is something that we will
> continue on for the next couple of years.
>
> As I close, let me come back to Board members. Two of our members are
> here for the last time. In fact, only one of them is here. Dr. Marian
> Nessle couldn\'t be here today, but today is her last meeting. But in
> addition, Greg Anders is here as his last meeting this time, and I
> very much appreciate the help that both of you have been during this
> time. Greg helped me as a member of our Science Advisory Board at NCTR
> for a number of years while I was still there, and I convinced him to
> come and be part of our Science Board here, as well. So, Greg, it has
> been a long time that you have committed your attention to us, and I
> really appreciate it, and thank you a lot.
>
> In addition, I would remind you that over the next year\--and please
> don\'t stand up and cheer when I say this\--we do have more members
> whose term will be coming to an end, so I would ask you to be thinking
> about other colleagues of yours whom you would like to recommend as
> replacements, as we look at five new members coming on next year. So
> we can deal with that down the road, but be thinking of names.
>
> Bob, I think I\'ll turn it back to you.
>
> CHAIRMAN LANGER: That sounds great. Let me now turn it over to Norris
> Alderson to give us an update on the action items from the April 2001
> meeting. Norris?
>
> DR. ALDERSON: Thanks, Bob. Let me tell you that, first, I\'m looking
> forward to working with all of you at the coming meetings, assuming
> I\'ll be here. That is still an unknown. But I promise that the next
> time we meet, I will have the title correct.
>
> I do want to remind you that Dr. Schwetz mentioned the two Board
> members, that this would be their last meeting, we have selected two
> members to replace them and I want to tell you about those.
>
> First is Dr. Jim Riviere. He\'s from the College of Veterinary
> Medicine at North Carolina State University, and he\'s a veterinary
> pharmacologist. The second is Dr. Josephine Grima, who is Director of
> Research and Legislative Affairs for the National Marfan Foundation.
> Her expertise is in biochemistry, molecular biology, and cell biology.
>
> Another little update is, I\'m sure all of you remember Sue Bond. I\'m
> glad to tell you that Sue and Rod Bond are the proud parents of a baby
> girl born in October, and so Sue is out on maternity leave at this
> time, and she will be back in February. In her absence, Celeste Bove,
> to my right, has been filling in extremely well, and I\'m extremely
> proud of the fact that we\'ve had the staff to fill in behind Sue.
>
> Two other people I do want to recognize that have helped in this, and
> that\'s Donna Mentch and Monica Spence. And particularly Monica today,
> if you\'ve got problems with travel and things like that\--I already
> heard one person that needs some help\--Monica can help you take care
> of those problems. She will also be dealing with you in getting your
> reimbursement for your expenses, so don\'t forget that.
>
> Now, an update from the last meeting. Bern has mentioned the peer
> review, so I won\'t mention that anymore. One other suggestion that
> came out of the April meeting was that we have an Ethics Advisory
> Committee, and remembering back, this came up in a discussion, I
> believe by Dr. Zoon, on tissue engineering and cloning.
>
> The leadership council of the FDA has looked at this and decided to
> establish a list of ethicists that we will maintain in the Office of
> Science Coordination and Communication for our use. We looked at that
> and felt this was the best way to address it. So we took your
> consideration and we put something in place to have that for us when
> we need it.
>
> The second item is, if you recall last meeting, Dr. Skulnick made some
> comments regarding institutionalizing our peer review system. Since he
> is not here today, we\'d like to hold off on discussing that because I
> think he has a big interest in that, so we will bring that up at
> future meetings.
>
> I do want to bring your attention to the upcoming FDA achievement
> awards. If you will recall, that\'s a process that you are the final
> determining body on who gets those awards. Our in-house review
> committee has completed their review of these. We will be forwarding
> to you in the next two weeks two candidates for each of the
> categories, and you\'ll get the opportunity to vote, I hope by
> December the 7th, on your recommendations for each of those awards.
>
> These awards will be presented at our Science Board in February. So
> this is very key to us. We\'ve got a lot of good scientists in the
> agency. This is one way we are able to recognize those, and we think
> it\'s very important to them.
>
> One final point. We communicated to all of you this summer about
> coming in early for one of the meetings to visit our laboratories. I
> think all of you responded to that in an affirmative way. You\'ve told
> us before that you wanted to hear more about how we establish
> priorities for our research, and this is one way we can start that
> discussion with you, is with you going out to our laboratories and
> really talking to the scientists and the managers there to address
> this issue.
>
> So this will require you to come in a little earlier. We would like to
> do this the afternoon before this meeting. So at the same time we\'ve
> had to change the date of our April meeting because of a conflict with
> the Food and Drug Law Institute meeting. So we want you to respond
> back to us as soon as possible about your available dates, April and
> May time frame. If we don\'t hear from you shortly, we will take the
> initiative to get back to you.
>
> So that\'s my comments, Bob.
>
> CHAIRMAN LANGER: That\'s terrific, and very concise. That\'s very
> helpful. Thanks a lot.
>
> Well, I think we\'ve got a very exciting morning ahead of us, and the
> issue that we\'re going to discuss is the emerging science issue of
> pharmaceutical manufacturing, and Janet Woodcock is going to lead that
> discussion. I\'ll really turn this over to her. Janet?
>
> DR. WOODCOCK: Thank you. Good morning, everyone. If I can get the
> shift P\--shift key? All right. Now, what else do you want me to do?
> You\'ll do it? All right.
>
> While we\'re getting our audiovisual stuff working, what I want to
> talk about today, and the program we have put on, relates to science
> issues in the regulation of pharmaceutical quality. Now,
> pharmaceutical quality we think is really\--it\'s the roots of drug
> regulation for the FDA. It was quality problems that, in the early
> part of the 20th century, that really led to the formation of the Pure
> Food and Drug Act, the Food, Drug and Cosmetic Act.
>
> CHAIRMAN LANGER: Janet, microphone.
>
> DR. WOODCOCK: Oh, microphone, sorry. Okay. That led to the formation
> of the FD&C Act eventually. There were improper constituents, there
> were impurities based on manufacturing and so forth that led to
> various tragedies.
>
> Since that time, drug quality is really felt to be the basis of our
> findings of safety and effectiveness, because if the quality of the
> product fluctuates, the findings from the clinical trials of safety
> and effectiveness can\'t be relied upon to project into what the drug
> actually is. So this is a fundamental issue for the FDA, but we feel
> that is currently being challenged, and let me explain how.
>
> How do we regulate drug quality right now? Well, I\'m going to go over
> this a little bit because some of you may not really be aware of this.
> The pharmaceutical industry manufacturing sector is extremely tightly
> regulated by the FDA. That\'s the first fact.
>
> As most of you may know, before a product is approved by the FDA,
> before a drug product is approved, there has to be pre-review and
> approval of both the process, the synthesis, the manufacturing process
> and so forth, all the documentation that has been assembled by the
> firm, and aspects of the facility submitted. All of that is reviewed
> in a prior approval way before a new drug would get onto the market.
>
> In addition, the facility is inspected by FDA inspectors and
> everything is gone through extremely carefully there. And once a drug
> is on the market, if there are changes to the product or the process,
> these usually have to be submitted to the FDA and reviewed prior to
> being instituted.
>
> And in addition the ongoing manufacturing facility is subject to FDA
> inspection and has to conform to standards called Good Manufacturing
> Practices. And according to the statutory framework, that is supposed
> to be done at least every two years, so every firm should be inspected
> by the FDA every two years.
>
> So this scheme, which has been in effect for many decades, is how a
> pharmaceutical quality is currently regulated by the FDA in the United
> States. Now, we think, one of the reasons we are coming here today is
> that we think there are some issues regarding this.
>
> The goal of regulating pharmaceutical quality this tightly is that the
> product be of the highest possible quality. In other words, that\'s
> why we do this regulation, to ensure the highest possible quality of
> the pharmaceutical products that are regulated, but we feel that we
> may not be totally achieving this goal in some ways.
>
> We are seeing at FDA an increasing trend toward manufacturing-related
> problems. These include things like recalls. When there are
> manufacturing problems, it may disrupt manufacturing operations, and
> we may see shortages or loss of availability of important drugs. And
> this also can have, manufacturing problems or issues can have a
> negative impact on getting new drug approvals out.
>
> So that is one issue. Although we think the products now are of high
> quality, we will have some presentations today that discuss the fact
> that the pharmaceutical manufacturing sector may have low
> manufacturing and quality assurance process efficiency. And this is an
> issue because the cost of drugs is a real issue for health care in the
> United States, and this contributes, a lack of efficiency in this
> sector contributes to the cost.
>
> Now, not a lot of people have talked about this. I don\'t think it\'s
> a real popular subject. So I think this may be a somewhat
> controversial set of presentations that you\'re going to hear this
> morning.
>
> And, in addition, we find, we feel that innovation, modernization, and
> adoption of new technology in this sector has been slowed. And what do
> we base that assertion on? Well, we know that in other countries where
> products are manufactured not for the U.S. market, there has been a
> more rapid introduction and adoption of new technologies of various
> kinds. And that might be for the same product that is actually
> manufactured for U.S. use where those technologies are not employed.
> And these technologies we\'re talking about usually lead to a better
> level of quality assurance.
>
> Now, the final issue for us in the current system of how we regulate
> pharmaceutical quality is, it really does place a high burden on FDA
> resources. Our regulation of pharmaceutical quality is
> resource-intensive for the FDA.
>
> We get about 4,000 supplements submitted yearly. These are what I
> talked about earlier. When a change is going to be made in the
> manufacturing process or in the product in some way, a supplement must
> be submitted to the FDA. Some of these have to be reviewed by us. Some
> of them are simply noted by us.
>
> Our FDA inspectors are unable to meet, currently, the biennial GMP
> inspection requirement, so we are not in the plants every two years,
> as Dennis very well knows. And unfortunately for the non-domestic
> industry\--and globalization is causing a major shift, especially in
> the bulk drug manufacture, to overseas facilities all around the
> world\--our presence is even less there.
>
> And some of the cause of this is the financial issues that I think
> Bern and others have introduced the Board to, some of the financial
> challenges that the FDA faces. However, nevertheless, whatever the
> cause, the bottom line is, we are not in the foreign plants even as
> often as we are in the U.S. plants, which is much less often than we
> are required to be under the statute.
>
> This graph just shows, from the previous 10 years, sort of the rate of
> increase of us getting these manufacturing supplements. You can see as
> we approve new drugs, very frequently they go through a lot of changes
> in the next few years. Especially with current drug development, where
> things may not be completely worked out or optimized at the time the
> drug goes on the market, we\'re seeing a lot of supplements filed, and
> I think this reflects that. It also reflects the success of our
> generics program. We\'re getting a lot of generic drugs on the market,
> and they have a lot of manufacturing supplements filed to them.
>
> Now, due to the efforts of our chemists in developing new guidance,
> many of these in recent years have changed from requiring
> pre-approval, where the firms have to wait when they submit these
> until they\'re approved by the FDA, they have changed to what we call
> changes being effected, where they simply can notify us. They simply
> can send in the supplement, notify us, and go ahead and implement the
> change. But nevertheless you can see this is an increasing burden for
> the FDA at a time we don\'t have additional resources to deal with
> this.
>
> Now, how did this system\--how did we get here? Well, this whole
> system evolved starting about 30 to 40 years ago, at a time when the
> sectors of industry, many of them, by no means universal, but there
> were parts of industry that really lacked rigorous manufacturing
> procedures, so it was totally appropriate, the changes in regulation
> that were implemented at the time.
>
> But more importantly than lacking SOPs, there was really\--at that
> time the science had not advanced to the point where there was some
> predictability in what factors affect a formulation\'s performance, if
> you follow me. So it was really what I call sort of a \"know nothing\"
> approach. We know nothing about what impact a change will have on a
> formulation. Therefore, we must control and check everything, because
> we cannot predict, we cannot model what\'s going to happen if we make
> a change.
>
> And subsequent to that, the science and technology base\--and again,
> this is going to be controversial\--it hasn\'t evolved as quickly as
> in other manufacturing sectors, and there are probably a number of
> reasons for that, which I\'ll go into a little bit.
>
> Now, the standards that I referred to earlier, the Good Manufacturing
> Practice standards, which are the standards that we impose for
> inspecting plants, process standards for manufacturing facilities,
> these are empirical standards. They are not scientifically based
> standards. And the reason for that, again, is that we didn\'t have the
> underlying science to be able to predict what factors were important.
>
> Now, over the last 10 years, the Center for Drugs and the Center for
> Biologics have worked on the International Conference on
> Harmonization, which is a sort of international standards
> harmonization setting body that developed consensus-based standards in
> a number of quality areas. And most of these had to do with the review
> aspects, what we review in terms of stability, how you test for
> stability and things like that. So some of those may have a more
> modern science base to them, but nevertheless they were primarily
> consensus-based, based on the experience and standards of the three
> regulatory agencies, Japan, EU, and U.S., that actually were putting
> these standards together.
>
> And finally, I have to mention this because I think it\'s a very
> strong factor, why has the science base and technology base\--and I
> see people nodding in the audience\--not evolved rapidly like it has
> in other sectors, aerospace or, I don\'t know, computer chips or what
> have you?
>
> Well, for the innovative pharmaceutical industry, the most important
> thing is to get the products on the market rapidly, and we all know
> that. Manufacturing is really an impediment, in a way, something that
> shouldn\'t get in the way of that happening.
>
> And so the industry, in the face of this intense regulation, I think
> has been very risk-averse in introducing new technologies or in
> challenging the FDA standards, because the bottom line was to get the
> product on the market or keep the product on the market. And this has
> sort of played into, I think, the issues around adoption of new
> technologies.
>
> Now, where are we now? That\'s how we got here. Where are we now?
> Well, you know, the drug discovery revolution, which I\'m sure you all
> have talked about quite a bit, has really increased the early
> pipeline, and there\'s really not that many barriers to developing
> candidates, molecular candidates, so there\'s a push at the very early
> part of the pipeline.
>
> There are a lot of ongoing efforts in companies to improve how drugs
> are developed, the pre-clinical to early clinical paradigm, to move
> that along quickly. What we are seeing, I think, is that as the
> clinical drug development time shortens, as there is an emphasis on
> speed, there is less and less attention paid during the clinical drug
> development phase to formulation development, manufacturing process
> development.
>
> Now, all of this we think is feeding into some of the issues I talked
> about earlier, some of the problems that we\'re seeing, so that we
> feel it\'s probably unlikely that the innovator industry will slow
> down drug development in order to get their formulations finished, and
> so forth, and perfect. So what we really think is needed is some
> innovation in manufacturing process R&D, introduction of new
> technologies, so when these products come onto the market, we can all
> have confidence that they will perform reliably, and that innovation
> can continue to be incorporated into the manufacturing sector.
>
> Now, the challenges for FDA in this regard are\--and this is our
> challenge everywhere. It\'s our challenge in the clinical area and
> everywhere, in regulating an innovative industry. It\'s how do we
> encourage innovation while ensuring that the quality is maintained.
> That\'s one of our big issues.
>
> We know, or we certainly all hypothesize, I think, that successful
> adoption of new technologies will actually improve overall quality of
> pharmaceuticals, and also probably efficiency, and you\'ll hear about
> this in the presentations. But how do we do that? How do we enable the
> introduction of new technologies while maintaining the quality
> standards? And this is the essential issue that we\'re dealing with.
>
> In particular, in this case, how do we successfully shift from
> empirical, the art of manufacture based standards, to science-based
> standards for manufacturing process quality? How are we going to do
> that? It\'s a huge challenge.
>
> In addition, we need to try to further decrease reliance on
> pre-approval review and on the physical, actually getting in there and
> touching the product and the lines and so forth, not because that\'s a
> bad model, but in fact we don\'t have the resources to do it, and that
> has been clearly demonstrated over the last decade. We are not getting
> in there all the time. So what other ways can we use to evaluate
> quality? And, finally, how to recruit and train a scientific work
> force that would be proficient in the application of these new
> technologies.
>
> Now, today\'s approach, what we\'re going to do, we\'re going to
> present the problem to you from a variety of perspectives and go into
> much more detail, and we\'re going to use Process Analytical
> Technology as an example of new technology. By no means are we saying
> that this is the only new kind of technology that needs to be
> introduced, but we felt that we needed some firm example that people
> could look at to see what we were talking about, and so we\'ll be
> using some process analysis technologies as an example of the kind of
> new technologies that could be helpful.
>
> Our speakers, we\'re first going to have Doug Dean and Frances Bruttin
> from PricewaterhouseCoopers talk about it. Then we\'re going to have
> G.K. Raju, who is from academia at MIT, their Pharmaceutical
> Manufacturing Initiative, so an academic perspective on the study of
> manufacturing processes. Norman Winskill and Steve Hammond from Pfizer
> are going to give you the industrial perspective from their point of
> view, and Pfizer has been adopting some of these technologies, not in
> their regulated lines but in other aspects of their R&D. And finally
> we\'ll have an FDA perspective from Ajaz Hussain, who is the Deputy
> Director of our Office of Pharmaceutical Science.
>
> Hopefully, by presenting from these various perspectives, you\'ll get
> a broad view of what the problem is and also some of the various
> approaches that we might take to this problem. For the Science Board
> specifically, we\'ll be asking you at the end of the day if you are
> able to support our approach and what your comments are on this
> approach. What resources, external, scientific, academic or whatever,
> what resources do you suggest we would draw on to bring this about,
> assuming you do support the approach? And, finally, are there
> additional aspects to the regulation of pharmaceutical quality that we
> should focus on, that we are not adequately highlighting in this
> presentation and approach?
>
> So, with that, I\'ll call on the first speaker.
>
> DR. ANDERS: Janet, do you have time for a quick question?
>
> DR. WOODCOCK: Certainly. Go ahead.
>
> DR. ANDERS: In your third slide, you\--I\'m trying to quantify the
> magnitude of the issue. So you talk about recalls and loss of
> availability of essential drugs. Can you educate us a little bit,
> what\'s the magnitude of this problem?
>
> DR. WOODCOCK: All right. Well, sometimes it\'s difficult for us to
> talk about these things, which is unfortunate. But I think even in the
> era of bioterrorism, for example, there are certain antibiotics and
> other drugs that used to be manufactured, that are in short supply or
> are not manufactured.
>
> One of the contributing factors to not manufacturing drugs is that the
> process, it is felt it would be so expensive to bring those processes
> up to the modern standards, do all the validation and all the other
> work that is required to be done, that companies abandon the
> manufacture, abandon that product. And so we get into situations where
> we have more single-source manufacturers, where we have manufacturers,
> we have products where people abandon the manufacture.
>
> DR. ANDERS: Is it 5 percent of the drugs that are recalled, or 50
> percent?
>
> DR. WOODCOCK: Oh, you mean what is the relationship of recall to
> manufacturing problems?
>
> DR. ANDERS: What\'s the magnitude of this problem? And then, again,
> the loss, I guess you just now addressed the loss of essential drugs
> that a manufacturer may say, \"Well, I\'m going to quit making this
> compound,\" and so we have one provider.
>
> DR. WOODCOCK: Right.
>
> DR. ANDERS: But what\'s the recall? What are recall numbers like?
>
> DR. WOODCOCK: We can get you the numbers. They have been rising over
> the past few years, but that\'s only one aspect. Let us go through the
> entire presentations, set of presentations, because that\'s just one
> facet of this problem.
>
> I\'m not saying that manufactured pharmaceuticals are of low quality
> now. That\'s not really the issue. All right? But getting into
> problems that lead to recalls and other shortages and so forth, that
> represents a problem, a system problem, you know, and we are
> constantly dealing with that. We\'re dealing with shortages that are
> generated by different manufacturing problems. I can tell you that we
> are constantly dealing with this. And I can\'t give you a figure, like
> how often it happens, but it\'s a constant theme that the FDA has to
> deal with.
>
> All right, we\'ll move on to the first speaker.
>
> DR. DEAN: Good morning, everyone. My name is Doug Dean. I am from
> PricewaterhouseCoopers. I\'m based in Basel, Switzerland. And I am not
> an accountant.
>
> You\'re going to get a double act this morning. I\'m here with my
> colleague, Frances Bruttin. Together we have been working in the
> pharmaceutical sector for a number of years, myself for about 25 years
> in pharmaceutical manufacturing, and we\'re going to share with you
> some of the observations that we have had working with our clients all
> over the world for the last decade or so.
>
> And I really like this image to start with, because I think it sums up
> where we\'re coming from. It\'s a combination of cost, time, and
> regulation. Before we get into this, I\'d like to just declare some
> biases here and make sure that you understand the perspective that
> we\'re coming from.
>
> First and foremost, we\'re engaged by our clients to solve business
> problems. This typically means looking for ways to improve the way the
> business operates and generate greater return to shareholders. We\'ve
> been doing this exclusively in the manufacturing sector, largely
> looking at new processes, new ways of working, and new systems to
> support those ways of working for the past decade or so, primarily
> focused on working with R&D based large pharmaceutical manufacturing
> organizations.
>
> I think what we\'d like to shortly talk to you about today are the
> perspectives that we have seen in the past decade and the conclusions
> that we\'re reaching, basically that the way things currently are in
> the sector and in the industry is something that can\'t be sustained
> going forward. I think we\'ve already heard from Janet this morning a
> couple of comments about the state of pharmaceutical manufacturing in
> general, and I\'d like to emphasize that. Compared to other sectors,
> the capabilities and the state of pharmaceutical manufacturing is
> actually quite poor.
>
> We are going to show you how the way that we traditionally go about
> measuring our performance in manufacturing actually hides the
> opportunity for improvement, and we need to consider some different
> ways to measure it. The infrastructures that we put in place to
> support the need for the regulations that we have to work within tend
> to be not very economically feasible.
>
> So there\'s opportunities there for improvement, and that through the
> introduction of new technologies, but I think critical to emphasize,
> technologies that are not put in in isolation. And I would like to
> draw that point out very clearly today.
>
> And we will conclude by showing you that there is a massive potential
> for win-win, both for the consumers, for the industry, and for the
> shareholders, chiefly through four different aspects here. We\'re
> going to show you how we can reduce risk; increase the effectiveness
> of our ability to be compliant with the various regulations that we
> have to deal with. In so doing, we will show how it\'s possible to
> dramatically reduce cost in manufacturing; and by doing that, to give
> some increased return to the shareholders.
>
> And these things combined together, then, are going to create a win
> for the regulators and the consumers and a win for the business, and
> we\'ll show you how these things are strongly linked.
>
> I think it\'s important to understand the environment that we are
> currently working in. I mean, here big pharma. If we look at what has
> happened in the industry over the past 30 years, we\'ve seen a
> dramatic decline in growth, from double-digit growth 30 years ago to
> what seems to be a level of growth in the market that\'s leveling out
> at about 6 percent per year. Every economist has got a different
> opinion, but when you talk to them, they are generally in agreement
> that the industry will continue to grow in an environment of about 6
> percent per year.
>
> If we look at the total annualized return to shareholders over a
> five-year period, and look at that over the last number of years,
> it\'s been steadily declining. It\'s the investment from the
> shareholders that provides the capital to grow the business, to look
> for new products, so it\'s important that the shareholders do get a
> return. But I think it\'s important to draw out here that in this
> environment of reduced growth, there has been reduced return to those
> shareholders.
>
> If we look in the engine room of the industry here, the innovation and
> the discovery and bringing to market of new drugs, we\'ve seen a
> dramatic fall-off overall in the productivity in research and
> development. We as an industry are pouring tens of billions of dollars
> into research and development but we\'re getting less and less out of
> it, measured in terms of the number of NCEs or NMEs that are brought
> successfully to market each year.
>
> When we are bringing new drugs to market, what we\'re finding is that
> over the past 30 or so years there has been a dramatic decrease in the
> window of opportunity that we have to get a return on that massive
> investment. So decades ago one could enjoy a window of therapeutic
> exclusivity on the order of years, but lately we\'ve seen that
> shrinking down to a matter of months or even weeks. So bigger
> investments, market growing more slowly, less opportunity to make a
> return on those investments, emphasis on time, time, time, get to
> market more quickly.
>
> When we look in more detail at manufacturing in general, and I would
> say this is across the board in virtually every dosage form, whether
> we\'re talking about active ingredients or secondary production, we
> generally see that the levels of asset utilization in the sector are
> very, very low, typically about 15 percent. But because of the way
> that we measure the way we use our assets, we often fool ourselves
> into thinking it\'s a lot higher, and I\'ll draw this out more clearly
> for you later.
>
> We tend as an industry to accept the fact that we\'re going to have to
> throw away 5 to 10 percent of everything that we produce, or we\'re
> going to have to rework it, and we plan it in.
>
> It typically takes, in a new product introduction environment, a good
> deal of time to actually get the scaled-up commercial level processes
> effective, working to the levels that we would like them to work at,
> and this is taking far, far too long. And it\'s basically accepted, I
> would say.
>
> And as we\'ll show you, very typical across the board to see a total
> cost of quality approaching 20 to 25 percent in some cases of period
> costs in a given pharmaceutical manufacturing plant, and this is
> accepted as being just the way it has to be in the business. So
> that\'s the environment that we find ourselves in.
>
> Conclusions here is, it\'s tough and it\'s going to get tougher, so
> there\'s going to be an increasing, an intensification of competition
> within the business for resources. So if we\'re asking for capital
> investment to improve manufacturing, well, R&D are asking for more
> capital as well, so we have to have and be able to demonstrate a very
> good return on that investment.
>
> And I think the other key conclusion here is that manufacturing has
> been really regarded as a Cinderella function in the industry, the
> poor stepchild, and there has been a \"cause no problems\" mentality
> which has really led to what I can only characterize as benign neglect
> of the need for higher and better performance in manufacturing
> operations. Steven Wheelwright did a number of studies showing that
> manufacturing as a function has to stop being internally negative or
> internally neutral and become an external supporter to organization
> strategy. So manufacturing is going to have to contribute more than it
> currently is.
>
> Now, when we start looking at why is it like this and where do the
> problems come from, we find that actually the problem happens
> downstream. It happens, begins to happen long before we ever get to
> commercial-scale production. We find that processes are transferred
> into manufacturing that are in most cases not well understood, and in
> many cases are not capable at the scales that we have to manufacture
> at. They are capable in laboratory or at clinical scales but not at
> commercial scale.
>
> We find that the emphasis and the focus on new product introduction
> has resulted in masses of data that are going into the CMC section,
> but somehow we are missing a lot of critical information that helps
> people to actually understand the processes to be able to operate them
> effectively in a production environment.
>
> We have done a number of studies that have showed that long before we
> get to Phase III clinical trials, approximately half of the
> manufacturing costs are already locked in, and therefore we\'re not
> able to do anything about it in terms of reducing them when we finally
> do get to production.
>
> And, finally, we find that there is little basis, little scientific
> basis to take a decision to trade off the pressure to get a new
> compound to market more quickly, to trade that time off in exchange
> for maybe a month or two more to spend more time understanding the
> process in order to enjoy the benefits of increased quality
> downstream.
>
> Just to give one example here, a client that we worked with a number
> of years ago, a very simple example, this is an emulsion product. The
> critical quality attributes relate to the size of the droplets in the
> emulsion, and it\'s measured in an in-line process environment by
> shining light through and looking at the degree of absorption of the
> light.
>
> And there were some upper and lower control limits set on this process
> in order to get the emulsion the way that it should be. The usual
> validation studies were done, three batches at exactly the middle of
> the upper and lower bounds there.
>
> The problem was, the process was not well understood, and in fact it
> had been noted earlier in clinical manufacturing that the function of
> absorption as a function of the control parameter created a situation
> where we were actually out of limit in one of the quality attributes,
> but this was somehow not understood in transferring the process to
> manufacturing.
>
> So we\'ve now got a situation where we have a process in
> manufacturing, we\'ve got an upper and lower control limit, we have
> operators who are doing their best to keep the process within those
> boundaries, but it\'s fundamentally flawed. Even though we\'re within
> those boundaries, we\'re still producing a product that does not meet
> its quality attributes and will have to be scrapped or reworked.
>
> What we\'d like to show you, and I\'ll turn over to my colleague
> France Bruttin here to take you through this, three key things here in
> order to start to address this problem.
>
> One is that in looking at manufacturing operations, we need to clearly
> understand where the value-adding activities are and where the non
> value-adding activities are. We find that non value-adding activities
> add cost and time but they don\'t add value to the product.
>
> We\'ll take you through one or two examples that show how, as an
> industry, our traditional approach to measuring performance in
> manufacturing hides the potential to improve and reach higher levels
> of performance that we really need. So as a non-accountant, I can
> blame the accountants for this, and we\'ll take you through some of
> that.
>
> And we\'d like to show you some rigorous approaches that are being
> used in other industries to apply a more rigorous and scientific-based
> approach to determine the ability of a process to be right the first
> time.
>
> I\'ll turn it over to my colleague Frances Bruttin now to take you
> through this. Frances?
>
> MS. BRUTTIN: I think, building first of all on a point that Janet was
> trying to bring across, where she was saying that the manufacturing,
> the pharmaceutical manufacturing tend not to be taking opportunities
> of the new technologies and the innovation and bringing them into
> their daily work hangs around them being adverse to change, hangs
> around them being afraid of bringing change into the manufacturing
> process because of the impact with the regulators and the amount of
> paperwork that they would have to go through, so they prefer to stay
> with today\'s inefficient processes and ways of working and continue
> to get the product out the door.
>
> I think we are going to tell you a little bit today that it goes a
> little bit deeper than that; that in reality, within the basis of
> manufacturing, there are a lot of inefficiencies, there is a lot of
> emphasis on trying to test quality in and prove quality, whereas if we
> take a few steps back and go back to basics, there are some
> fundamental things that we can change, and we will get quality and
> regulatory compliance out as a consequence. So I\'m going to take you
> through some of them.
>
> First of all, if we look at what actually happens in the plants and we
> distinguish between value-added activities and non value-added
> activities, this is an example of a dispensing process. The process
> actually takes three days to be completed. Of those three days, 1
> percent of that time is actually value-added. That is the weighing of
> the material before it goes into the hopper or the dispenser. The rest
> of that time is dedicated either to transportation of material;
> scanning in bar codes. It\'s waiting while the QA come back with the
> results of the bar code. It\'s moving the pallets from one area to
> another area. So over three days, 1 percent of all that time is
> actually value-adding.
>
> If we take all of the subprocesses that make up the process from the
> raw materials to finished goods, the actual value-added time as we go
> through dispension, granulation, compression, coating, and packaging,
> over a 35-day process, three days are actually value-added. And these
> are real numbers. These are numbers from the studies that we have done
> actually in the shop floor, on the factory floor.
>
> To make it a little bit more realistic, we\'ve actually taken photos
> of where these delays can be observed. what we have here is, after
> dispensing, the material is actually stored. In this case it was
> actually in the alleyways between the various different rooms where
> the production processes were taking place. So here we have delays.
> They were staying here for maybe typically five or six days.
>
> Work in process, again, waiting until the next piece of equipment was
> ready; waiting for results coming back from QA for the in-process
> controls. Again, all this material is captured, which has been held
> up; it\'s work in progress.
>
> And a very typical photo of what turned out to be 100 percent
> inspection. There was a problem here with the blister pack, and so
> these ladies over three shifts for a period of two or three weeks did
> 100 percent inspection for a single batch. This is non value-added
> activities. This is not contributing to the quality of the product,
> and it\'s certainly not contributing to the health of the final
> patient.
>
> If you measure what is actually value-adding and non value-adding, and
> the way we do this is through an activity-based analysis\--so we look
> at what the people are actually doing, we\'re looking at what is
> happening to the product as it moves along the process\--you can
> identify those processes that are not actually adding value, you can
> reconfigure them, and you can make a much more effective manufacturing
> process. The best we have seen is about 50 percent. That means the
> ratio between non value-added activities and value-added activities is
> 50-50. So in this example it is possible to go through the entire
> manufacturing process in 6 days as opposed to 35 days.
>
> So value-added/non value-added is one aspect. The next aspect\--and I
> have to say this is probably due to our colleagues accounting\--is how
> we measure the effectiveness or the output of a factory. We use
> standard accounting methods. This is also driven by the various MRP
> systems that have been in place. We talk about standard costs. We talk
> about standard utilization.
>
> This is typical of what you will see. For asset utilization, what is
> defined as the total availability of an asset? We have here 80 hours a
> week. That represents two shifts per day, and there is of course the
> scheduled downtime and the scheduled conversion time. But since the
> accountants know that there are traditional losses and other expected
> losses and delays and waits, then they also schedule in a certain
> amount of time that they know will not be operational. Because they
> schedule it in, it\'s planned in, so suddenly we lose visibility and
> transparency of it.
>
> So the people who come later say, oh, well, the allocated operational
> utilization is set at X percent. That X percent has already taken in
> the fact that the actual equipment is sitting idle. And therefore if
> they hit 90 percent of that X percent, they feel they\'re doing a good
> job.
>
> If we look in reality at what is happening\--and remember these assets
> that we have, we have capital investors in those assets, so those
> assets are alive, let\'s say, 24 hours a day, 7 days a week, 365 days
> a year. So when we\'re calculating asset utilization, we should be
> calculating it on that basis. So instead of it being 80 hours a week,
> it\'s actually 160-hour-a-week availability.
>
> If we then look, we find out that we have quite a high percentage
> which is unscheduled downtime, so downtime due to problems on the
> line, due to problems on line switch-over. Then we have operational
> time losses which are due to, in some cases to poor planning; to
> delays, again, delays with suppliers, delays with other material
> coming in. And then which I think is actually quite sad, when we look
> at what we\'re doing with our machines, we\'re actually spending quite
> a significant amount of time producing scrap, i.e., all those batches
> that do not meet the quality control that we\'ve set on them, or
> reworking that scrap.
>
> So at the end of the day, the actual effective up time is actually a
> very, very small percentage. From our studies this has come out to be
> around 15 percent asset utilization.
>
> So we\'ve looked at value-added versus non value-added, we\'ve looked
> at the difference between measuring for accountancy purposes and
> measuring for performance. So some people may be saying now, \"Well,
> that\'s fine. I can blame the plant manager on all of that. This has
> nothing to do with our scientific approach to manufacturing.\"
>
> Let\'s get to the main point. The main point is around the
> pharmaceutical process. We have been arguing that this process is not
> well understood. It\'s not well understood when it\'s transferred from
> R&D over into manufacturing. And what we have here is a way of
> measuring the processes, a way of comparing processes from one process
> to another. Obviously it\'s sigma. It\'s not rocket science. It\'s
> based on standard deviations.
>
> It is a measure that has been used in various other industries. For
> example, if we start from manufacturing, Motorola and Siemens, around
> consumer electronics, but also in service industries, GE Capital, so
> for people who provide financial services, and also Caterpillar. So
> it\'s a way of measuring lots of processes, not only the
> pharmaceutical process but all the processes, so the steps that people
> go through to support manufacturing, how people take those let\'s say
> manual steps, how they started, and how repeatable those processes
> are.
>
> What this lets us do is see how well we are performing, see how
> repeatable our processes are through the plant. Obviously a higher
> sigma value indicates better performance. If we look here in terms of
> defects a 2 sigma process has around 300,000 defects; a 6 sigma
> process has 3 defects. This is what you may have heard about in terms
> of zero defects manufacturing.
>
> If we see where the various industries are, semiconductors are between
> 5.5 and 6. Baggage handling in airports is a 4 sigma process. So where
> do you think pharmaceutical manufacturing is? Probably if I asked a
> CEO, he would tell me, \"Yeah, we\'re somewhere between 4 and 4.5.\"
> Some people are saying uh-uh. We\'re actually about 2.5 consistently.
> Consistently 2.5.
>
> Two ways of seeing this. You can measure the actual processes, and you
> come up with a 2.6, 2.5 measurement. Or you look at the cost of
> quality, or should I say the cost of poor quality. There is a direct
> correlation between the two, and as Doug had previously mentioned, we
> are all the time coming up with somewhere between 20 to 25 percent of
> period costs are costs that are related to poor quality, not only the
> costs for the QA and QC function, but it\'s the costs of rework, it\'s
> the costs of scrap, it\'s the costs of prevention appraisal, 25
> percent.
>
> Obviously everybody here understands standard deviation and sigma, but
> just very briefly, obviously there\'s two aspects that you\'re trying
> to control. One is the deviation around the particular process,
> between its upper and lower limits, so the spread. And the second is
> the ability to maintain the particular process between those limits
> over time, so the shift. So what you want to do is obviously keep the
> process with precision and with accuracy.
>
> Now, if we take all of these together, what does this mean for the
> pharmaceutical manufacturer. Well, one point is, obviously it\'s unit
> costs. Taking these four together, we can have a dramatic influence on
> bringing down unit costs.
>
> We start off by material costs. Obviously the reduction in scrap and
> waste, I think Doug mentioned is between 10 and 15 percent, so you can
> immediately reduce that down to I think somewhere\--2 percent is the
> max in terms of scrap and waste.
>
> With the reduction of non value-added activities, there is obviously a
> possibility to reduce the period cost. Part of this is reducing those
> costs of compliance, so reducing the amount of internal and external
> failures, and then once you are confident with the high level of
> quality you\'re getting out because you know your processes and they
> are highly capable, you can then reduce the amount of money that
> you\'re actually spending on prevention and appraisal.
>
> On the other hand, your efficiency is going up because you\'re
> increasing the process yield due to the less amount of scrap, and your
> plant volumes can go up. Why? Well, if we look at the argument around
> non value activities, previously that process was taking 35 days.
> It\'s now taking 5 days. If you can absorb the capacity, you can now
> do five runs in the time it was taking you to do one run previously.
>
> So the net result of this, if you address these factors, is it\'s
> possible to significantly bring down the unit cost of production.
>
> Let\'s shoot forward to , I don\'t know, five years, to the company
> that is performing, that\'s outstanding, that\'s leading terms of
> pharmaceutical manufacturing. They are operating at a 5 sigma level,
> so what does that mean?
>
> Well, their quality and compliance costs are down to somewhere between
> 3 and 5 percent. The unit cost of production is 60 percent lower than
> the competitor\'s, who are still operating at 2.5 percent because they
> weren\'t at this presentation today. Cycle time has gone down to 5
> days, so obviously their productivity is up, their yield is up.
>
> And this point, again, newly introduced processes are effective
> immediately. We saw again when Janet showed that slide with the number
> of supplements that were coming in, that\'s all the\--the process has
> been transferred from development into manufacturing, and then we
> tweak it. We get it a little bit better and a little bit better and a
> little bit better, and we blame those people in development because
> they didn\'t give us the right process.
>
> What we\'re saying is, if you can use process capability and 6 sigma
> concepts already in development, so that you know that you understand
> the process, and the process is capable and is able to stay within the
> limits that you have set, you can pass this then on to manufacturing,
> who then know that from day one that process is effective. They can
> then do some fine-tuning, but you shouldn\'t be seeing all of these
> supplements because the fine-tuning is based on a statistically stable
> process which development and manufacturing understand.
>
> Key enablers to make this move? First of all, I think I would really
> like to focus on process understanding, understanding what is
> happening in the process. Second point is understanding the parameters
> that influence that process, those parameters that you are going to
> measure, those parameters that you are going to control to keep that
> process within the defined limits. The process capability hurdle is
> already in development to ensure that the processes that manufacturing
> get are actually effective and capable from day one. Obviously
> technology is a huge enabler in this area, as well.
>
> And just some examples, we\'ll hear more later from my colleagues:
> Near infrared analysis of raw materials and in-process controls;
> continuous high-volume microwave sterilization; on-line measurement of
> variables, and supported by sigma tools, so you know exactly where
> your process is.
>
> With these technologies there is also a need for encompassing
> enterprise technologies. So, for example, once you have all of these
> points, they need to be integrated into electronic batch records, so
> that again you\'re not wasting time waiting for the results to come
> back from QA or putting the whole batch record together manually.
> There is no point of having these technologies in place and then
> taking the paper results and pasting them into your batch record. And
> I won\'t even go near 21 C.F.R. 11 at this point.
>
> And then finally, obviously, electronic document management solutions
> to enable you to share information between development and
> manufacturing. And, oh, yes, the thought of the manufacturing people
> being able to contribute early into the development of the CMC
> section, before it goes in for the submission, rather than achieving
> that as it\'s thrown over the wall from development and being forced
> to live with consequences of what happens in development.
>
> So what\'s the upside of this? All of those elements contribute to
> something which we call the compliance infrastructure, the
> organization, the people, the procedures, the policies in place to
> ensure compliance with internal quality management systems. Let\'s not
> forget that we\'re doing this to ensure the quality of the end
> product. And the second point of compliance is with the regulators.
>
> What this can do is fundamentally shift the cost of compliance curve.
> What we see, the blue curve is where it is today in terms of your
> typical 2 sigma performance. By bringing in these new changes, you can
> move that curve down to 5 sigma performance, and you immediately get
> direct cost recovery but you also get a compliance gain.
>
> What does this mean for the industry? Well, in a win-win situation the
> industry will be moving not only towards quality to meet the
> regulatory needs in terms of, if we take point 3, if that was the
> paradigm, then point 3 would be going straight up. But here what we
> want to do is a balance the need for quality and the need for
> productivity. So in the move of moving from 3 sigma to 6 sigma in
> terms of doing the right thing right, we get quality and we get
> productivity, so we end up with a win for the regulators, a win for
> the consumer, and a win for industry.
>
> So, to summarize, the industry needs to measure for productivity and
> not for the accountants. The solution is not just a collection of
> technologies. It\'s more complex than that,. And there is a win-win.
> The economics of compliance, where is the point on the cost of
> compliance where there is a win for the industry and a win for the
> regulators and the consumers?
>
> Thank you.
>
> DR. WOODCOCK: Perhaps we can hold questions as we go through, if
> that\'s okay with the Board. If you have specific questions, perhaps
> you would like to ask them now, or clarifications. Otherwise, we\'re
> going to have a long discussion period.
>
> All right. Thank you. Now, the next speaker is Dr. Raju from MIT, and
> he is going to talk about pharmaceutical manufacturing from an
> academic perspective.
>
> DR. RAJU: I\'m going to try to follow up on a number of things. What
> I\'m going to try to summarize in the next half an hour or so is a set
> of research activities we have done within the MIT Pharmaceutical
> Manufacturing Initiative. We are a technology university and a
> business university, and so we try to use some of those skills to try
> to understand the opportunities and communicate them to society, the
> regulators, and the companies who fund a large fraction of our
> research.
>
> The purpose of the Pharmaceutical Manufacturing Initiative is to
> describe and capture the opportunity to improve pharmaceutical
> manufacturing. Let me see what that means. What that means is, if this
> were the pharmaceutical industry, and the industry and the
> academicians are focused on many different aspects of it, we\'re going
> to choose to focus on this aspect of it. And really it\'s very rare to
> focus on that aspect, and that\'s going to be the subject of my talk
> for the next few slides.
>
> This is something that has been the course of many years of working,
> and we have had a chance to work with almost every brand name company,
> a large number of biotech, and some branded generic companies as well,
> and so over the years we feel we have had a reasonable set of
> experience base that makes us feel that maybe we can begin to make
> some conclusions.
>
> We were very excited to start this manufacturing initiative at MIT,
> and if this was our goal, it seemed like a good place to start is to
> find out what pharmaceutical manufacturing really was. So we went
> around to the vice presidents of manufacturing, to the companies, to
> society, to each other, and said \"What is manufacturing, what is this
> piece here?\"
>
> We were all excited. What we saw was something very different. What we
> saw was an organization that was told, \"Don\'t be on the critical
> path.\" \"You\'re not as important as R&D.\" \"You\'re a cost.\"
> \"Don\'t stock out.\" \"Be sure you do it the same way you told us for
> the next 12 years, and show compliance, and we\'ll come every couple
> of years to your plant when we can to see how well you\'re doing.\"
> And that\'s the investigators, as well.
>
> From a society, from the rest of the organization, there was a message
> that says, \"Just don\'t screw up.\" \"You\'re a cost center.\" And I
> can\'t think of anything worst for somebody to tell me, because it
> means I don\'t add value to society. The vice president of
> manufacturing says, \"How can I win?\" And the definition of a win
> almost seems nonexistent.
>
> The result of that shows up in the implementation of the technologies,
> and we\'ll show you some of the consequences and some of the
> opportunities of those technologies as we go forward. But if this was
> pharmaceutical manufacturing, then either starting this initiative at
> MIT was something we shouldn\'t have done, or maybe this problem,
> so-called defensive mind set, is really the opportunity.
>
> And we said yes, that\'s what it is, let\'s try to understand why,
> let\'s try to understand the drivers of the system, let\'s get to the
> common things of science and technology, and then we\'ll change the
> results that come out of the system. We then brought a significant
> number of vice presidents of manufacturing, who all said \"How can I
> win?\" and said \"Let\'s all get together. Let\'s begin to formulate a
> winning strategy.\"
>
> This is for the MIT Sloane School of Management, which has a very
> leading management of technology program, the Department of Chemical
> Engineering, and the Department of Industrial and Physical Pharmacy.
> Although disputable, the Business School, Chemical Engineering School,
> and the School of Pharmacy are rated to be one of the best in their
> disciplines.
>
> And we said, here is a set of vice presidents who are trying to figure
> out how they can win. Science we think should help society, and
> science could be a win-win situation. Let\'s begin to listen to their
> concerns. Somewhere along the way, since this is a regulated industry,
> we will have to figure out what we do with the FDA, but let\'s keep
> them in the equation. Let\'s figure out what we want to do, what the
> opportunities are. And somewhere along the way we\'ll start talking to
> the FDA, when we feel we are ready, but we have said we\'ve got to do
> it sometime. And I have been fortunate to be involved in all those
> three different disciplines through formal affiliations.
>
> If that was that tiny little box that we call pharmaceutical
> manufacturing, and we all want to analyze it together to understand
> why it looks the way it is, let\'s standardize on a few boxes around
> that box. And if you think of pharmaceutical manufacturing as this 12
> to 15-year process, sometimes more, sometimes less, over time when you
> have lab scale, pilot scale, and manufacturing scale work being done,
> and over space where you have the chemistry or the biology of the
> system done in the active ingredient, then the dominant physics around
> the components, and then the pill finished, and then the packaging
> which is the paper around it.
>
> And if we say let\'s look at this over time and see what decisions we
> make, and over space and begin to understand why, and figure out if
> there is a win-win, what is the role to transform pharmaceutical
> manufacturing, we said those are the boxes we\'re going to talk about
> for the next few slides. What aspects of those boxes should we talk
> about today? And we said, let\'s draw a big box around all those boxes
> and say, let\'s look at pharmaceutical manufacturing and discuss it in
> one of those dimensions of performance.
>
> Now when we talk about cost, that\'s going to be sensitive. When we
> talk about quality, between the regulator and the regulated there are
> different perceptions of cost and quality and the reasons for them.
> Safety is something that\'s universal. I think everybody is doing very
> well there.
>
> And among these choices, I will decide to choose to talk about time
> because it means the same thing to all of us. We all have the same
> watch. It\'s neutral. The cultural aspects, the accounting aspects,
> are something that we can deal with within our companies. And so the
> rest of my talk, I\'ll focus on time, but a lot of my work involves
> cost and quality as well. We can\'t do it all. Let\'s focus on
> something that we can all have a win-win on.
>
> So let\'s take the simplest possible step, blending and blend
> uniformity as a central performance measure of that simple step
> that\'s supposed to take five minutes. And being a chemical engineer
> who comes from the fermentation area, when I began to focus on this
> five-minute step, I was really disappointed because it\'s such a
> simple step and we worry so much about it. I wanted to find out why
> and I wanted to find out what the opportunities were.
>
> So the focus is only on this tiny step as an example of the
> possibilities over time. We look at blend process development from
> here to here and say, off-line, today\'s technology, versus on-line,
> tomorrow, day after tomorrow\'s technology. Where is the win-win? What
> is it? What\'s stopping us now? What can we do about it?
>
> First, it didn\'t seem like it was the technology itself. We were
> fortunate, we had a professor from the Mechanical Engineering
> Department who said, \"Here is light, here is lasers. Let\'s shine
> them in through the blender, and I think through the window you can
> look at uniformity as well as that piece that you\'ve been using for
> so many decades because somebody put their hands into the blender that
> way.\"
>
> So this is MIT\'s duct tape technology here, not necessarily
> FDA-approved, on a pilot plant, through a window looking at blend
> uniformity. The decision is a very simple one. The question is a
> simple one that says, \"When are we done blending?\" which is \"When
> is the relative standard deviation or the signal at the end below some
> number?\" And the number is 6 percent, 5 percent, 4 percent, depending
> on where you draw the line.
>
> But if that was the simple question, the answer was not very
> disputable. We could do it very reliably, depending on where you
> start, what the technology is. LIF, one of our inventions, together
> with NIR, something that brought up together, and a lot more
> analytical technologies can do this very well.
>
> The technology was easy to develop, relatively\--is pretty well
> developed today. This is an opportunity for us to do something about
> it. Now what? We have something with duct tape in our labs and some of
> our plants. Who are we going to start talking to? What do we compare
> it against?
>
> And the obvious question that says, compare it against what you have
> already, and that is the thiefing assay that I told you about, these
> rods that are put into the blender and then samples taken out
> physically. We know it\'s the thieving itself that drives the
> variability rather than the on-line sensor.
>
> And then we say, \"Can you compare the on-line sensor with the
> off-line sensor for different active concentrations to determine end
> point? It\'s clear that on average, you can. It\'s clear that the new
> technology is less variable than the old technology.
>
> The question then is, do I still have to use that as a benchmark to
> prove my new technology, when it\'s the old measurement that\'s the
> problem? If it is, then I\'m going to have to collect a lot of data,
> not because it\'s a blend uniformity problem but because I\'m
> comparing against an old measurement technology where the measurement
> is the problem.
>
> The question then is, how do we begin to formulate if this is the
> right strategy for us to go forward, or we should look at the process
> and the product uniformity, which is really what CGMP should be all
> about, and we all agree it is.
>
> So what? We have a sensor, developed pretty quickly, that\'s mountable
> technologies that are similar, can do the same thing, may be less
> variable. Let\'s figure out that it means something to all of us, as
> otherwise it\'s not worth a purely scientific exercise.
>
> Let\'s define cleaning. Cleaning, yes, it\'s that five-minute step,
> but it has a lot of steps before and after it. If we want to
> understand \"So what?\" we want to understand what the consequences
> are on the two sides.
>
> Blending really has these different unit operations where you clean a
> blender, you load a blender, you mix, you sample, you transport to a
> lab, and then you have a result and a decision here. You can be
> undermixed, mixed, or then you have to discard it if you\'re
> overmixed, and this is a new phenomenon that is quite well described
> within the industry, called segregation. You can actually overmix
> something.
>
> The point being that while the physical process here of making
> something is here, the information process of measuring whether you
> have succeeded is far away in another functional department. When the
> material process is disconnected from the physical process, what is
> the space between the two called? It is called inventory. That\'s the
> difference between the material process and the information process,
> and that\'s why we have all these inventory levels.
>
> So if we were to transform from on-line to off-line technology, we
> have to get the information and the material flow to be in the same
> place. And so if we can get the on-line sensor onto the blender, on
> that simple operation, we can change the business processes that were
> talked about in the previous presentation, and we can put material
> information flow on the same place. We can not only do that, but once
> we know when to stop the blend, we can start figuring out what to do
> about variability within the blends.
>
> And so we said, \"This looks like it\'s important. It looks like it
> could make a difference. Let\'s try to figure out how big a difference
> it is, because the bigger the difference, more likely we would want to
> do it, more likely we are going to start communicating, more likely
> we\'re going to start sharing data.\"
>
> And so we said, \"Let\'s capture all of those steps,\" the blending
> steps that I told you about, the cleaning, the charging of the active,
> the blending, the sampling, the QC, the decision, and the retrieving.
> \"Let\'s capture all those steps, collect data from all these
> companies.\" We have a consortium, so we have a basis to collect data.
> \"Let\'s try to figure out how we do it today and then ask how can you
> do it tomorrow.\"
>
> This, for example, charge active can be modeled by each of its steps.
> You clean the blender and then you load the blender. You can then go
> inside the QC lab, and you can see you transport to the QC lab. You
> hold in the QC lab, you retrieve in the lab. You then prepare, test,
> and analyze. And then you have the people in the lab, and they\'re all
> busy moving from here to there trying to do a measurement of product
> uniformity based on this old technology.
>
> Let\'s look at process development of just blending, now, just blend
> process development versus the old technology versus the new, and say,
> let\'s say that in that day, January 1, 2000, when we celebrated the
> new millennium, we continued, and we do, to use the old technology.
> How long will it take for us to actually get a good blend, based on
> today\'s industrial practices?
>
> And so we start the blend process development process, and you can see
> the blending taking place, the sampling taking place, going to the QC
> lab, a decision being made. Is it uniform? Is it blended? You then go
> to the lab and you have a different organization figuring out whether
> to approve it or not.
>
> The arrow there indicating we just got our first blend below the RSD
> specification, and we\'re so excited. We look at our date, and it\'s
> the 4th of January in the morning. We started on the 1st for this 5,
> 10 minute operation. Now I\'ve got one. There\'s this thing that says,
> if you can get three in a row, you\'re all set for the next 12 years,
> or at least the interpretation of it that says\-- one, I\'ve got two.
> All of a sudden we\'re not getting the third. But I got the third.
> It\'s now five days in. I go into my lab and I look at what everybody
> is doing.
>
> Now you can look at what people are doing, and if it\'s red, it means
> that they\'re very busy, all your QC people. Now they\'re really busy,
> and they\'re really busy moving the samples within the lab to figure
> out if it\'s uniform. Because I\'m not sure this one is going to pass,
> I\'m going to take a few extra samples.
>
> Since most of our analysis is based on wet chemistry rather than
> something you can do in the process, and most of our products are
> solids, you have a whole bunch of wet chemistry based HPLC equipment,
> red, indicating that they\'re very busy. We have a lot of busy
> equipment and people in the lab, and since we\'re not sure whether
> we\'re going to succeed, a lot of material information leads to a lot
> of samples waiting in the lab, right there.
>
> You can go down to our plants, not just the lab, and you can say,
> \"What are the operators doing?\" Fairly busy, not fully busy, because
> they finished their part. They\'re waiting for what to do next.
> Blenders waiting to figure out what to do next, because they don\'t
> know the result. The result of information is separated from the
> physical aspect of the actual making. And what is the difference
> between the two called? Inventory. That\'s where the period costs, all
> the costs show up. Now what do we do?
>
> Well, we say we\'ve done three. There\'s this argument that\'s a very
> common one. If you look at the industrial average, 27 percent is our
> cost of goods sold, 73 percent as a result is our gross margin. We\'ve
> done three in a row. We now want to ask the question, should I do a
> fourth? Should I do a fifth? That would become the trade-off of time
> versus cost versus quality\--
>
> CHAIRMAN LANGER: Can you use the microphone?
>
> DR. RAJU: \--versus cost versus quality. The question, the common
> response to that is no. I\'ve done three. I pretty much understand our
> process, given the technology that I have. It\'s now five days
> forward, and I\'m going to go forward to do this for the next 12
> years.
>
> Now, during the next 12 years you have another argument. It\'s not a
> time-to-market argument now, if you\'ve been approved. It\'s now a
> cost of changes and a cost of supplements argument, and there you have
> this so-called cost of supplements and paperwork argument that I\'ll
> talk to you later. But before we go into manufacturing, let\'s stay in
> process development and do it right, and go back to the same date of
> January 2000 and see if we might learn something.
>
> So let\'s go back to January 1, 2000, the same date again, and say
> this is exactly the same, exactly the steps. I\'m not cheating here.
> Charging the active, loading, and cleaning. It\'s exactly the same
> date. No practices around changed. Nothing changed around cleaning,
> nothing changed around sampling. The only thing that has changed is
> you\'re using the on-line sensor that you took a few months or a few
> years to discover, although there is a lot of research that was done
> before it. Let\'s get started and see what kind of a trade-off we have
> across quality, time, and these competing alternatives that make our
> life difficult.
>
> So we start at the same time. It\'s the 1st of January. It\'s still
> the first day, and we just got our first batch. A little bit more than
> a day, we finished two, changing no other practices. One and a half
> days, we finished our three batches.
>
> Now, how much inventory do you think we have? You\'ve redesigned your
> process using technology that gave you cost, quality, and time all
> together. What is everybody in the lab doing? Let\'s look at the QC
> people, red indicating busy. The question then becomes, \"Oh, my God,
> do we need those people anymore?\"
>
> \[Laughter.\]
>
> And then you have the CEO, vice president, saying \"What is the right
> head count? Can you benchmark across the industry and tell me whether
> it should be 20 percent or 30 percent?\" And the opportunity here was,
> when you had the right technology, you didn\'t have to have that thing
> called QC. The same people, instead of focusing on moving samples
> which is a doing job, maybe could think about the blend itself and the
> uniformity self, which is the process understanding job, and maybe
> they\'ll have more fun, and maybe you\'ll keep them a little longer,
> and maybe you can pay them a little more.
>
> You just got three. You\'re not exactly, in removing some non value
> activities, potential for value-added activities, you have a whole
> bunch of equipment that was once busy and now is not necessarily busy.
>
> You now have another question. You know, if it took you a day and a
> half to do three, maybe you can go back to those three and figure out,
> \"You know, I\'ll have a higher standard.\" You can do four and it\'s
> still two days. Take three days, you can do five. You can do six in a
> little bit more than two days.
>
> You now have done twice as many runs, you have done twice as much,
> maybe more, process understanding. You now have a basis to say, \"I\'m
> going to do something I understand for the next 12 years, because I
> chose to open my eyes, to develop some basic technologies.\" What
> would the regulators, to make them understood and communicated? And
> while I think we all want together, because actually my uniformity may
> be better, my measurement is certainly better; I may be faster, I am;
> I might be cheaper, I am. And it didn\'t seem like anybody in this
> overall societal framework lost along the way.
>
> That was product uniformity, and we can keep going forward on that.
> Let\'s skip to the next step, because I want to give you another
> representation as well.
>
> If you were to look at old versus new, by looking at the business
> transformation of these processes based on technology, that means
> looking outward and deciding to work together. We have fundamentally
> changed the performance measures, whether you measure it as cost,
> quality, or time.
>
> I said I\'ll focus on time because it\'s neutral. The impacts are not
> 10 percent; it\'s 10 times in terms of blend process development time.
> This is the old technology where you have one, two, or three blenders.
>
> Whether you do on-line technology versus off-line technology, it is
> not necessarily the factor of 10 improvement. It\'s the variability
> reduction, because the predictability comes when you automated and
> understood and then automated your processes, and there are all on
> that sensor right there, instead of being in a human variability of
> deciding whether it\'s Monday, Tuesday or Wednesday, and whether I\'m
> going to wait until Monday to move my samples to the lab.
>
> But there\'s an investment that has to take place across all of us to
> get this to happen. This is an argument of the potential, that you
> catalyze us to all work together to make it happen.
>
> So this is not 10 percent here. We\'re talking about 10 to 15 times
> improvement in manufacturing. If CGMP is all about variability
> reduction, we get that certainly. To become independent of some of the
> product and organization I think would allow for a lot of
> generalizability beyond.
>
> So we took a little piece called blending, it\'s five minutes, and we
> saw this huge opportunity. That was the opportunity across time.
> Let\'s look at the opportunity across space, and say let\'s look at
> routine manufacturing rather than process development, and say where
> is the time being spent on average, first? And if we look at 6 sigma,
> it\'s about looking at below the average, but let\'s start with the
> average. We have to simplify life. We have to start with averages
> because that\'s one number, a summary of reality at that point.
>
> For the sake of simplicity I will not talk about the active
> ingredients. Since we finished this example, I\'ll focus on this
> example, and we can have so many different products once we decide to
> look at horizontally, and if I choose just a high volume product you
> might say, \"You know, you forgot the others,\" so we look at all the
> different representatives and look at where time is being spent.
>
> If you look at our processes, you\'ll find they look unbelievably
> similar. If I go with the standard set of color coding, blue for the
> process steps and red for the QC testing steps, you\'ll find that we
> measure quality very much at the end. Wow, it takes a lot of time.
> Wow, it was pretty expensive. We don\'t really necessarily measure
> significantly in-process tests in a few places. Very rarely is there a
> feedback loop. We often, if you don\'t feel happy about something, we
> throw it out.
>
> There is raw material testing. While the steps here are all about the
> chemistry, and this is about the physics, most of our specifications
> are around the chemistry, even though we really do physics afterwards.
> That\'s one argument.
>
> The other argument is saying, given this process flow, where is my
> time being spent? And so let\'s draw that same process flow diagram in
> time, and you\'ll find here is where I\'m spending my time, and here
> is where spending my time. And the actual process, as you saw on the
> previous slide, takes a lot less time than the testing itself.
>
> Let\'s look at another process, so that we make sure that I\'m
> representative, and this is the benefits of being in a consortium.
> Looks very similar, testing. Missing here, a lot at the end. You then
> say, let me open that up in time, and then you see time, and you see
> 60 days for just the physical formulating part of it. You see a lot of
> that in testing. And then you expand that out and say, \"Let\'s
> include the API, and let\'s look at the time from the beginning to the
> end.\" And then you say, \"This is close to half a year now.\"
>
> Now, if I was making potato chips and it took me about half a year
> from the beginning to the end, I don\'t think I would like what I get
> at the end. But if it\'s tablets, I think clearly we have different
> kinds of time dimensions.
>
> But somewhere along the way there\'s an opportunity to look at time.
> And half a year may not be necessarily the place we want to be, but
> let\'s look at the drivers behind the time. And before that, let\'s
> make sure we look at complex and liquid products, so that you are
> convinced that we have looked beyond a few examples.
>
> Here are examples of the QC time, which is the process time, in a
> liquid line. Here is the sterility test that totally dominates the
> time. And here is the testing time versus the process time, and if you
> were to summarize them all, in red are the testing times, in blue are
> the process times, six examples. Do they look similar or do they look
> dissimilar? The reds look very similar. The red looks very big.
>
> Now I began to wonder whether I should have called in the MIT
> Pharmaceutical Manufacturing Initiative or the MIT Pharmaceutical
> Testing Initiative, because it seemed like all the time was being
> spent in testing. But is it just testing? What are the drivers behind
> that testing is the next question, because we\'ve got to understand
> why.
>
> And if you look at the drivers under that testing, you\'ll see in
> green is the process itself, and here is the actual test itself in
> blue. But all the red are the manual transfers, the interruption of
> the process, the securing of the samples, the documentation, the
> transferring to the lab, the testing at the lab, so-called non
> value-added processes.
>
> So if we were to develop technologies, it doesn\'t matter whether
> it\'s LIF or NIR, what is it that matters? If it\'s LIF or NIR, it
> would only impact this part of it. What really matters about any
> technology that we would develop is the word \"on-line\" rather than
> the words \"LIF\" or \"NIR\", because those are the ones that drive
> many of these paper operations. There\'s an investment we have to put
> in place to get there. It seems like it\'s quite a doable task. It
> seems like many of the technologies are very much in place.
>
> If you then broke that detail down further, you would find that the
> actual test itself takes 2 percent of the time, and it\'s the paper
> aspects of the preparation before and after that takes 98 percent of
> the time. You\'ve then got to say, what is the technology opportunity
> to deal with these, too? And that will come along the way, but that is
> surely not the high leverage place at this time.
>
> If we were to now summarize what did we learn here, quality testing is
> discontinuous; testing times are large; testing times are more than
> the process times; and it\'s the off-line nature of the test times
> that drives the overall time. The word \"on-line\" is a very important
> part of what we want to do.
>
> Obviously we want to look beyond the average, and that\'s where the
> learning is going to begin. So let\'s look at those same processes
> that I just showed you, those six, and start looking at different
> aspects of the time rather than some average number of that time. And
> you will find that all times are not created equal, and you will find
> that while you will think your cycle times were 25 days or 30 days,
> and that\'s the one I showed you, there is another cluster of batches
> here in different colors that are totally different from everything
> else.
>
> These are the so-called exception batches or variance batches. And all
> of a sudden something happened, because you did just three runs,
> maybe, to some extent; because there\'s a paper trail, there\'s a lack
> of access to all information in the same place. You now have to find
> out why you had that exception, and you have to have the same amount
> of rigor whether you\'re going to use it or throw it out.
>
> You now have to say why you got an exception, you\'ve got to say which
> lots it happened to, why it happened and what is the probable cause,
> and there\'s a significant additional time taken for that. And as I
> looked at that, I said, \"Okay, it was the Pharmaceutical
> Manufacturing Initiative. Maybe it should have been the Pharmaceutical
> Testing Initiative. But maybe it really should have been the Exception
> Explanation Initiative, because the consequence of explanation
> initiatives shows up in the \"So what?\" category.
>
> If you look at all these times on average, and you look at how much of
> an impact does that make, you say the average cycle time is about 100
> days; the cycle time, standard deviation, is 100 days, which says if
> you\'re talking about 6 sigma, that\'s a lot of cushion that you have
> to build in. And exceptions increase variability by 50 percent,
> increase variability by 100 percent, on the average by 50 percent.
>
> So when you told the vice president of manufacturing, \"Just don\'t
> screw up.\" \"Don\'t come in the way.\" \"Never have too little
> inventory.\" \"Don\'t stock up,\" what does he do? He builds a plant
> about 10 times bigger than he needs, about two years earlier than he
> needs, and he deals with the consequences for the rest of the 12
> years. And as we measure the numbers, they show up in these places.
>
> We need to have a fundamental technology: one, on-line sensors, but
> not only just LIF and NIR, but a way to look at these exceptions in a
> systematic way, and that\'s the next technology opportunity as well.
>
> Let\'s try to look at asset utilization numbers in a manufacturing
> sense, very similar to what I showed you, so that we can understand
> where the time is being spent. Just like we said \"So what?\" around
> on-line technologies, we said \"So what?\" around routine
> manufacturing.
>
> Again, since we have a consortium of companies, we collect from the
> batch records all the detailed process steps, and we capture all the
> time spent in every batch for all the batches ever made, and we figure
> out how much time is spent by the operators versus testing, versus non
> valued versus value-added, and here is the first process that I showed
> you in terms of its time.
>
> We started this batch, and we say, \"Let\'s start pharmaceutical
> manufacturing given a start date, we\'re now in the market, and see
> where is the time being spent.\" And you can see the physical product,
> which is the round product right down here, and the paper product
> which is the square product going along with it, the so-called batch
> records. And you can go inside any one of these steps and you can say,
> \"Where is the time being spent?\"
>
> And you can say very quickly the physical product goes through, the
> paper product takes a long time, because somebody has to sign, has to
> figure out that they did what they\'re supposed to do, and the
> technology opportunity there would be the electronic batch record
> opportunity. That\'s number one.
>
> We can now go inside the lab and figure out what tests we do, and we
> can say here are the different tests we do, the appearance, color,
> fill weight, and these are very solid, nice tests that have been in
> place. And we look at the bottom line drivers within those tests, such
> as the assay test, and you can find that it\'s the on-line nature of
> those tests that is going to impact those tests, and you can see that
> many of the paper and physical aspects of it drive today\'s
> performance.
>
> As I started this simulation in the beginning of June 1997 in this
> case, let me figure out where I am, because if I got a batch at the
> end, I would get a number bigger than zero. It\'s about a month now,
> and I haven\'t got a batch out of the other end. Let me try to figure
> out where those batches are.
>
> DR. WOODCOCK: Can you clarify, these are real numbers?
>
> DR. RAJU: Yes, these are real numbers.
>
> DR. WOODCOCK: From a real manufacturing plant?
>
> DR. RAJU: That\'s right, yes. These are real numbers from the actual
> manufacturing plant.
>
> And you can see that we just got our first batch out and approved. In
> the meantime we\'re collecting finished goods inventory at the end,
> based on the real numbers, and we\'re trying to figure out why is that
> inventory being held up there, and it\'s being held up and it\'s
> growing, and we\'re now going into July and it\'s a month since we
> started.
>
> And let\'s try to figure out why those batches are sitting there, and
> so let\'s go and figure out what\'s happening that might make them sit
> there. And you would go inside, and you\'ll find that there is an
> exception here that\'s waiting to be decided on, and unless that
> information process can end up with a result, the physical processes
> are all waiting for the information process because they have been
> disconnected.
>
> There\'s a technology opportunity here that has not been addressed.
> Why? Because it\'s so difficult to talk about. Exception represents
> what we didn\'t necessarily know, what happened that we didn\'t
> anticipate, what happened that may be different from what we thought
> should happen for the next 12 years, and now you have two multiple
> organizations getting together, saying, \"What should I do? Where
> should I sign? Who should sign, and how long should it take?\"
>
> And where the information is not necessarily there, it\'s difficult to
> do. There are legal, social, political consequences. What do we do? We
> wait, and waiting costs money. It costs money because I\'m going to
> have to find out a few months later what I did and how to connect
> these two things, and that\'s the finished goods inventory, tracking
> up.
>
> And if you were to now say, \"What is the finished goods inventory,\"
> you will see a huge number. They are waiting for the decisions. Not
> only are you waiting for the decision on that, but you\'re waiting for
> the batches soon after that, because you want to be confirmed about
> why there was an exception.
>
> So this would be the third technology, and the result of this is a
> capacity utilization that is extremely low. I would say that many of
> the numbers that were discussed in the section before us are really
> not that far away from reality.
>
> We have to find a way to remember and agree that we really make two
> products: a physical product which is a tablet or a capsule that has
> great cost benefit to society and is used for patients, and I think
> that\'s one of the greatest things that the pharmaceutical industry
> has ever done. It\'s much better than all the other alternatives.
>
> But we make another product, a so-called documentation, information
> product, and that second product has its primary customer, we think,
> for the FDA, but it has a lot of information and a basis to look at
> exceptions. And I think working together with the FDA around that
> technology, I think can fundamentally change pharmaceutical
> manufacturing as well.
>
> Coming to the end of my talk, I said we got together, said we want to
> find a way to win, and we had a large number of vice presidents who
> decided that there was a way out. We\'ve looked at technologies for
> all the aspects that I\'ve told you about. We\'ve carried out
> different aspects of these technologies in different places for
> different products, in different parts of the product life cycle, and
> we\'ve got some really exciting data, and we\'ve called this
> initiative Continuous Quality Verification.
>
> And we say that we have many pieces of the puzzle that we think can
> become part of a transformation of this industry. We have got an
> understanding of the needs. We have some of the best universities in
> place. We have presented this to the Division of Pharmaceutical
> Sciences and the Advisory Board. We have got a very favorable
> response. We have now talked within CDER to a number of people. We
> have gotten really excited.
>
> If you remember, I showed you that slide that said, \"We want to talk
> to the FDA at some time.\" In the last three or four months we\'ve
> been talking a lot, and we\'ve been very impressed with the openness
> and the awareness and the good intentions of the people that we\'ve
> talked to. This is today. This is the Science Board. And as we go past
> this and we go forward, somewhere along the way we want to be able to
> also talk to the investigators who might be behind the curve in some
> of the new technologies.
>
> And this is where we\'re headed. To summarize, we think technology,
> when you come back to science, understanding of the needs, we have put
> together a place where it could be a huge win for the industry, the
> FDA, and society. But we can only capture this potential if we win
> together, and we really mean it. And I think if we don\'t, we\'re all
> going to lose, and it\'s very, very likely that if we leave any one of
> the wins-wins out of the three wins, that we will be doing this and
> saying the same things 50 years from now. Let\'s find a way to all
> win.
>
> Acknowledgements: The consortium itself; two colleagues of mine,
> Professor Charles Cooney and Professor Steven Byrn. And particularly
> relevant for a presentation such as this, these are my personal
> opinions and nobody is liable for them except me. Thanks.
>
> DR. WOODCOCK: Thank you very much. I think I\'ll turn it back over to
> the Chair for a break.
>
> CHAIRMAN LANGER: How long a break would you like? 10 minutes, 15?
>
> DR. WOODCOCK: Ten minutes.
>
> CHAIRMAN LANGER: Why don\'t we take a 10-minute break, then?
>
> DR. WOODCOCK: Thank you.
>
> \[Recess.\]
>
> CHAIRMAN LANGER: If everyone would be seated, we\'ll get started
> again.
>
> DR. WOODCOCK: Our next speakers are from the industrial sector. Dr.
> Norman Winskill and Dr. Steve Hammond are going to be talking about
> quality regulation from the pharmaceutical manufacturer\'s
> perspective.
>
> DR. WINSKILL: Good morning, everyone, and thank you, Janet. It\'s a
> pleasure to be here this morning to give you an industrial perspective
> on what I think is a very important and a very timely topic.
>
> As you can see from the slide and as Janet mentioned, we have a double
> act from Pfizer. I\'m Norman Winskill. I\'m going to be followed by
> Steve Hammond. We\'re going to share the presentation between us. One
> of us is a pharmaceutical technology expert and the other one isn\'t,
> and I\'m the other one.
>
> \[Laughter.\]
>
> I\'m not interested in the technology per se. I\'m interested in what
> the technology can do for me. So I\'m going to try and explain a
> little bit of that, and Steve will concentrate on the technology
> itself, and then we\'ll come back together and see how we put the two
> together.
>
> So, just running through the order of what we\'d like to
> cover\--actually we have the wrong presentation up here, I think. Do
> you have another presentation that we\--
>
> DR. WOODCOCK: A shorter one?
>
> DR. WINSKILL: The title is right, but there was a long version and a
> shorter version. Sorry, you\'ll have to give us a moment or two. We
> have to switch computers.
>
> CHAIRMAN LANGER: While this is happening, are there any questions
> anyone wants to ask?
>
> DR. WOODCOCK: David Feigal had some information on recalls in the
> device sector that might be germane to this.
>
> DR. FEIGAL: One of the questions that was asked before is, how many
> recalls are there? And in the device area there are about 1,000
> recalls a year, so if you figure there\'s approximately 200 business
> days in a year, that\'s about five recalls of products per day.
>
> There\'s about 80,000 products on the market, or 80,000 actually types
> of products on the market, so if you look at the number of products
> newly approved each year, which is sort of another sort of metric,
> there are about 7,000 products approved each year. So it really isn\'t
> anything that approaches 6 sigma, if you do the math.
>
> Now, many of the recalls actually probably have more economic
> consequences for the company than public health impact. About half of
> them are the lowest class recall, where there is something about the
> packaging or the labeling or some other type of issue that is a
> significant cost to the manufacturer but there\'s no health risk
> associated with the problem.
>
> But there have been some fairly important recalls that actually
> happened due to manufacturing problems in the device area this year.
> Probably one that\'s still getting quite a bit of publication is the
> Salzer hip implant, which actually threatens the viability of that
> whole division of that company, which I think the company\'s theory
> still is that that was a problem with leaving a bit of residual oil on
> the surface of the hip implant so it didn\'t seat properly and it
> would loosen, and that has been a problem.
>
> But there also has been a worldwide recall of ceramic hips, which
> fractured when there was a change in the manufacturing method, in the
> type of firing and heating of the ceramic material. So, although most
> of the recalls are in that low-risk category, there are important
> examples of products that are recalled where there really are not only
> quality problems but there are health implications for the patients,
> as well.
>
> DR. WOODCOCK: Other questions?
>
> Are you about ready to go?
>
> DR. WINSKILL: Yes, we\'re ready. Sorry about the delay.
>
> So what we\'d like to do in the next 25 minutes or so is give you a
> very brief history of the evolution of process analytic
> technology\--I\'ll refer to it as PAT quite often\--and also our
> vision for the future. I\'ll then hand over to Steve, who will
> describe some of the specific applications that are of interest to us
> right now and how we might use those to improve our process knowledge
> and control of our processes. I\'ll then come back and describe how we
> might introduce some of those technologies or how we might now
> introduce them, and what sort of environment we could create to make
> sure that we do introduce them appropriately and use them
> appropriately, and that\'s referred to as \"the win-win scenario,\"
> and I\'ll describe what that is.
>
> So first a quick overview of the evolution of this technology within
> Pfizer. A lot of the examples I will use are obviously taken from
> Pfizer. I decided to use specific examples rather than hypotheticals
> because I think they illustrate the point. I don\'t apologize for
> using Pfizer examples. I think it is essential and probably necessary
> to see specifics, but I don\'t try to claim that what we are doing is
> anything different from what a lot of our colleagues in the industry
> are doing, and I think it\'s fairly representative. But rather than
> hypotheticals, I decided to use specifics.
>
> We started looking a process analytical technology, particularly near
> infrared and mass spectroscopy, in the mid-\'80s, early to mid-\'80s,
> and we were looking at control of fermentation processes. That proved
> very useful, and we quickly developed and applied the techniques to
> other processes, particularly near infrared. So in the middle to late
> \'80s we expanded the use of near infrared to synthesis operations,
> raw materials, packaging operations.
>
> And at this point the application in drug product manufacture, which
> is what we\'ll focus on mostly today, was really for a troubleshooting
> mode. However, in using it for troubleshooting, we found it gave us an
> awful lot of information we didn\'t previously have and that
> conventional tests didn\'t have.
>
> So at the beginning of \'90 we created a dedicated group\--and we
> called it the NIR Group, and it was headed by Steve, who is coming up
> next\--specifically to spread the word and to develop applications and
> put them into our processes to enhance process knowledge. And so that
> dedicated group was formed.
>
> At that point in time it was very difficult to go and buy instruments
> off the shelf and apply them to the production plant, so a lot of what
> the group did was develop\--not only work with vendors on the
> instrumentation, but work on a lot of the engineering solutions like
> sample presentation, automation, and robotics, and that was essential
> to enable us to put near infrared and other techniques into the drug
> product plants. We did that in quite a big way in the early \'90s. I
> think I\'ll show you some of the applications that have ensued from
> that.
>
> Later, and probably for the last five or six years, I think, other
> techniques have emerged. Near infrared is still important, but as
> others speak, as they have emphasized, it\'s not just near infrared.
> It\'s not a panacea. So LIF, mid-IR, acoustic, and a whole range of
> other, Raman techniques, are now being studied and they are
> increasingly being applied.
>
> So, given that evolution, where are we today? And this is just a
> summary of some of the applications that we have in commercial use on
> our drug product plants around the world, and it\'s in chronological
> order, and you can see that we are using it actually in a commercial
> environment, everywhere from the beginning of the process, raw
> material testing and release, evaluation of packaging components,
> blending, tableting, encapsulation, tablet coating, packaged product.
> We can actually scan tablets in a blister pack, not just to make sure
> that the tablets are present, but we run a spectrum on the tablet to
> make sure it\'s the right tablet in the right pack. So quite an
> extensive use, and then at the end of the process we use different
> process analytical technologies to help with cleaning verification, to
> ensure everything is ready for the next step.
>
> There\'s a footnote at the bottom I think that has been referred to.
> Janet referred to it at the beginning. Interestingly, I think there
> are over 30 discreet applications in use around the world, very few in
> the U.S., less than 15 percent.
>
> And I think that\'s not atypical of novel technologies in general.
> Process analytical technologies is a model, but I think if you take
> any of the new technologies we\'ve looked at\--microwave drying,
> automated guided vehicles, you name it\--it tends to be evaluated and
> implemented and shaken down overseas, and it takes a long time before
> that technology is then brought back into the U.S. or used to make
> products for the U.S. market. And I think a key question is, why is
> that? Is that the right environment? And if it\'s not, change it. So
> we\'ll talk a little bit about that.
>
> So that was the current state of process analytical technology. What
> does the future hold? Now, this is obviously a personal vision, and
> the future for me is about 5 to 10 years in this example, but I think
> we will see a significant increase in the number of applications. I
> think we will see a broadening of the type of applications\--Raman,
> light-induced fluorescence, etcetera. Acoustical is increasingly used
> to hear what\'s going on in the processes, gives a lot of information.
>
> I think what we will see, and what will help spread this technology
> throughout the industry, is the availability of off-the-shelf
> solutions from vendors. Right now a lot of us have to develop our own
> engineering solutions, and go in and, like G.K. showed, adapt them
> onto blenders to use them. I think that within five years we\'ll see
> them being offered by the equipment manufacturers as an option, and
> that will increase the utilization tremendously.
>
> The other thing I think we\'ll see, what I described on the previous
> slide was a lot of individual steps that are being controlled. I think
> where we are going to is to see all of those steps integrated so we
> control the whole process. Instead of doing conventional control up to
> one step, and then we have a nice process analytical technology
> on-line to control, for example, blending, and then we take it back
> into lab-based testing for the rest of the process, we\'ll integrate
> the process from cradle to grave, so it can operate at a fast cycle
> time with tremendous process knowledge which we don\'t have today.
>
> So our vision of the future is\--and this is a pictorial
> representation of what others have described\--moving away from
> discrete unit operations with laboratory-based testing at the end of
> each step. And the reason we often wait for that laboratory testing is
> that if we proceed to the next step\--which we can do, there is no
> regulatory reason why we have to wait for the result to proceed to the
> next step\--but if that laboratory result comes back, and it\'s our
> only information today, if it comes back and says there is something
> wrong with the blend, it\'s not uniform, if we\'ve taken it through to
> a tablet, there\'s a huge cost involved in having to go back and
> reprocess that, or if there\'s no rework option, throwing it away.
> That\'s the scrap. So it\'s risk management that forces the long cycle
> times and the discrete unit operations with lab-based testing at the
> end of each, not regulatory.
>
> Where we want to get to, and the vision for the future, is what I
> think G.K. called continuous process verification: continuous, more
> frequent, more meaningful on-line analysis at every step of the
> process, so we can proceed to the next step of the process knowing
> that what we did before was compliant and of correct quality. We
> don\'t have to wait six hours for a lab-based assay. And that is the
> sort of manufacturing paradigm that we\'re trying to evolve to in the
> not-too-distant future.
>
> What are the challenges in getting there? Some of them of course are
> technical. However, I think the progress that we have seen, and Steve
> will describe a little bit, is sufficient that it really is not a
> significant barrier at this point in time. Technical issues can be
> overcome.
>
> We have made considerable progress in the areas of chemometrics,
> robotics, the industrialization of instrumentation. Yes, there are
> still some opportunities, and probably more significantly I think in
> the development of faster, smaller, cheaper instruments, so they can
> be put in more places more often, and probably still some work to be
> done on the sample interface, how the instrument interfaces with the
> sample, and how that can be an off-the-shelf solution.
>
> But I think there are solutions to those, and I think that\'s not a
> hinderance right now to the widespread application and moving towards
> the paradigm I described on the previous slide. And maybe the major
> hurdle for the U.S. right now is the real or perceived regulatory
> hurdle, and maybe it is more perceived than real, and we\'ll come back
> to that at the end.
>
> At this point I\'d like to hand over to Steve, who will describe some
> of the particular applications of interest, or the ones that we are
> particularly interested in, and then we will come back and talk about
> implementation.
>
> MR. HAMMOND: Thank you, Norman.
>
> I just briefly want to go through three examples of where installing
> PAT, this is being driven, the latest advances in this are being
> driven by a new potent API that we\'re dealing with, and we\'ve had to
> look a systems that are totally automated and work in a containment
> facility where just can\'t have plant operators even sampling blenders
> or even sampling off the tablet presses. So we developed a system, and
> I\'m going to start with on-line blending, we developed a system that
> uses a battery-powered radio communicating spectrometer. It\'s very
> small, fast diode array instrument. We actually mount this on the
> moving blender. We control it and collect data from it remotely in
> another room.
>
> This is a schematic of the installation that we\'ve just finished
> performing in our plant in Brooklyn, in New York. The blender is
> contained in a separate room. There are two containment barriers you
> have to go through to get into that room. So we have the NIR mounted
> actually on the blender in a separate room, and our PC controlling
> that system is actually out in the corridor in this instance. When
> this gets to a full manufacturing plant, there will actually be a
> containment area again for the blender, and the control of it will be
> in a specialist control room adjacent to that particular room.
>
> For this example I\'m going to show you now, the point is that the PC
> driving the spectrometer and where the data processing is done is some
> 25 feet away from the blender in another room. This is what the full
> GMP installation looks like, and you can see that there are two blue
> boxes actually mounted on the blender. So everything that\'s back to
> the right-hand side of those two blue boxes is stationary. What\'s to
> the left of the two blue boxes all rotates.
>
> The top box is actually the box that contains the battery and
> radio-communicating modems. They are what is sending the spectra, once
> we have collected them, back out to the PC which is outside the room.
> The bottom box, the bottom blue box, the smaller of the two, is
> actually the spectrometer. It\'s a solid state instrument, so it can
> be put up with being spun round as the blender moves.
>
> The business end of this is actually the thing that looks like a black
> cylinder on the bottom of the bin, that\'s actually shining the
> infrared light through a window we put into the lid of the IBC, and
> it\'s collecting spectra when the bin is inverted. We have some
> gravity switches that only fire the spectrometer when we know the
> blend has fallen down against the sapphire window mounted in the lid.
> The spectrum is collected with the fiberoptic that goes from that
> reading head on the bottom of the bed back up to the spectrometer.
>
> Now, Norman talked a little bit about the design of the sample
> interfaces, and with this particular application it\'s very important,
> because what we need to do is to collect the spectrum from a known
> amount of material, and that amount of material must be something that
> is, in terms of unit dose, reasonable. So we\'ve done a lot of work in
> designing this reading head, that we collect the spectrum of between
> 200 and 300 milligrams of sample. We\'ve done a lot of work in looking
> at depth of penetration, density of the blends, and how much sample
> actually contributes to the spectrum.
>
> I\'ve seen a lot of publications recently on doing on-line blend
> analysis using near infrared, but this fundamental thing of how much
> sample actually contributes to the spectrum is critical in getting
> these systems to work and give you realistic answers that you can
> match to off-line HPLC, and the design of this head allows us to do
> that. We illuminate an area of some 3 centimeters, a circle 3
> centimeters across, with the right intensity to get depth of
> penetration of about half a millimeter, and we know we collect
> information from the whole of that sample. So it\'s very controlled in
> how many unit dose weights are we seeing.
>
> The sort of information that we\'re looking to get, the plot on the
> left shows you the near infrared spectrum of ingredients in a
> simulated blend that we used to commission this piece of equipment. We
> couldn\'t actually use the active because it is a Class V material, so
> we substituted that with saccharin, which is innocuous but has the
> right sort of near infrared spectrum to compare to the active we would
> have used.
>
> What you can see here on the left is the spectra of those pure
> ingredients that we scanned before we started the exercise. The change
> in pattern you see on the right is the movement in the spectrum of
> saccharin at a specific aromatic absorption for that molecule. That is
> what we try to do, we find specific absorptions for these molecules
> and watch the movement at those specific absorptions, so we can track
> just that one ingredient.
>
> But we don\'t just focus on the active, we focus on every ingredient
> in the blend. We look for the specific parts of the spectrum where the
> movements are really reflecting that ingredient in the blend. So as we
> run the blender\--and this is the first stage of the exercise that we
> did, this ran for 15 minutes\--we can track the change in absorbance
> for each ingredient.
>
> And there I\'m showing you the change in absorbance of saccharin,
> which was our active in this case, and lactose and Avicel, two other
> ingredients in that mixture. So we can track this. As the curve comes
> down to the bottom and we finally flatten out, we know we\'ve reached
> the end point of blending, but we can watch the end point of blending
> for the active and for the other two ingredients in that blend.
>
> Now, to turn that into the normal sort of measurement that we would
> look to make on a blend, content uniformity, what we do is to take the
> spectra we collect in groups. The blender was actually rotating at
> eight revolutions per minute, so what we\'ve done is collect eight
> revolutions, or the spectra we collected from eight revolutions
> together, and then calculate a variance across those eight points.
>
> And this is mimicking taking eight samples from the blender into a
> laboratory, doing HPLC analysis on them, and calculating the content
> uniformity. So this is a variance measure, so the Y axis is the
> variance across eight scans. Along the bottom we\'re plotting time. So
> what we can see is the movement in essentially content uniformity for
> the ingredients in that blend, but not just the active, all of the
> ingredients.
>
> There\'s one big advantage to this technology. It is gaining more and
> more process understanding. The other things that have been talked
> about, cycle time, are obviously of value, but one of the big
> attributes of this is the amounts of process understanding that you
> can get, and plotting the uniformity of all ingredients in a blend is
> one of the key gains in this sort of technology.
>
> And really to illustrate that, I want to show you the second step in
> our blending. Once we had blended the main ingredients, we did the
> normal thing you would do, which is then to add a lubricant, and we
> blended that. What you see here is the change in uniformity of the
> lubricant as it\'s added to the second stage of the blend.
>
> So with this system we can, in real time, watch the mixing of all the
> ingredients, look to see when the blending is done, and for the high
> potency\--the product we have to make in a containment facility, we
> will develop specifications for the amounts of variation that we will
> allow in the spectra, and that will be validated against conventional
> HPLC measurements.
>
> The value to us in that on-line blending system, where we have a new
> product that must be made in a containment facility, the major benefit
> is no operator contact. Robots will load the bins into the blending
> area. the near infrared will be placed onto the bin using robotics.
> Measurements of blend uniformity will be performed in that room, but
> the data will be transmitted into a control room, so we can avoid
> operator contact with that product altogether.
>
> There are other benefits. There is no sampling, there is no sample
> thief error. We get real-time information, which can help recycle
> times. We get these multi-ingredient uniformity measurements. We gain
> a lot in process understanding. We can actually fingerprint the
> process. We know that those curves I showed you, you can actually
> change them by the order in which you load the bin, so we can
> fingerprint even the way that you load the bin and what impact that
> has on blending. And what this really comes down to in the end is the
> objective to go to \"right first time\" manufacturing.
>
> I just want to now show you the sorts of things that we\'re doing with
> tablet core analysis because, as Norman said, we\'re trying to look at
> cradle-to-grave control of the manufacturing process, and one of the
> key steps is obviously monitoring what you\'re doing when you\'re
> making or pressing tablet cores.
>
> This really started in an at-line situation in our manufacturing plant
> in Australia. These people you see there are the plant operators, and
> they are people that have been using near infrared in that production
> plant to look at tablet cores and actually at-line, looking at blends
> as well.
>
> What I want to focus on is the fact that about once an hour those
> operators go to the tablet press and they take a handful of tablets.
> They go to the near infrared and they test content uniformity and
> potency of those tablets. They do that by passing near infrared
> through the tablet as a bulk measurement, which means that we do
> capture everything that\'s in that tablet and we\'re not subject to
> variation at the surface, which can be a problem in some measurements.
> So we see everything there is to see in that tablet.
>
> Just to illustrate the information value of that, this is a product
> that was manufactured in the Australian plant, and the conventional
> analysis suggested there was a problem with blend segregation, maybe,
> during the process. Using near infrared and looking at 300 tablets
> across that batch, rather than just 10 tablet as we would
> conventionally test, allowed us to pinpoint exactly at what point in
> that batch there was a problem, and then it became very simple to cure
> it because it was just a transfer chute that was causing some
> segregation in the blend. But the extra information that you get from
> using these sorts of technologies to get analysis of 300 tablets a
> batch rather than just 10 or 20, really allows you to get to grips
> with that sort of issue very quickly.
>
> The at-line system I\'ve shown you is fine for most of our products,
> but with this high potency product that we\'re going to introduce, we
> needed to take that further, and we\'ve needed to automate that near
> infrared testing. And what we\'ve done now is to design this unit,
> which actually takes the conventional weight, thickness, and hardness
> modules that are very often at the side of a tablet press, and then
> introduces near infrared transmission capability into the unit as
> well.
>
> So tablets feed into this box, they are weighed, they are scanned on
> the near infrared, and then they go back to be measured for thickness
> and hardness. And this is actually at the tablet press. It\'s fully
> automated. We\'re actually having two companies make one half each of
> this device. Bruker are doing the near infrared side of this
> instrument, and a company called Schleuniger Pharmatron from
> Switzerland are making the other half of it. But it is to be a totally
> integrated device.
>
> I just want to show you some of the spectra behind using a device like
> that. This is actually spectra of this new high potency product that
> we have. The black line that you can see there is a placebo tablet,
> and then the colored spectra are tablets of different strength of that
> product. So you can see that we have specific information about the
> active if it\'s present in that product, and changes in concentration
> that we can actually measure from that spectral information.
>
> We can use that spectral information to compare HPLC values for single
> tablets against the value that we would get from the near infrared
> based on the spectral change that we see. And what I\'m showing you
> there is the correlation between spectral information and HPLC, but
> what I want you to note is the concentration in that product. This is
> from .1 percent to 2 percent, so this measurement is extremely
> sensitive if it\'s set up correctly.
>
> I want to finish by describing some work that we\'ve been doing
> introducing microscopy to look at pharmaceutical formulations. What
> I\'m talking about here is to look at a blend, but not as a bulk
> measurement, but actually to get in there and have a look at the
> matrix of the blend close up, and to do the same with a tablet, to get
> in and actually look at how each of the ingredients are lying
> alongside each other, and how do we actually make a tablet matrix.
>
> The way we do this is to take an area of a tablet, usually about 2
> millimeters by 2 millimeters, we take each of the pure ingredients
> that we manufacture the tablet from, and we collect their spectrum and
> we file that into the computer, so we have the spectrum of each pure
> ingredient.
>
> And then that 2 millimeter area of the tablet, we divide it into
> squares, usually around 10 microns by 10 microns, and we use a
> microscope to collect a spectrum from a minute piece of that data
> matrix. So each square is scanned in turn, each square of about 10
> microns, and we collect a spectrum of that square using a microscope.
> Then we match the spectrum that we get for each square against the
> spectrum of the pure ingredients.
>
> So what we can do is to take each square and color it in. If we find
> the active, we usually color it red. If we find Avicel, we\'ll usually
> color it blue. Disintegrants, we usually color them green. But we can
> build up a color map of the matrix of the tablet at a microscopic
> level.
>
> This is just one illustration of the sorts of information that you can
> get from doing that. This is an example of two blends of the same
> product. One blend would flow correctly into the encapsulation
> machine; the other blend would not flow correctly. The microscopy
> information revealed that in fact our lubricant was clumped in the
> bad-flowing blend and nicely distributed in the well-flowing blend.
>
> In fact, it was interesting, the plant manager when we showed him this
> information said, \"Yes, that\'s exactly what I thought it was.\" But
> at least you can go back and get good scientific data on exactly what
> is causing that sort of problem, using microscopy.
>
> Here is another illustration of a product that occasionally suffers
> sticking problems on the tablet press. We analyzed matrix using
> microscopy. You can see there is a big difference in the way that that
> tablet matrix is actually sticking together. And what I\'m showing you
> here is the mixing of an inorganic diluent with one of the
> carbohydrates that goes into that formulation.
>
> In fact, what microscopy has shown us is, if those two ingredients mix
> together really well, we actually get a slightly weaker tablet that
> has a tendency to stick to the tablet presses. In fact, you can track
> back and explain what that difference is. It\'s a difference in the
> particle size of the sugar, the carbohydrate that\'s fed into the
> process. By controlling that particle size well, you can avoid this
> problem, but only after you got the information to explain what the
> problem was could you go back and cure it, and microscopy really has
> an enormously powerful contribution to make to explaining process
> problems.
>
> Up to now, getting that sort of data has taken a long time. Most of
> the maps I\'ve shown you, our spectrometer and microscope have to work
> very hard for up to 24 hours to make those maps, because there are
> about 8,000 spectra in each of the maps. But just recently imaging
> systems have started to appear that can actually collect the same
> information in about 10 minutes.
>
> We\'re hoping within a few years to get these systems so fast that we
> could take the spectrometer I showed you on the on-line blending
> system off, and actually put an imaging camera there in place, so we
> could image the blend as it\'s mixing. And the sort of information
> that we should get from doing that should improve our process
> knowledge orders of magnitude beyond where it is at the moment.
>
> I\'m now going to hand back to Norman.
>
> DR. WINSKILL: I\'ll finish up very quickly here, but I hope you got a
> sense from what Steve has described, that we are quite excited by the
> additional information we can obtain on our manufacturing processes if
> we can get this technology into the plant routinely. And we think we
> can, and we think it can be part of the vision I described earlier.
>
> Certainly the technical challenges I think we can overcome. I think
> what might influence the speed at which it\'s rolled out and the
> general acceptability of the technology might be the real or perceived
> regulatory hurdles. And history has taught us over these last 10 or 15
> years generally about the introduction of technology, that it may not
> be as smooth as we would like to see it.
>
> In fact, I\'m going to describe three possible scenarios, all real
> life examples that we\'ve lived through. One I will call the \"don\'t
> use\" scenario. The \"don\'t use\" scenario is a worst case.
>
> These technologies are not used or developed during the product
> development basically because of our fear of delays in the regulatory
> approval. We don\'t want to put novel technologies into an NDA.
>
> Once we\'ve transferred a process with its controls into production,
> there may be a tendency not to want to \"waste\" resources to develop
> duplicate methodologies and controls when the existing ones work okay.
>
> And, quite frankly, there may be a concern on our behalf of raising
> the bar. The more information that\'s available on a process could
> possibly be used inappropriately against us, and that\'s a genuine
> concern.
>
> The problem with that is, if that leads to the technology not being
> used, I think we all lose. And there is a whole body of information
> that\'s just going to remain unavailable to anyone, and that\'s not a
> healthy situation.
>
> But again, I said I would use real-life examples. This is a real-life
> example of \"don\'t use.\" It\'s taken from one of our recent
> products. It\'s an antifungal polymorph. Conformation for this product
> was key to the product attributes. During the development, we
> developed and looked at two different methodologies to conform, to
> confirm the polymorph, powder x-ray diffraction, obviously a
> well-established technique but not common on our manufacturing plants
> to QC labs, didn\'t exist at the site of manufacture. So the only way
> to confirm the right polymorph was to send a sample 3,500 miles and
> then wait about a week for the result to come back.
>
> We developed an alternative, near infrared, common in the lab,
> available at the site. We could get results within minutes, but it
> wasn\'t a standard technique for polymorph conformation. Our initial
> draft of the NDA included both methods, but our fears and our
> conservatism made us take the near infrared out of the NDA because we
> were fearful of questions and delays, and so right now we have the
> method on the left, and we send samples across the Atlantic, and we
> don\'t use near infrared, not a very healthy situation.
>
> The second scenario is \"don\'t tell.\" Under this, we want the
> information so much, we use it but we don\'t register it and we don\'t
> openly talk about it. So we have one set of methodologies that are in
> the files, and these are used for regulatory approval, and we conform
> to the specs, we conform to the dossiers. But in addition to that, and
> in addition, not instead of, we use all these model techniques in
> parallel, and really we operate in two parallel universes. We have a
> regulatory universe with old-fashioned conventional technologies. We
> have another universe that really is the one that counts, but we are
> afraid to share it.
>
> Another real-life example, and this goes back to, I started life with
> Pfizer more than 25 years ago in the fermentation area. That\'s where
> a lot of the near infrared came from. On the left, you don\'t need to
> read that, it\'s an eye test, but on the left there\'s three or four
> registration specifications and control methods which are fairly
> conventional, lab-based assays, 12-hour turn round time, and that is
> still the case.
>
> Today that\'s the registration method, but over 20 years we\'ve
> developed a whole set of advanced near infrared, mass spectroscopy,
> and probes, on-line probes that we really use to control the process.
> And basically we, as I say, operate in a parallel universe.
>
> The conventional methods work. They give product that will conform and
> is fit for its intended use. There\'s no question about that, and then
> final end product testing is the gatekeeper to make sure of that. But
> it\'s inefficient, and really the advanced control and the reason we
> are prepared to duplicate the universe is, we get much better
> batch-to-batch consistency, less impurities, fewer byproducts, less
> rework, etcetera, etcetera, all the advantages we talked about
> earlier.
>
> We could take this slide from this example and, I think, apply it to
> today\'s situation for drug product manufacture. I think the universe
> for fermentation control has evolved significantly from a black box
> art 20 years ago, to a very highly controlled environment with dual
> networks and advanced computer control, using this information to give
> us assurance of quality.
>
> We\'re nowhere near there on drug product, but we could be. And we
> have to find the right environment to get there, and I think if we
> could, that\'s the win-win situation we\'re talking about. So that\'s
> a description of the win-win situation. I mean, we don\'t need to do
> the parallel universe and the duplicate testing.
>
> What will it take to get there? I think basically it will take an
> environment in which the methodology is understood and accepted by
> regulators and industry alike. We have the same information, the same
> concerns. We see the same opportunities around the use and application
> of this technology.
>
> We are certainly not there yet. I think we\'re making a lot of
> progress, and I think today\'s meeting is a good example of that, but
> we have a little way to go. And really what we\'re trying to do in
> this is, we\'re dealing with, we\'re removing the real or the
> perceived regulatory hurdles.
>
> And I think to do that, we need\--and these are personal suggestions
> on how we can create that environment\--I think joint forums to openly
> discuss the technology and openly discuss the issues and concerns and
> describe the technology, I think goes a long way. And I know Dr.
> Hussain, Ajaz Hussain and others, have believed very strongly in this
> and are starting to do that, and that\'s encouraging.
>
> I think we need to create an effective process to evaluate these
> technologies, for example, PAT. And part of that, I think, and maybe
> the root of it, is appropriate guidelines for the development, for the
> implementation and the validation of these methods, scientific-based
> guidelines that we can follow and we can understand, and then you can
> measure us against. Absent that, it\'s down to personal
> interpretation, and that\'s where our perceived fears some into how it
> might be interpreted differently by different people.
>
> How can we do that? Well, obviously we can sponsor joint forums, I
> would suggest industry/FDA forums, to work up some guidelines. I think
> we have to recognize that process analytical technology is different
> from lab technology, and you have different expertise that need to be
> at the table to develop those guidelines, people from the process
> control, instrumentation side of the industry.
>
> Another suggestion is to participate in \"dummy runs.\" We have
> introduced a lot of these technologies. We don\'t do so without
> appropriate internal controls for development and validation and
> implementation, and we have them. We have SOPs for all of that. Like I
> say, we don\'t share them because it\'s a parallel universe in most
> cases, but we would be willing to share them, and we would be willing
> to make some dummy submissions. We will submit some methods that
> we\'ve developed to see what you think of them. We will submit the
> controls and the methodology and the SOPs we have used, to see what
> you think of those.
>
> Quite frankly, I call it \"dummy\" because we will submit things that
> are not linked to an NDA approval, so there is less risk for us, and
> probably that is a way to create a win-win situation. If that helps to
> evolve to a set of guidelines that we can all understand quickly, then
> I think we\'ll be better off.
>
> And then finally I think what\'s important to us, probably to all of
> us, is consistent use of those guidelines not only by Center but by
> field investigators, and that will remove an additional concern that
> we may get approved but we may get additional questions and a
> different interpretation of the technology on an investigation. And a
> set of guidelines that we can all\--a bible, if you like\--that tells
> us how to do it, that we can all refer to, and refer to the same
> chapters in the book, I think will go a long way to remove those
> perceived concepts.
>
> So, thank you.
>
> DR. WOODCOCK: Thank you very much. I appreciate Pfizer\'s willingness
> to come and talk about these things.
>
> The next speaker, who will speak fairly briefly, is Dr. Ajaz Hussain
> from the FDA, and he\'ll give the FDA\'s perspective and some ways
> that we perceive we could move forward on this, and then we\'ll try to
> save enough time for discussion and questions.
>
> DR. HUSSAIN: Thanks, Janet. I did have an extensive presentation, but
> to the time, I\'m going to cut back. But when I sort of put together
> that presentation, I thought I would have to defend an FDA position:
> Why do we require product tests, and so forth? But in many ways I
> think the case has been made by others, and I\'ll use an example to
> illustrate some of the challenges from and FDA perspective, and then
> follow up with a set of steps that we have taken and we are planning
> to take, and then pose the question Dr. Woodcock posed to you at the
> beginning of the presentation.
>
> One aspect which I just want to share with you is, why did everybody
> talk about blending? It\'s mixing of powders. I mean, it\'s at least a
> 150-year-old technology. But for last 10 years we have been debating
> that, industry, FDA, so extensively, we probably have spent millions
> of dollars just talking about it in workshops and so forth. That
> illustrates in my mind the state of the manufacturing today. That\'s
> not the only unit operation. There are a number of more complex unit
> operations that we have to deal with, but we are stuck on blending.
> And so that is the situation from my perspective.
>
> Please pardon me. I\'m going to skip through some of the slides and
> get to the most important ones which I want to make some points on.
> The original outline I had was to just redefine the emerging
> regulatory issues, share with you my perspective, FDA perspective,
> look at the problems, and see how we can proceed from here.
>
> The main issue here is that science and technology is progressing
> rapidly. It is, in fact technology is not a problem right now. I think
> getting it into practice is.
>
> Just to reemphasize, I think the discussion topic on process
> analytical technology, we use that as a model and initial focus point
> to facilitate discussion on emerging regulatory science issues in
> manufacturing in general, so that was a model. People have talked
> about near infrared and other vibrational spectroscopy methods. Again,
> as a case study, there are many different technologies, any different
> tools, and not discussing those here doesn\'t mean we are not
> considering those.
>
> I think one major issue I think in my mind is why is FDA leading this
> effort. But when we started talking about this, the reactions that we
> received from industries, \"You\'re going to do what? This is not
> FDA\'s role.\" But we felt it is, and think we have to take the lead.
> If we don\'t do that, we get blamed for it. I think the one aspect we
> keep hearing is, we are the hurdles, and I think our perspective is,
> we don\'t need to\--we are not, and we don\'t want to be. So how do we
> move forward?
>
> So just to summarize, we have heard before industry is hesitant to
> introduce process analytical technology in the U.S. They have done it
> in Australia. They have done it in other places. It\'s in practice.
> Not in the U.S. The points that are made is regulatory uncertainty,
> risk. That leads to \"don\'t tell\" or \"don\'t use\" practice. I
> translate that into uncertainty or lack of understanding or knowledge
> of how FDA would assess that, as new technology leads to new
> questions. These questions would be in method suitability,
> chemometrics. This is status of pattern recognition and validation of
> that.
>
> The other concern we hear is, old product plus new technology leads to
> new regulatory concerns which could be added burden, so how to do you
> deal with that? And clearly a mind set: Why change? One contributing
> factor to that is, this, when we bring it to FDA, will become an
> additional test. We\'ll be asked to do the old method and the new
> method.
>
> And so those are some of the concerns that we kept hearing, and we
> said that\'s not how FDA operates. We are more open to that. Why is
> this perception out there? And we started talking about this
> extensively. Clearly we are approaching this from a public health
> perspective, and to ensure high efficiency of the U.S. pharmaceutical
> industry from many different views.
>
> Also I think I\'m going to start skipping the slides. The point here
> is, we hesitate to improve or learn about our process during new drug
> development because we don\'t have the time. We don\'t do it after
> approval.
>
> So when is the right time for process improvement? In some cases,
> never. We have product, I\'ll give you an example from a 1997 warning
> letter. This is a narrow therapeutic index drug which is used in a
> controlled release formulation. How are we making it? Just read this.
>
> XXX, drug XXX, \"time release pellets are prepared by hand-coating
> powder\...This manual process results in formation of agglomerates and
> in an accumulation of ingredients on the sides of the coating pan.
> Operators sporadically scrape this undistributed material\...manually
> breaking up agglomerates\...and crushing them during processing.\"
> This is, in some cases, the state of the art, not an example that can
> be generalized, but this is reality.
>
> Clearly, the point has been made that regulatory risk and uncertainty
> is a hurdle, and we have been working for last several years to remove
> those hurdles, and there are significant challenges. I was going to
> talk about the guidances that we have already developed, but let me
> move on.
>
> The heart of the matter is science. Where is the science in product
> development? And clearly there are trends where we are going from
> dosage forms to drug delivery systems to more intelligent drug
> delivery systems. That is happening, but that has to happen more
> quickly.
>
> The molecules that we are developing as drugs are more complex. They
> need to be managed more carefully. And so design of intelligent drug
> targeting systems and so forth is happening, but we are still stuck in
> a 100-year-old technology at the same time. The principles of what we
> do originated 100 years ago in the art of compounding. In many ways we
> are still\--a lot of those things remain. Most dosage forms are
> complex multi-factorial systems, yet we treat them as univariant or
> multi-incident systems where we study them one at a time.
>
> From an FDA perspective, when we have to establish classification,
> when we have to establish controls, what we face is a high degree of
> uncertainty on what the impact of independent variables have on
> performance. So when you want to change something, we have no clue
> generally what that impact may be, so the additional tests come in.
>
> So not to belabor, not to just harp on that point, I just want to move
> on, but at very fundamental levels, material science, if you look at
> polymer science, if you look at all other fields, do we understand our
> materials? Not necessarily. In many cases the functional attributes of
> the materials we use, the ingredients that we mix in a tablet, are not
> well understood.
>
> The official monographs that we have are focused on chemical identity
> and purity, and that\'s probably what it should be. Defining the
> functionality of an excipient in an official monograph is probably
> very difficult to do and probably not necessary to do, because when
> you mix powders, you lose their functionality and you have to really
> deal with the functionality of that powder mix. So doing things
> on-line, doing analysis for that mix, is more relevant.
>
> So just I\'m going to quickly focus on the current paradigm is testing
> to document quality, and predominantly with wet chemistry, and that
> case has been made. But that\'s not what our FDA policies are. In
> fact, it\'s to look at the guidances and, say, the GMP guideline.
> These are the words that we use. Quality cannot be tested into
> products, it needs to be built in.
>
> That\'s what we say, but we do focus on testing. And the main reason
> for that is, if you want to build quality in, quality has to be built
> on knowledge, not data, and the level of sophistication and the
> details that our data can resolve is either medium to low. So we are
> in the bottom of there, where you\'re looking at historical
> trial-and-error data to establish specification and so forth. That is
> a contributing factor.
>
> We have talked about blending. I\'m going to quickly skip through this
> and say, why are we debating this? What is this debate all about? For
> 10 years we have debated this, and from an FDA perspective one could
> argue it\'s assuring quality. From an industry perspective it\'s
> simply to document. There is no quality problem we have to document,
> and we struggle to document that.
>
> But it is question of representative samples, and it is an indicator
> of art versus science debate, and is illustrative of test versus
> control mentality. Blending assay that we do in process is actually a
> test. You take a sample, test it. If it\'s not homogeneous, and if it
> don\'t have a protocol for reprocessing, you would throw away that
> batch. If it was a control, you would blend until it\'s homogeneous.
>
> Just to illustrate, from an FDA perspective, why we raise some issues
> here is, how do we control the quality of tablets right now? Suppose
> you have two steps. You have blending and making a tablet. You would
> blend, take 10 samples or 6 samples, and if the percent RSD or
> standard deviation is less than 6 percent, it\'s homogeneous. Then you
> would make your tablets. And how many tablets do we test for content
> uniformity? Ten. If the batch is 10 million, 20 million, that defines
> what goes up.
>
> And we recently did some research in collaboration under a consortium
> that we formed, Product Quality Research Institute, and a major
> company in the industry who did this work for that thing, sent this
> data to me. And this was a commercial, is a commercial product. They
> actually did this test to support the research efforts that FDA is
> having, and found a problem in a commercial product. And the problem
> was, those 10 tables were not really, truly indicative. They had to go
> back and correct that process.
>
> I\'m not going to get into how blending is done in chemical
> engineering. I was planning to do that, but let\'s skip to certain
> advantages that we see moving towards PAT. You are shifting the
> paradigm towards feedback control. You are helping to build quality in
> by improved and more efficient control of raw materials. You have
> process data that can be used for scale-up and modeling. Adequacy of
> mix with respect to all critical components, and Steve Hammond made
> that point.
>
> And just to illustrate that point, content uniformity is one
> attribute. Dissolution, drug release, is another attribute. If we do
> 10 tablet testing for content uniformity for a 10 million batch, we do
> six tablets for dissolution. Dissolution depends on a number of
> factors. We do not require content uniformity for critical excipients.
> You only do for drug.
>
> Here is an example. The person who provided, again, is from a major
> company. He is in the audience. He didn\'t want to be named, so I\'m
> not naming him here. This is a situation where we would not even have
> tested for blend uniformity because the amount of drug is so high, and
> the tablet was failing, and was failing in dissolution as a function
> of time.
>
> So if you have 10 million, what happens early part of the run, late
> part of the run, you might miss that. And new technology\--this is
> from Steve Hammond\--can address that.
>
> Something that I just wanted to point out, which is, our experience is
> slightly different from Steve Hammond. We have been working in our
> labs with near infrared imaging, and we can actually do image analysis
> where you\'re looking at the chemical image, the grey and white spots,
> so each pixel of that has the complete spectra. And actually we
> acquire that in less than a minute; he said 10 minutes.
>
> So we can actually look at a tablet, take a visual picture, and each
> pixel can give you full information, so non-destructive and so forth.
> And you could see whether it\'s uniform or not within a minute, and
> you can distinguish whether it\'s not mixed properly and so forth. But
> the technology is not an issue. We can do this step. That was the only
> point I was going to make here. And it is a win-win opportunity from
> public health as well as industry.
>
> And one point that was raised was out of specification and recalls. On
> the average, I think from a quality reason\--not average\--last year,
> the number is in my mind, I don\'t have an accurate number, we had
> about 150 recalls due to quality reasons on the drug side. Now, there
> were more recalls for other reasons, packaging, labeling, and so
> forth. But in my mind, the number 150 is in my mind, so I\'m pretty
> sure, but that\'s the score. The large percentage of out of
> specification recalls are for deviation to the physical attribute
> changes, and we right now are not focused on physics, we\'re focused
> on chemistry.
>
> One win-win situation from a public health perspective is, when
> somebody wants to go on-line to save money, time, and so forth, to do
> that you really have to understand your process well. And that is a
> win-win. You cannot just put something on-line and be happy with it.
> So it does support development of more robust processes and a high
> level of process understanding is needed, and that\'s one win-win that
> we are.
>
> Let me just quickly go to what we are doing. What should FDA do to
> facilitate introduction of PAT? Clearly in my mind, in our mind right
> now is, eliminate regulatory uncertainty. We have stated repeatedly
> the official FDA position: FDA is a science-based organization. FDA
> will accept new technology that is based on good science. We have done
> that repeatedly.
>
> What we don\'t have right now are standards for PAT, for its
> suitability, validation, and a whole host of things. In fact, you will
> have to approach this broadly, and every aspect of the process,
> including all of specification, how to deal with, has to be developed.
> We don\'t have that. In this regard we probably are lagging behind
> Australia and other countries, which is a bit unusual, for FDA to lag
> behind.
>
> What should we do? Just to continue on that. Define a clear,
> science-based regulatory process. That we feel is important. Current
> system is \"adequate for intended use\" would be one part of that. We
> will have to think about a win-win scenario, and to do that, defining
> that the current system is adequate, it may not be as efficient as it
> can be.
>
> So if it allows introduction of new technology without becoming a
> requirement, we have to think about that. So introduction of PAT, at
> least for some time, should not be a requirement, would be one
> approach.
>
> Define conditions under which PAT may replace current \"regulatory
> release testing\" is important. Don\'t simply keep adding the number
> of tests and hope that helps. You have to give something up, so you
> have to balance, based on what is needed, based on the redundancy that
> is required, balance the number of tests that are required.
>
> We have to develop a clear understanding of how to deal with invisible
> problems that are not visible today, but will become visible when you
> have process analytical technology. We will have to have science-based
> review and inspection practices, and we will have to work towards
> international harmonization.
>
> Again, the point I\'m making here is, generally FDA has led the way in
> those things. Here, we might be following, and we need to catch up.
>
> So the challenges we have, limited institutional knowledge and
> experience, we have to work towards building that. Seek input and
> collaboration, we feel that is the only way right now.
>
> What we have already accomplished is, we discussed this at the
> Advisory Committee for Pharmaceutical Science and got strong
> endorsement from that, and the committee actually recommended that we
> form a Subcommittee on Process Analytical Technology. The Federal
> Register notice has been out. End of November is the deadline to
> apply, and we encourage all of you who are here from industry to
> consider being part of that subcommittee. It\'s an open process. And
> we are going to define the objectives of that committee in terms of
> defining what the questions are for FDA.
>
> We also think we have to partner with industry, maybe with individual
> companies through a creator mechanism. Clearly we are already linked
> to academic pharmaceutical engineering programs and process analytical
> chemistry programs. We already have a consortium, PQRI, that we are
> using for that.
>
> So I\'ll leave it, stop my presentation with the questions Dr.
> Woodcock raised: Are you able to support what we are trying to do?
> What resources do you suggest FDA draw on? And are there additional
> aspects to regulation of product quality that we should focus on?
> Thank you.
>
> DR. WOODCOCK: Thank you, and we\'ll open it, if that\'s all right with
> the Chair, we\'ll open this for discussion now.
>
> CHAIRMAN LANGER: Yes. I would love to get comments from, questions
> both from our Board as well as anyone in the audience, and
> particularly, you know, along these lines. Bob?
>
> DR. NEREM: I mean, number one, it seems almost like a no-brainer that
> this ought to move forward, because it seems like FDA has a mission.
> Part of its mission is in fact to facilitate the use of advanced
> technology for the benefit of the American public.
>
> Having said that, what is it in the regulatory process of Australia or
> of other countries where they have been able to bring this on board,
> that makes it easier to bring it on board there than here?
>
> DR. WOODCOCK: Yes. Do you want to ask Pfizer?
>
> DR. NEREM: Right.
>
> DR. WOODCOCK: While you\'re coming up to the mike, let me give a stab
> at it. I think many of the other countries have less extensively
> developed regulation in the manufacturing sector, frankly. That makes
> it more difficult for us to change.
>
> DR. NEREM: Does that suggest that we have too many regulations in the
> manufacturing sector?
>
> \[Laughter.\]
>
> MR. HAMMOND: The difference in Australia really was the attitude of
> the TGA, the regulatory body there. They had an instant interest in
> the technology, to the point that they didn\'t just want to hear about
> it, they actually wanted to touch it.
>
> They came into the Pfizer plant, they brought staff, it was actually
> other companies, and they played with the equipment. They had heard a
> lot about it, but actually wanted to see really what it could do, play
> with it themselves, and went away with their own conclusions about
> what it could do.
>
> And I think that was the difference, such an interest, and I have to
> say Ajaz is treading down the same path. But that was it. It was a
> real, \"Let\'s get to know this, let\'s touch it, feel it, play with
> it.\"
>
> DR. NEREM: Is Australia the only place where this has happened, or has
> it also happened in Europe?
>
> MR. HAMMOND: It\'s happening very quickly now in the U.K. The MCA,
> with a meeting we had with them in March, they basically said to us,
> \"Well, what\'s your problem? Why haven\'t you brought this to us?
> What are you waiting for? We like it.\" So it\'s happening in a number
> of countries now.
>
> CHAIRMAN LANGER: Yes?
>
> DR. DOYLE: Are these technologies that you have developed in-house,
> are they proprietaries, so you don\'t want to share them with the rest
> of the industry?
>
> MR. HAMMOND: No, it\'s the exact opposite. In fact, we have developed
> these with commercial instrument companies, and the only way we can
> get those companies to develop these systems with us is to agree that
> they are available to anybody. That system I have shown you is a part
> number for Zeiss. If you go to Zeiss and say, \"I want,\" I can\'t
> remember what the part number is, but that\'s what you\'ll get. It\'s
> commercially available.
>
> DR. DOYLE: Well, in the microbiology arena we use the, what, AOAC, the
> Association of Official Analytical Chemists, to run these, I guess you
> would say validation studies, to compare to the gold marker. Couldn\'t
> something like this be developed?
>
> MR. HAMMOND: Yes, I think it could, and in the U.K. we\'re
> doing-we\'re running a program with the London School of Pharmacy to
> take these technologies, particularly near infrared, and develop gold
> standard guidelines on how you would actually set them up and use
> them. So I think that\'s a very good idea, yes.
>
> DR. WOODCOCK: The Product Quality Research Institute, which is a
> foundation, a separate foundation, was set up partly to do this type
> of work, which is to collaborate amongst industrial, academic, and
> regulatory sectors in doing the scientific work to, you know, develop
> scientific understanding, partly for introduction of new technologies.
> So there is already an existing mechanism, as Ajaz said, wherein if
> general kind of work needed to be done, that it could be, that would
> be generalizable.
>
> CHAIRMAN LANGER: Other questions or comments?
>
> DR. PICKETT: Yes, I just had a question. You know, this is, I would
> agree it\'s almost a no-brainer to really try to get this implemented,
> and one of the issues that I was wondering if it is an issue, is
> whether or not within the agency, if there is the appropriate
> scientific expertise in the agency to really begin to address some of
> these newer technologies as they come on-line.
>
> DR. WOODCOCK: Yes, that\'s one of the things we wanted to talk to the
> Board about, actually, because as Ajaz pointed out, much of the
> emphasis within pharmaceuticals for the last 100 years has been in the
> wet chemistry laboratory. Much of this is in chemical engineering and
> mechanical type of sciences and technologies that need to be brought
> in. And no, we don\'t have the range of expertise, neither in the
> field nor within the Center for Drugs, right now.
>
> CHAIRMAN LANGER: Any comments from, we have lots of people in the
> audience? Yes?
>
> DR. WOLD: I am Svante Wold from Umetrics, Incorporated. We are going
> to give a brief comment after lunch, but right now, I think that one
> way to get things rolling, we represent a technology that exists since
> many years, and one thing I wanted to say is that this technology, the
> pharmaceutical industry, interestingly, are far behind.
>
> Like the semiconductor industry that was mentioned, they applied this,
> exactly the same technology, and the semiconductor industry is very
> much a chemical process industry, which we don\'t understand what it
> is. All steps of making chips and wafers and so forth are chemical. So
> it\'s very much the same technology, the same instruments, near
> infrared is coming, and so forth, and it can just be lifted over.
>
> Now to be lifted over, I think one very interesting initiative would
> be if FDA and some drug industries agreed, let\'s set up a feasibility
> study on some existing processes where the traditional quality control
> works in a certain way. What will happen if we now put on proper
> process analysis chemistry and proper multi-variate evaluation and see
> what happens? And then we would all learn, and hopefully one would see
> that this is a win-win situation.
>
> CHAIRMAN LANGER: Any other comments? Maybe we could put those three
> questions up on the board for a second. But I mean the first one
> basically is, should you go forward, so maybe just to get a consensus.
> I think we sort of heard it\'s a no-brainer, but is that a fair sort
> of preamble to the questions?
>
> \"Are we able to support the approach?\" So does anybody have any
> disagreement with that? That\'s a no-brainer. I think several people
> said that.
>
> How about the other two questions? Are there any comments? I mean I
> guess there were comments kind of made. Are there any particular
> questions, Janet, that you want people to focus in on?
>
> DR. WOODCOCK: Well, I would appreciate any ideas the members of the
> Board have about academic, other resources that you know of.
> Obviously, we are prepared, as we said, to collaborate with the
> industrial sector on this, as well as the academic sector that we know
> about, but it strikes me there are many broad areas of expertise that
> need to be brought into this, as well as we need to hire some broader
> skill sets within the agency.
>
> And the other part is the additional aspects of regulation. I mean, I
> think the question that was asked earlier about why haven\'t we
> adopted this and so forth, it\'s hard to recognize, I think, unless
> you are actually involved in this, what a large paradigm shift this
> will be for the method of regulation of product quality, the way it
> has been.
>
> And we plan to go about this by taking some examples, as the person
> who just spoke said, taking some pilots and so forth and moving
> forward on small pieces, but moving to this approach really does pose
> a lot of challenges for the FDA. I don\'t want to underestimate that.
> And I guess those are\--
>
> DR. NEREM: Challenges\--
>
> DR. WOODCOCK: Pardon me?
>
> DR. NEREM: Challenges because of your mind set or what?
>
> DR. WOODCOCK: Yes, I think that\'s a fair\--well, it\'s really
> changing, yes, it\'s changing the philosophy or the paradigm, okay,
> from a testing paradigm to a reliance upon physical, chemical,
> on-line, and other types of trend methodologies, pattern recognition
> and so forth. It\'s a very different paradigm.
>
> It\'s going to cause some disruption to the industry, too, because
> we\'re going to find out stuff, as Ajaz was saying, we\'re going to
> find out things about existing products. There are existing products
> out there in market. We know they have problems. We know they fail
> their specifications intermittently. We don\'t know why. Now we\'re
> going to find out why.
>
> And so we\'re going to have a large range of issues that we\'re going
> to have to deal with as we go forward on this. But if you all feel,
> and I see you have some thoughts on this, you ought to share them with
> us.
>
> CHAIRMAN LANGER: Bob, did you want to share something? Do you want to
> say something?
>
> DR. NEREM: I want to let Alexa speak. Then I\'ll share something.
>
> DR. CANADY: As I listen to you, if I were an industry person, I\'d be
> terrified by your attitude. You know, I mean, in a sense of the
> concept that there\'s going to be tremendous dislocation. And I guess
> to me the idea of a successful transition is the avoidance of that
> dislocation rather than the acceptance of it.
>
> DR. WOODCOCK: Yes, that\'s a good additional aspect to keep in mind.
> Obviously, to make this a win-win, we\'re going to have to avoid those
> consequences.
>
> DR. NEREM: Yes. I guess, you know, that last question\--and obviously
> I\'m not speaking as an industry person\--but the word \"additional\"
> seems to me not to be the right modifier. Because presumably, you
> know, if one does a zero base analysis of the process with new
> technology now in place, you will come up with different regulatory
> aspects which won\'t necessarily be additional regulatory aspects.
>
> DR. WOODCOCK: Okay. Well, I wasn\'t talking about adding regulatory
> aspects. I was talking about what Dr. Canady was talking about. What
> are the implications of this are we going to have to be careful about
> as we move forward?
>
> Obviously, if this is set up in a way that people perceive severe
> negative consequences from this, that\'s an additional aspect that we
> need to keep in mind. I wasn\'t talking about should we add more
> testing. That wasn\'t the meaning of the question.
>
> CHAIRMAN LANGER: Owen, you wanted to say something?
>
> DR. FENNEMA: Well, I\'m a little puzzled about why there\'s so much
> concern about the difficulty of executing this kind of an advance. It
> doesn\'t seem that difficult to me. Maybe that\'s\--maybe I\'m naive
> about this. I don\'t know. But it doesn\'t seem that difficult to me,
> from FDA\'s standpoint, to adopt these kinds of new methodologies.
>
> What is needed, I would suggest, is simply a rather short document
> describing what FDA\'s expectations are when somebody comes forward
> with a petition proposing a new methodology. You know, what kind of
> validation procedures they use, some data they have collected to show
> that this is effective and accurate and repetitive. That is, to me,
> not a very difficult thing to do, and it should be done.
>
> CHAIRMAN LANGER: Any other? I\'m just going to make\--you know, when
> you mentioned on the academic thing, one thought that occurred to me
> was, you know, maybe to give some seminars at universities and
> chemical engineering schools, and certainly at MIT. Maybe Dr. Raju and
> I could work on that.
>
> But there\'s also other schools that we might be able to do that. I
> mean give, you know, a lecture and a seminar series, I think might,
> you know, get departments realizing that that would be useful, and
> maybe some students and post-docs seeing that.
>
> So maybe if you\--I\'ll be happy to help\--you could take some
> initiative to do that at MIT, and maybe Georgia Tech might, you know,
> and just different schools, there\'s a lot of chemical engineering
> departments that are around that might, I think, benefit from that. So
> that would be a useful way of, you know, maybe trying to sow some
> seeds.
>
> DR. WOODCOCK: Ajaz?
>
> DR. HUSSAIN: No, I think we are very cognizant and we are actually
> working towards that right now, and\--
>
> CHAIRMAN LANGER: How?
>
> DR. HUSSAIN: Well, at present, for example, right now I have a faculty
> appointment at Michigan and Purdue, and we are sort of downlinking
> University of Michigan pharmaceutical engineering seminars to FDA. We
> are making presentations on this quite often now.
>
> CHAIRMAN LANGER: Is this just pharmaceutical or\--
>
> DR. HUSSAIN: No, the School of Engineering has a pharmaceutical
> engineering program now.
>
> The point I want to make is, there is a transition. Pharmacy schools
> have lost the focus in this area, because they\--I came from pharmacy
> school, I was a teacher there\--they moved towards clinical, and a
> hole got left behind. And Rutgers, Michigan, have now a pharmaceutical
> engineering program in their engineering school. So we are working
> with them to get our ideas and our needs expressed, so that as their
> curriculum develops, as their research programs develop, they keep
> that in mind. So yes.
>
> CHAIRMAN LANGER: I think that\'s good, but I think that some of the
> comments that people in the audience made, as well as here, is that
> there is a lot of work going on in, say, materials, you know,
> semiconductors, material science, chemical engineering. And so
> somehow, again, I think people look for good problems, and this is a
> good problem. So that may be a very different set of people that you
> also want to, you know, get acquainted with.
>
> I\'m sorry, Bob. Did you want to say something?
>
> DR. NEREM: No, I would just simply, and you probably know chemical
> engineering better than I do, Bob, but it seems like a number of
> chemical engineering departments have initiated efforts in industrial
> bioprocessing. I think that\'s becoming wider spread than many would
> think.
>
> CHAIRMAN LANGER: That\'s right, yes, but I think that some of these
> particular things, I don\'t know that they are necessarily focusing
> on. So I think it\'s actually a good point. I think it\'s actually a
> natural thing that they would probably be quite interested in this.
> Yes?
>
> DR. PICKETT: Bob, just another question. I mean, we haven\'t heard
> from some of the other division directors, but I would be curious
> whether or not there\'s any lessons to be learned here, because some
> of the other divisions like CBER certainly have receive innovative new
> products, have had to rapidly accommodate new technologies in order to
> release those products, and are there things that can be learned from
> other divisions that would be applicable here?
>
> CHAIRMAN LANGER: Kathy?
>
> DR. ZOON: Again, I think a number of comments were made on the
> importance of an adequate science base for the agency and supporting
> the scientific underpinnings, to understand both from a process point
> of view and an analytical point of view the implementation of those
> processes into the biopharmaceutical field, for instance, which CBER
> primarily deals with.
>
> And one of the aspects is really trying to understand the technology
> early enough, and right now I think some of the areas that we\'re
> trying to focus on really deal with microarray and proteomics and
> looking at their eventual adaptation to processing of
> biopharmaceuticals in a way that has a quicker turn-around time and
> reliability and quantitativeness that will be utilized in the future.
> So I think having the scientific underpinning within the agency is
> extremely important no matter what discipline in whatever area we
> have, and each of the different Centers can lead the way for their
> particular areas of expertise that they may have.
>
> One of the interesting thoughts in hearing the presentations this
> morning, though, which I see as maybe not so much an FDA willingness
> to deal with the change, it\'s actually how willing the broad
> cross-section of the pharmaceutical industry is in accepting this
> change, because I think people are in different places. And certainly
> some of the older conventional products that have been around a long
> time, it will not be as easy for people to adapt the technology to
> those processes, or they may not want to make the investment. And then
> it becomes, if it becomes the state of the art, then that becomes
> CGMP, and then how does that relate then to the standard for the
> industry across different product areas?
>
> I think it\'s an important discussion, and where we have the
> capability, I don\'t think FDA should be the stumbling block for this
> at all, but I think we do need to investigate in the broader
> cross-section of the industry where people are in this, and have an
> understanding. And then how can we help get people into this field, to
> have better and more consistent products using the technology?
>
> DR. WOODCOCK: Ajaz said this so quickly, I think, that people may have
> missed it, but I really think that one of the things we will have to
> do with introduction of this new technology is that it cannot become
> the new standard against which all else is judged for a very long
> time, to be fair, that that be a stumbling block. If three people,
> three different firms or lines, production lines, have this
> technology, then that could not be considered the state of the art.
>
> And many of you are not aware of how this usually works, but there is
> a current Good Manufacturing Practices regulation, and one of those
> has to do with sort of continuous improvement of the basic standards
> for manufacturing, and we don\'t think that should be part of this
> early implementation.
>
> CHAIRMAN LANGER: Any other comments or questions?
>
> DR. FEIGAL: Could I comment about devices, just very quickly?
>
> CHAIRMAN LANGER: Sure.
>
> DR. FEIGAL: One of the interesting things to consider about devices is
> that some of the things you can do with pharmaceuticals, such as rely
> on pharmacology and pharmacokinetics because they are all drugs, you
> can\'t do that for devices. They are such a heterogeneous group of
> products. And so it\'s interesting to look at how the structure of the
> consumer protections were built around devices.
>
> As you are probably aware, the majority of devices are approved with
> the 510(k) mechanism, by which they show that they are substantially
> equivalent to another product. There is no manufacturing section in a
> 510(k) application. The kinds of manufacturing controls that they have
> to put in place do not get any type of pre-market clearance in that
> process. There are still manufacturing standards and controls that are
> required, but they are to be established by the field at the time of
> the inspection.
>
> So it creates a very different environment that actually allows rapid
> changes in that kind of a sector, because there is no pre-market
> clearance, there is no manufacturing supplement, none of those types
> of features. Now, there are times when that creates a problem, and we
> have a real concern about the products.
>
> There have been implants, for example, that have had sort of
> constantly changing design features in terms of thinness of material,
> method of casting, which plastics were used as cushions for\--it was a
> weight-bearing implant. And it was very hard to know, as we looked at
> failures of that implant, what we were dealing with, because there was
> no requirement for us to be told when all of the different kinds of
> changes were taking place. And that is, it\'s actually one of the
> nuances of the device regulations, is when do you change it enough
> that you actually owe us another application because now it\'s a new
> device?
>
> The 60 or so devices that are novel enough to be approved under the
> PMA process have similar types of manufacturing requirements, but
> again because of the fact that devices are so different from each
> other, I think there probably is a climate where we are much more used
> to change.
>
> And like drugs, one of the things that Janet mentioned earlier\--or I
> think you did, I can\'t remember if you did or if this was a
> discussion on the break with someone else\--but one of the things that
> has happened is that many more things have moved towards no longer
> requiring pre-approval from us, but being things that they notify us
> change is being effected, or things moving into annual reports, or in
> our case we have something called real-time review which is used in a
> lot of the manufacturing, manufacturing changes.
>
> But it\'s actually one of the hardest things for us to know, is when a
> change enough that you actually should go back and learn something
> about the product again? It\'s a big issue for biologics. There are
> times when a subtle change actually has an unintended disastrous sort
> of effect. And the hard judgment in science-based regulation is to say
> which of those make enough difference that you want to see those in
> advance, want to stop and think about those, versus what happens with
> many things, including most recalls, which is you discover a problem,
> you go back and figure out what caused it, and see if you can prevent
> it the next time around.
>
> CHAIRMAN LANGER: Any others?
>
> DR. FENNEMA: There are some questions in the back.
>
> MR. PARSONS: John Parsons, and I represent Umetrics, but my background
> is 25 years in the industry from the commercial side. And I would just
> like to, now that I\'m not in the industry, make a comment I think
> that isn\'t addressed here.
>
> I think, as I listen to what Ajaz and the group here have presented,
> it\'s invaluable to the industry and to patient. I think that\'s the
> key here, that we deliver the quality as a commitment to the patients,
> and obviously that\'s what the agency is all about.
>
> But from the commercial side I can tell you, as a member of an
> executive board, this kind of discussion from an investment standpoint
> and a risk standpoint just turns my stomach, because of the concerns
> that were expressed before. It\'s a reengineering effort that has been
> described by Pfizer, by Norman and Steve, that has to be done through
> the process change and also all of the investment in terms of the
> equipment. And it\'s also a risk I think that has been identified in
> terms of what will we find that we didn\'t know about the product
> before, particularly for the older products.
>
> I would just say this. I would encourage the agency, as you move
> forward, that you do this as a cooperative effort with industry, and I
> am sure that you will do that, so that there is a transition period
> with the enforcement necessary to bring this to fruition, because
> it\'s absolutely necessary, but also where there is a cooperation, so
> the industry doesn\'t rise up and with the powers that are there,
> perhaps interfere with something that\'s necessary and that absolutely
> will benefit the patient in the long run. Thank you.
>
> CHAIRMAN LANGER: A comment back there?
>
> MR. ROY: Suva Roy, Otsuka Maryland Research Institute.
>
> Having lived on both sides of the fence, so to speak, being in FDA,
> being now in industry, I don\'t think the regulatory hurdle is as big
> as people think it is. There is the process of alternate controls that
> can be applied, and FDA doesn\'t even need to approve those things.
> Perhaps what the FDA can do to change that, to make it a formal
> process, is allow the companies to submit supplement to the
> application, and allow that for approval which is not a current
> process that is entertained or used.
>
> And secondly, the other comment I wanted to make is that it is very
> heartening to see that now, after probably about 25 years after I had
> played with something, that something else is coming to fruition. Back
> when I was working in industry, I had worked with, played with,
> literally with tablet compacts and acoustic vibrations to see if that
> tablet fractures. However, back in the early \'80s there was not
> enough computer power to do that quickly. As a result, it was just an
> academic thing, but it is very interesting to see it coming through,
> and I really, really like to see this develop, and I commend Ajaz for
> bringing it to the attention. Thank you.
>
> CHAIRMAN LANGER: Any other comments? Yes?
>
> MR. TURJAC: I had to say something. Emil Turjac. I\'m with Purdue
> Farmer right now, but I\'ve taught and I\'ve been a consultant, and
> I\'ve been around even longer than the last gentleman, about 30 years.
>
> To our academic friends, I was there early enough, when we tried to
> introduce HPLC, and the FDA did not have instruments or people who
> knew how to run it. And as a time-consuming thing, to keep stalling,
> it was \"What\'s wrong with titrations? They\'ve worked for 40
> years,\" until they could hire the people and get the material.
>
> Having done that, and most of the people of my genre are now directors
> or the like, and they\'re sitting back saying, \"If we put something
> new in, it\'s going to delay our NDA, so let\'s just go to the USP. We
> know it\'s better, and for alternatives we would have like laser light
> scattering for particle size as our alternate method, and for thermal
> analysis for melting rings as an alternate method, because God forbid
> we hold up, because we\'ve got 15 years of our 17-year patent already
> shot. We can\'t have that come back to us.\"
>
> So I think it\'s gun-shy. The younger chemists and the younger FDA
> people are going, \"What\'s wrong?\" But the people who make the
> decisions have been burned and they don\'t want to do it again.
>
> CHAIRMAN LANGER: Any other comments? Yes?
>
> DR. HUSSAIN: Just to comment on the alternate approach, the alternate
> approach is fine. I think that leads to the two parallel universes
> that Pfizer talked about. You still have the old method that you have
> to do for regulatory compliance, and then you can have an alternate.
> It doesn\'t solve the problem. I think we really have to bring the two
> universes together.
>
> CHAIRMAN LANGER: Any final comments before we eat?
>
> Well, I think that the consensus is certainly that everybody seems to
> think that you should go ahead with this
>
> \--oh, is there another, another one?
>
> MR. ROY: I just wanted to add to Ajaz\'s comment, that if FDA has got
> a process of approving the alternate methods once they are mature
> enough and the company wants to do so, that solves the problem. Then
> it solves the problem of parallel universes. Unfortunately, that\'s
> not a process that is right now in place or is actively entertained.
>
> CHAIRMAN LANGER: I think on that note we\'ll probably adjourn the
> session and meet back at 1:30, but I think hopefully the dialogue can
> obviously being continued, and people should feel free to give you
> feedback, and it will be great to hear in future sessions how this is
> going, but obviously it\'s very positive.
>
> DR. WOODCOCK: We thank the Board for their advice.
>
> \[Whereupon, at 12:45 p.m., the meeting recessed, to reconvene at 1:30
> p.m. the same day.\]
>
> AFTERNOON SESSION
>
> CHAIRMAN LANGER: If people could take their seats, we will get
> started.
>
> A number of people have requested to make comments, so the first one
> is Dr. Wold and Dr. Parsons and Dr. Josephson from Umetrics. What I
> was going to do is ask each group to hold their comments to 5 or 10
> minutes maximum, but if the first group would like to get started.
>
> DR. KETTANEH-WOLD: I would like to talk a little bit about real
> quality control of batches as they are evolving, rather than doing
> what we have talked about, was one waits until a batch is finished, do
> some quality control, find that it\'s not up-to-date. You cannot\--the
> accepts are not found, no correction can be done, and you get only
> scrap.
>
> Instead, one can have real-time quality control. How do we do that?
> Well, first of all you have to have some infrastructure. That is, on
> your batch you should be measuring on-line some adequate variable,
> adequate parameters, like temperature, pressure, whatever.
>
> We summarize that multivariately in a good way, and model the
> evolution of the batch, and once we have that, we have good
> representative set of batches. You can make a fingerprint. That is,
> you can have the average trace of good batches within three sigma
> limits.
>
> Once you have that, which is based on modeling the evolution and
> having this control chart, new batches as they are evolving in the
> real time are displayed inside this fingerprint, and you can see it.
> If they go out of the limits, all you have to do is find out which
> variable is causing that. You can just double click on the software
> and say, \"Why is my batch going out?\" And you can make immediate
> correction.
>
> And not only that, but when the batch has reached 50 percent of the
> evolution, we can predict what the whole quality will be, and you can
> see this prediction changing as the batch is evolving. And this is
> just based on multi-variate analysis and then taking the average and
> making control charts.
>
> And here I will show you a blending. This was a pharmaceutical process
> of mixing, and you can see here the trace, the fingerprint. This is
> the fingerprint. All good batches should evolve right in this little,
> little interval. The red line are the three sigma; the green line is
> the average trace, the golden batch, the average trace of the good
> batch, and these are two summaries of it.
>
> And you see now a new batch as it is evolving, and you see that there
> is first a starting phase, then there are levels that are changes of
> the variables, and then it showed evolving here. This batch has
> started increasing the level much too early, and if we just double
> click on that, it tells us which variable has been increased way too
> fast, and then you can immediately correct and bring this batch back
> to make it evolve within the limits.
>
> And if you want to see what is the control chart of this variable, you
> can just double click on the variable. You can see that for this
> variable it shows first there at 3,000 something here, and then raised
> the level, and they have raised the level way too early. And this
> allows for correction immediately rather than when the batch is
> finished.
>
> And if you have a lot of these and you follow them, and you know that
> these batches stay within the limits, you are almost sure to have a
> good batch. And this is very simple, it\'s visual, it\'s based on good
> science. It uses multi-variate analysis to take all the variables in
> account, including their correlation. It\'s like your Dow Jones
> that\'s a summary of our stock market. It tries to do the best
> possible summary of the evolution, and it also takes in account all
> the raw material and all the initial conditions.
>
> So the benefits are enormous. It brings the analysis of three-batch
> data to a simple framework. It allows interface as the batch is
> evolving. You can predict final quality. And it applies to both the
> evolving batch and the whole batch. The results are very easy to
> interpret, and it can facilitate compliance with regulation, because
> instead of sending numbers, just send the fingerprint.
>
> And one last comment on everything. As somebody once said, that change
> is the practice complicated and frightening, but not changing is
> worse. It\'s just that one has to manage the change with a transition.
> Thank you.
>
> CHAIRMAN LANGER: Are your colleagues talking, or just yourself?
>
> DR. KETTANEH-WOLD: No, that is\--
>
> CHAIRMAN LANGER: Okay, great. Any comments or questions?
>
> Okay, then we\'ll go on. The next statement and comment will be by
> Gideon Kantor.
>
> DR. KANTOR: The purpose of this talk is not for you to find out
> whether I\'m ambidextrous. By the way, you need to change gears
> because you are now going\--excuse me, you have the page on that, what
> I\'m going to cover, and it\'s a little bit of a different topic. And
> what I\'m talking about is enhanced regulation, regulatory science,
> for animal research.
>
> First I think I should kind of give you a little bit of a sketch of my
> qualifications. Okay, what I\'m going to talk about is first my
> qualifications, then I\'ll talk about the rationale for my proposal,
> then I\'ll talk about the enhancement considerations, and then finally
> one thing I always end up with is final comments.
>
> Okay, my qualifications. I am a past president of the FDA Sigma Xi
> Chapter. I would like to brag a little bit here. I was the first CDRH
> president of the FDA Sigma Xi chapter many years before it reached
> popularity at CDRH. And I am a member of the chapter now.
>
> In 1995 I retired as a research physicist from CDRN/OST, and since
> then I have regularly taught as Adjunct Associate Professor,
> Biomedical Engineering Department of Catholic University of America. I
> have taught a course in neural stimulation in rehabilitation, and I
> also give some lectures on regulatory aspects. I am trying to teach to
> the students that really want to go into biomedical engineering in a
> practical manner, if they don\'t like to get involved in regulatory
> aspects coming up as a part of it, they better change their field.
>
> And I am presently a member of the Institutional Animal Care and Use
> Committee, and I want to emphasize that my statement below is strictly
> my own. I would like to reiterate that. My statement is strictly my
> own. Any members of the committee, in this particular case guilt by
> association does not apply. But I am mentioning that to the membership
> of this committee to explain how I developed an interest in the
> regulatory science issue of enhanced animal research.
>
> Now let me talk about the rationale. The unjustified death of a
> volunteer at Johns Hopkins Medical Center, and previously the
> unjustified death of a volunteer at the University of Pennsylvania
> Medical Center, are of great concern to me. I would like to say why
> this is of concern to me. I am a product of Hitler Germany, and I do
> know I exaggerate, but whenever I see what I consider clinical
> experimentation which is not carefully regulated, I get the jitters.
> But this is strictly a personal problem and it\'s not meant to
> convince anybody else about the point of view that I have.
>
> And there are more cases that were discussed in the August 6, 2001
> Newsweek issue on page 36-42, thanks to my wife pointing it out to me.
> These are the reasons that I would like to propose here that possibly
> enhancing the role of regulatory science, animal research, might
> result in minimizing these types of fatalities.
>
> Before I become more specific, I would like to first refer to the FDA
> 2001 Science Forum that was concerned with establishing linkages
> between various scientific disciplines. On the sideline, I would like
> to say I am very much interested in this whole question of linkages,
> and it is my opinion that a meta search engine that links different
> type of data banks with their keywords is essential for us to move
> into the 21st century and not feel inundated with information.
>
> Okay, excuse me. I believe that there is another opportunity to
> establish new linkages between animal and human research, and by doing
> this possibly increasing safety of volunteers in clinical trials. That
> is one thing that I noticed, I am very much clinically oriented in
> terms of a biomedical engineer, and one thing I noticed when I joined
> the IACUC committee is that that linkage was really not there, at
> least the way I saw it. I did not notice any linkage. People did their
> animal research but they didn\'t realize that it has some links with
> human research. Again, this is my personal point of view.
>
> Based on my own research, I have gotten involved in discussion of
> global-local thinking and the information explosion, so I really felt
> pretty good. Sometimes when you go on your own, you feel that you are
> really kind of crazy. I still am probably kind of crazy, but at least
> here was an instance where I was not.
>
> Enhancement considerations. Since I do not have specific data
> available pertaining to results in regulatory science animal research,
> all I can do is ask a few intuitive questions and then hope that the
> Board will have time to respond to them, and I\'ll be covering three
> topics: IRBs, FDA reviews, and in-house animal research.
>
> Institutional Research Boards. Could the Institutional Research Boards
> enhance their awareness of considering animal research in terms of
> trying to minimize fatalities in clinical trials? And as I was
> re-reading this paper here, what came to my mind, maybe my immediate
> training in this respect might be purposeful.
>
> Number two, FDA reviews. Could the awareness of FDA reviewers be
> enhanced in terms of assessing whether animal research is needed
> before human trials are approved? Since I worked in FDA until 1995, I
> realize that the FDA reviewers are under terrific pressure to get
> things done, so this is here kind of a rhetorical question. It seems
> to me that if this were done at all, then some more money must become
> available to project for this particular purpose.
>
> In-house animal research. Could the FDA focus on doing animal research
> in support of clinical trials be enhanced. Now, that I think is
> something that you can subconsciously develop, because you can always
> have ideas at night where you don\'t get paid for them and bring them
> in in the morning. But it seems to me that if this is in the
> background of animal researchers, this idea that yes, that thing of
> those clinical trials, that kind of self-consciously it seems to me
> eventually they would go in that direction, but again this might mean
> some training.
>
> Final comments. In support of my proposal of enhancing regulatory
> science animal research, I would like to refer to the statement of Dr.
> Schwetz in his introduction to the 2001 Forum: \"As we continue to
> enhance the science foundation of FDA, the effective training and
> retraining of our scientific and our medical personnel is among our
> highest priorities.\"
>
> And this really brings out not only the training at FDA which I
> greatly enjoyed while I was there, but also the outside world like
> hospitals and so forth. Can there be maybe a foundation that has too
> much money, could spend, could start a grant in this direction?
>
> Accordingly, it might be useful\--I kind of interrupted this, but
> based on the last Forum and the statement of Dr. Schwetz\--it might be
> useful to have a session on enhancing regulatory science animal
> research at the 2002 FDA Science Forum, if possible, or instead later
> on at the 2003 Forum.
>
> I like to thank the committee for giving me the opportunity to present
> my very, very, very personal views. Thank you very much.
>
> CHAIRMAN LANGER: Thank you. Any comments, questions? Thank you very
> much.
>
> The next person to speak is Scott Ratzan, who is the editor of the
> Journal of Health Communication.
>
> DR. RATZAN: Good afternoon. Thank you, Mr. Chairman, committee, and
> everyone here for the opportunity to speak today.
>
> I wanted to sort of switch the discussion, which I think presages what
> Dr. Nerem is going to talk about in terms of some of the challenges
> subsequent to the public comment period on the need of how we
> communicate risk and how we make regulatory decisions, and the impact
> that it has upon the public.
>
> As you can see, I edit a journal, the peer review Journal of Health
> Communication, and I\'m on the faculty at three different universities
> where I basically teach health communication, one in the School of
> Epidemiology and Public Health at Yale; at Tufts in the Department of
> Family Medicine and Community Health; and at George Washington in
> Public Health and Health Services.
>
> As I\'m told here, I\'m supposed to also disclose other conflicts. I
> consult on a variety of areas, with the common denominator being
> communication. I consult with about five different pharmaceutical
> companies, on and off, dealing with communication issues. I\'m on the
> study section for the Agency for Health Care Research and Quality, for
> communication. I consult with about six other Federal Agencies, NIH,
> CDC. I\'ve done consultations with WHO and a variety of others. I also
> have sat on two IOM committees, most recently in terms of
> communication with quality issues and health indicators for the
> country.
>
> With all that being said, nonetheless I\'m representing myself today.
> I\'m not representing any of these other groups that I\'ve spoken
> about. And I\'m trying to raise the debate to deal with ethical
> communication.
>
> There were busy Brueghels in the 15th, 16th century. Our life is just
> as complicated today. However, we try to explain a lot of things in
> two dimensions. We try to explain things with one versus the other.
>
> So what I\'m going to try to do is a 10-minute challenge for me, as
> Celeste had given me. Background on communication. Lessons that we
> have learned from BSE. Thimerosal and vaccine risk. And recent
> challenges that are very fresh in our mind, dealing with anthrax. And
> some ideas that I think this committee could well consider and advance
> the public health.
>
> Our goal is really similar to what the World Health Organization has
> presaged many years ago: \"Informed opinion and active cooperation on
> the part of the public are of utmost importance in the improvement of
> the health of the people.\" Clearly we embody that in the open
> process, and again, thanks for even speaking today.
>
> But how do many of us make decisions, whether we\'re on advisory
> committees, different committees, and so forth. Sometimes we say the
> data speak for themselves. Of course we know, we\'ve already heard
> data don\'t speak. There is data, information, knowledge, and wisdom.
> We can explain the issue with statistical significance. Can science
> always explain the areas? We have progress that is incremental with
> evidence-based hypothesis testing, the 21st century approach. And we
> still believe that scientific method can solve most dilemmas.
>
> But how does the public make decisions? Very differently. Many think
> the mouse is a little human, or even worse, the plural form of the
> word \"anecdote\" is evidence. And this goes back to what I think
> James Fennimore Cooper first said in 1831: \"They say\" is the monarch
> of the country. It doesn\'t matter who says it, as long as the public
> believes \"they\" say it. We have to think, who are they \"they\"? Is
> it the media? Is it us?
>
> And how ought we make decisions? George Campbell reminded us,
> \"Passion is the mover to action, but reason is the guide.\" And
> we\'re all here doing reasoned, evidence-based, but I believe that
> evidence also means hard\--and I\'m not saying soft sciences, but the
> social sciences. How we measure public opinion, as Walter Lippman had
> mentioned last century, in a whole variety of other ways. That we\'re
> goal-driven, thinking of the public health and the people that we
> basically serve. And then finally, we\'re using credible, trustworthy,
> understandable, and emotional and cultural sensitivity.
>
> So what does all this mean? It means what we do here today, sound
> science and evidence. We add value with deliberation, debate, and
> dialogue. And, finally, we\'re involving a variety of different people
> in the process, ideally a partnership that I think other speakers have
> already mentioned today.
>
> But nonetheless, when committees often sit down, we have a sound
> science and evidence approach. What is the strength of the evidence,
> and what are the scientific criteria for regulation? Or, on the other
> axis, how high is the risk? And if risk is so great, we have to
> regulate or do something specific.
>
> But there\'s been some changes, as you might know, over the last 47
> years or so. It was really just a randomized clinical trial that
> started in 1947. I mean, it\'s not like that\'s been the gold standard
> for centuries. And now we have new standards, a precautionary
> principle, which is the axis going down, of where we basically lower
> and have changed some of the burden of proof.
>
> And more recently, something that is very much of a concern to me is
> the Thimerosal issue, and we\'ll deal a little bit more with that in
> the presentation. Because Thimerosal, a recent Institute of Medicine
> committee has issued a different measure of biological plausibility,
> and whether you agree with where I actually put that arrow, I think we
> need to think where is that red line and how are we going to be able
> to continue to do that committee after committee after committee that
> has different views.
>
> So how do we deal with uncertainty? The precautionary principle has a
> variety of different definitions. Some people take it down to \"It\'s
> better to be safe than sorry.\" Others are saying no, in advance of
> having complete scientific knowledge, theory testing, basically we\'re
> using foresight.
>
> But the changing paradigm has really challenged us. It has challenged
> us that the burden of proof is shifting. It used to be to make a
> change you would have to say why something is better than the status
> quo. Now we have to, for the Thimerosal issue specifically, why is the
> status quo specifically bad? Scientific uncertainly, and hence
> subjective evidence, is in the equation. And, finally, scientists and
> regulators are requiring evidence now that still needs experimental
> design.
>
> What can we do? I\'ve been looking at the evidence based on this, not
> only with my journal, but also I edited a complete current
> bibliography of medicine with the National Library of Medicine on
> health risk communication, and there\'s 847 different articles we
> found. Institute of Medicine has done about three reports already. But
> still, nonetheless, we often don\'t follow the same science base that
> has been presaged by them, of how we deal with value judgments and how
> people make decisions about risk information.
>
> Vince Covello has done a lot of this work at Columbia in terms of his
> Center for Risk Communication, and what he shows us in a variety of
> different studies with other people is that trust and benefits are
> looked at as the most important elements. These are not scientific
> elements of what the actual risk is, or probability based. This is
> trust in the messenger. Who is saying it, and what does it mean? And
> we\'ll think about that just in terms of the anthrax issue that is all
> probably still fresh in many of our minds. Myself, living in
> Washington, I still haven\'t got my mail that\'s quarantined.
>
> This is the process, what happens. Policy-makers, experts, opinion
> leaders and the public are in partnership. And it says here, \"Upon
> further consideration, the evidence of fire is not as strong as first
> as it appeared. We regret any confusion that we may have had, and will
> continue to,\" and you can see everybody stormed out of the theater.
> This is my segue into BSE, vaccines, and anthrax, and some of the
> challenges that we face.
>
> I will very quickly go through the BSE issue, because I know I only
> have 10 minutes. And on the back cover of a book that I edited, \"The
> Mad Cow Crisis: Health and the Public Good,\" I have these three
> quotes.
>
> \"The biggest crisis the European Union ever had,\" according to Franz
> Fischler.
>
> \"The worst crisis the British Government has had since the
> Falklands,\" said John Major.
>
> And \"If one wanted to study the perils of imperfect policy-making,
> this case provides them all.\"
>
> I could probably update. The book came out in 1998. Last year, in
> 2000, the Frankfurter Allgemeine said BSE was going to be the Black
> Plague that had not hit Europe yet, and some people still say it\'s
> the AIDS crisis that the British never had.
>
> This is, however, a back report looking at it: \"There still is no
> scientific proof that BSE can be transmitted to man by beef, but this
> is seen by SEAC\"\--which is the Spongiform Encephalopathy Advisory
> Committee\--\"as the most likely explanation, and all our control
> measures are based on the assumption that it is.\"
>
> We have continued, and we could explore this everywhere from our TSE
> Blood Advisory Committees to a lot of different policies that have
> changed around the world, this has been a problem of where the
> scientific proof lies. Above the line here the trade union officials
> and others are who people trust, and below the line are who people
> don\'t trust. And as you can see, the government scientists, the
> business leaders, the politicians, the government ministers, and the
> journalists all have lost as part of this BSE issue. This is in the
> U.K. I don\'t have data in the United States. We haven\'t measured it
> as such, like this. It would be very interesting to see what this all
> means.
>
> Last, in terms of what the House of Lords report that came out last
> year reminded us, the government did not lie to the public about the
> BSE. Government was doing their job. They believed the risks posed
> were remote. Confidence in government pronouncements about risk was a
> further casualty. And of course it then says that this is actually
> affecting everything in the areas of science, including biotechnology
> and information technology. And the British, later in the report they
> actually recommend a committee for the public understanding of science
> be integrated at the federal level, at the U.K. level, and then in
> different universities.
>
> I\'m going to switch a little bit to Thimerosal, but I\'m going to do
> this quickly because this is very data-rich and it is still, the jury
> is still out, and part of it is early. You may recall that almost over
> two and a half years ago, Thimerosal, by part of an act it was
> released that it was a vaccine preservative that could have exceeded
> the actual mercury dosage.
>
> Needless to say, a lot of policy happened very quickly, our public
> health groups, our academies of pediatrics and so forth. And the long
> and short of it, if you read through the basic pieces, are that
> Hepatitis B vaccinations, despite that there was vaccine on the
> market, the real experiment, shall we say, once policy was made,
> caused thousands of people, of children in this country, not to get
> vaccinated, and there\'s already some documented cases. Particularly
> CDC has looked at four states, one state where there is a definite
> death and others that are still there. And this is how it is still
> ongoing, and right now because of the uncertainty, each state by state
> is only slowly increasing to levels of Hepatitis vaccination that\'s
> necessary. And as you see at the top, it could prevent as many as
> 5,000 deaths a year.
>
> And I\'m rushing through this, unfortunately.
>
> CHAIRMAN LANGER: It\'s about 10 minutes, if you could try to finish
> up.
>
> DR. RATZAN: Okay. I\'ll skip over the IOM stuff, and I just have three
> slides on anthrax. Who does the public believe in health, in issues of
> health? And if you see, on the bottom are the people we usually hear
> from; and if you see at the top, people who people trust, remember
> that\'s science-based trust.
>
> And these were the messages that came out in the last three weeks.
> Most of the messages that came out from politicians and government
> leaders are below the line in the mistrust area.
>
> This was what Scott Lillibridge said last week: \"We knew that
> communications would be important, but I don\'t think we knew it would
> be this dominant in the response.\"
>
> So what\'s the common denominator? And thank you, Mr. Chairman, for
> another minute or so here. Public health values need to be integrated.
> How do we do that with societal risk quotient? When we make decisions,
> how does it play out in society? And if we don\'t consider
> communication, we\'re going to have a fulminating, unintended effect
> by our policy efforts.
>
> So these are the questions I have and things that we should think
> about. If we embody on evidence-based approach by providing stringent
> scientific reassurance related to regulatory issues, we\'re not
> reassuring the public(s) that we serve. That\'s really not scientific.
> What we really need to do is think about value and trust driven, so we
> have a common rubric. And I think that this, the field that I am in,
> is the most humane of the sciences and purest of the arts, and we try
> to balance both of those.
>
> So these are the five questions: One, could every committee have an
> expert or someone who thinks about communication or public health, who
> could add the science of how this most likely will play out? If we
> make this decision, what will happen? And think about perceptions and
> practice. There is a scientific approach to this.
>
> Secondly, does the status quo consumer representative that we have on
> the committees really represent the public, or are they more advocates
> representing a subgroup of that public? That\'s an important question
> to think about.
>
> Can we develop a common metric? And this is something I think is one
> of the biggest challenges, particularly with all the different
> advisory groups, not only here in Washington at FDA but all around,
> and CDC committees and so forth. Can we try to have a rubric for
> biological plausibility and safety and precautionary principle?
>
> And the final questions: Can we integrate societal risk, that risk is
> not just for the molecule, it\'s not just in the Petri dish, it\'s not
> just in the laboratory, it\'s where we all live. And that\'s just not
> with vaccines, that\'s if we\'re thinking about how we may recall or
> limit certain drug use and then other potential morbidity and
> mortality to other drug use, on common over-the-counter drugs, for
> example.
>
> And then finally, could the FDA establish a coordinated communication
> program to inform the public and their intermediaries of how decisions
> are made under uncertainty, as well as the real risk of products? And
> that, I think, is the more opportunity to develop what my research is
> in, is in health literacy and how we can develop a health literate
> public.
>
> And unfortunately 90 million Americans can\'t read or write on an
> ongoing basis, to understand the level of what we\'re putting out in
> terms of informed consent and a variety of different scientific
> pronouncements, and I think it\'s our job as well as the public\'s and
> others\' job to really increase that communication and understanding.
>
> And I know it\'s tough to do all this in 10 minutes, and I appreciate
> the chairman and the committee and the public for hearing me. Thank
> you.
>
> CHAIRMAN LANGER: Thank you. Any comments or questions? Thank you.
>
> The next speaker will be Dr. Levin from Brimrose Corporation.
>
> DR. LEVIN: Thank you very much for an opportunity. As someone who
> spent like almost 16 years in a different industry, I wanted to bring
> a few things from my experience in another industry that can be
> useful, and then share with you some other information.
>
> My personal belief is that from our history, we will move in this
> direction for more real-time process control, more real-time
> nondestructive product testing, and biometric release. I believe it\'s
> going to go there because I think it doesn\'t have an alternative. The
> expected results will be high product quality and security,
> substantial cost reduction, benefits to shareholders, and benefits to
> the public, universal drivers.
>
> Can we learn from other industries? I worked 16 years in the aircraft
> engine industry. Both industries hold people\'s lives in their hands.
> You fly up in the air, you are in their hands. You take a drug, you
> are in their hands. Both are federally regulated. They are very
> competitive. They drive their products with strict performance limits.
> They are being chased by generic products behind them. They are also
> driven to lower prices by government and by the users.
>
> Okay, very quickly, aircraft engine industry in the \'70s. Product
> testing was the major quality thrust, backed the product. Pratt &
> Whitney, incoming house testing lab, 600 people. Ratio of inspectors
> to operators, two to three, about. Operators not responsible for the
> quality; the inspectors are. Statistical process control, nonexistent.
> Scrap factory, 20 to 30 percent of the total volume production.
>
> In the early \'80s they made a change to active and statistical
> process control, became a major Total Quality Management. Pratt &
> Whitney incoming, in-house testing, down to 100 people worldwide.
> Ratio of inspectors, about one to eight. This is a huge savings, cost
> reduction. Operators now become responsible for the quality, not the
> inspector who is supposed to catch something. Scrap factory down to 5
> to 8 percent, it\'s going down. Quality increased, engine failures
> became rare. This week I really got scared, because what if this
> American Airlines was downed by an engine, but it was not, so I kept
> this slide in.
>
> \[Laughter.\]
>
> But I really got scared. Cost, dramatic reduction. Typical cast blade,
> I was involved in this technology, is now 3 to 4 times cheaper for the
> cost but the quality is much higher.
>
> Where is the industry today? I think I can skip this one because you
> were already told where we are today, so I don\'t need to say much
> about it. Still product testing, on-line active process control is
> still minimal. I don\'t know what the range of QC to operators are,
> maybe one to two, I don\'t know. Statistical process control, I was
> told practically nonexistent. I don\'t know what the scrap factory is,
> but you were told today it was about 20 percent, something like that.
> Still too many recalls, 200 about a year. Product uniformity still an
> unresolved issue.
>
> Can we learn? Yes, we can, because the drivers are the same drivers
> for the change, the government and customer, pressure to reduce cost
> to operate, competition, performance, pressure to maintain
> profitability for shareholders, sense of \"dead end\" in doing more of
> the same. This is a huge driver. And the thing that today we see that
> there is a sense that if we keep on doing the same thing, more and
> more and more, it\'s a dead end. And the FAA provided strong support,
> anticipating the benefits to the public. Being a Federal agency, they
> thought about the public, and it\'s their duty.
>
> The conclusion that I draw from that is that the pharmaceutical
> industry will follow the same path taken by the aircraft engine
> industry in its bid to be more cost effective and, above all, more
> profitable. After all, you got to make money; otherwise, nothing
> happens, and we know that. So the facts are, same drivers, the FDA is
> providing now increasing support, realizing the benefits to the
> public, and we have Ajaz and other people, and the industry is getting
> again the sense of \"dead end.\"
>
> How? The question is, how we going to do that? And there is more than
> one tool, and we have seen some of them, but I still think that NIR is
> probably the most significant, and as success will create new and
> improved tools, soon we will not be able to understand how we could do
> it otherwise.
>
> Why is NIR so important? I think it is the only tool that really
> provides significant chemical and physical information on the bulk of
> the product, not just the surface. It is the only method that
> penetrates tablets and capsules for complete characterization. And it
> provides information on all ingredients, not just the active. Is a
> tablet good if some excipient missing? I think it\'s not. If it was
> there to begin with, it\'s supposed to be there when I take it, so I
> like it to be there.
>
> Sorry, forgot to turn mine off.
>
> DR. NEREM: That\'s your timer.
>
> \[Laughter.\]
>
> DR. LEVIN: No, no. Sorry. Forgot to turn mine off.
>
> Why is NIR, once very quickly, why is NIR so good? Because it
> penetrates. The light that goes into, either into reflectors, into
> powders made in a blender or any other operation, it penetrates to a
> depth between 2 to 4 millimeter. It doesn\'t just scrape the surface.
> That\'s why it is so important, being a tool that tells us enough
> information on the bulk of the product we are processing.
>
> Now I\'m going to represent my company. I don\'t own it. Why then is
> NIR so important? It is very fast, and people say today we need speed.
> It is simply rugged, and it was tested dropping on the floor, kept on
> working. It\'s a dual beam for real-time ratio, so we don\'t have to
> stop anything for taking some reference spectra from some reference
> sample to do some adjustment. It is always dual beam, giving real-time
> ratio.
>
> It is full scanning, to provide information on all the ingredients,
> not just the active. It comes with a full computer on board, so you
> can process as many algorithms as you may want. And it\'s miniaturized
> to do blenders, battery operated, you will see immediately. It is
> insensitive to ambient light variations, so it can operate in any
> ambience without any consideration to what\'s happening around. And it
> is backed by 21 C.F.C. 11 tested from Brimrose.
>
> It\'s important because I think it\'s the only analyzer that can do
> them all from one company. We can do incoming raw materials, fluidized
> beds, rotating blenders, tablets and capsules, various lyophilizers,
> spray dryers, blister pads, transdermal patches. So you have a company
> that has one source for every possible application that you may want.
> Why would you want to go and use application A from manufacturer A,
> application B from manufacturer C? We will provide complete solutions
> for every need.
>
> I turned it off, I swear I did.
>
> CHAIRMAN LANGER: Now I think it\'s getting to be the time.
>
> DR. LEVIN: I turned it off, I swear.
>
> CHAIRMAN LANGER: Dr. Nerem reactivated it.
>
> DR. LEVIN: This is all the material I need, but we also have ability
> to connect it to a multiplexer, so you can have a multiplexer for
> doing more than one location with one analyzer.
>
> This is a typical installation in a fluidized bed. You can see the
> globe, but we have done these fluidized beds not only with globes, we
> have done fluidized beds with what we call the free space, and we have
> an installation running now in New Jersey on that.
>
> This is our miniaturized spectrometer. It has two batteries. It\'s
> only 18 inches by 16 inches by about 4 inches. It has got a complete
> computer on board, so you can process more than one algorithm. It can
> be mounted on blender, it could be mounted on fluid bed dryers, it can
> be mounted against a bio line if you want to test bios, if you want to
> do reflectance on tablets.
>
> CHAIRMAN LANGER: We\'re at 10 minutes. Can you wrap it up in a minute?
>
> DR. LEVIN: Yes, just one more slide. And this has radio transmitter,
> this one has a radio transmitter to stop the blender. So all the
> processing of the data is done on the spectrometer. We don\'t need to
> transmit data.
>
> To the last one, I think. This is a tablet analyzer doing final
> testing before shipping. You can see again the whole spectrometry is
> in this case. It is operating on 24 volts coming from this cable, and
> has internal cable to connect to a site computer, but during
> operations you don\'t need the site computer, because actually during
> operation you have a model, an algorithm that you use on the
> spectrometer for decision-making, and it links the, connects the
> decision to some other. This connects automatically to a tablet press,
> and it sees the tablets from the press without the contact of hands,
> so it\'s automated and can be stored in a remote room or anywhere
> else.
>
> I think that\'s the last one.
>
> CHAIRMAN LANGER: Well, it\'s the next to the last one, but we\'re at
> 11 minutes. Why don\'t we wrap it up?
>
> DR. LEVIN: This is a typical multiplexer. That\'s it. Thank you.
>
> CHAIRMAN LANGER: Any comments or questions? Thank you.
>
> The next talk is by Robert Chisholm from AstraZeneca.
>
> MR. CHISHOLM: Good afternoon, everyone. My name is Bob Chisholm,
> International Technology Manager for Engineering Science and
> Technology for AstraZeneca, and I am based in the U.K. First of all,
> I\'d like to say how pleased I am to be back in the U.S.A., in
> Washington. Unfortunately, it\'s only for one day, but it\'s very,
> very nice to be back here.
>
> What I would like to talk about I hope will supplement and complement
> some of the excellent presentations that we had this morning, and
> maybe help you answer some of the questions that I\'ve heard posed.
> I\'ll keep this down to 10 minutes, so I may speak very quickly in my
> Scottish language, so you may find that incredibly difficult to
> understand. So if I need to slow down, tell me to slow down.
>
> What I want to talk about is TQMS, which is the AstraZeneca Total
> Quality Management Strategy in our facilities, and it\'s a very
> statistically based end process control with real-time quality
> assurance, and it\'s about a plant that we have designed and built in
> Germany, and I\'ll tell you all about that.
>
> What do we do just now in pharmaceuticals? Basically, traditional QA
> means that we validate processes, the usual three batches, etcetera,
> etcetera, and then we run them under standard operating procedures,
> virtually no end process control for a long number of years. We
> supplement this, of course, by testing a very small number of samples
> at the end of each batch, and that\'s our QA assurance, and typically
> that could be 10 samples out of a million, two million. Taken in
> isolation, clearly that is not statistically significant.
>
> The way forward, I think, for future products, the way we would like
> to go, is TQMS, which you have heard a lot about, I think, already.
> It\'s real-time end process monitoring and control which is being made
> continuous, and its real-time quality assurance which is statistically
> based throughout the batch.
>
> In our particular case that would be done automatically, but you could
> also do it at-line, so you\'re taking samples all the time. So you
> actually have an increased testing frequency, and that increased
> testing frequency which is statistically based, provides you the
> platform to discuss with regulatory authorities so-called parametric
> release. A term which I don\'t like, by the way, because we actually
> increase the testing, not decrease it.
>
> Okay, how do we do this? Well, I think first of all in any
> pharmaceutical company you\'ve got to have the sponsorship of your
> senior executive team or you won\'t succeed, because it is often
> harder to change your own company than it is to talk to any regulatory
> agency, believe me. There\'s a lot vested interests in the companies.
> This is a paradigm shift, and if you don\'t have the cooperation of
> your own board, you can forget it in the industry.
>
> We have created a process on what we call Technology Center of
> Excellence, which is based in Sweden, and they are looking at the
> whole range of methods, not just near infrared, and the product
> development using these methods. But the thing I want to talk about
> today is related to the Center practice. We have built a plant in
> Germany, in Plankstadt, which we sanctioned early \'99, and we have
> integrated TQMS at this plant, and I\'d just like to show you that. So
> this does actually exist and goes live on December the 1st.
>
> Okay, what have we done? Key process operations are now statistically
> in process controlled and monitored, so that identification of all raw
> materials in the dispensaries, things like control of fluid bed driers
> on line, continuous end line monitoring of blending similar to what
> Steve showed you earlier on\--okay, and that\'s end point control of
> blending. What that does, that\'s in process control. That ensures
> that everything that you put into that tablet press is in spec and is
> the way you want, and the blend has been correct every time.
>
> We then have the tablet analyzer automatically within the tablet
> press, and again it\'s looking at the tablets which are going though
> check, so it is monitoring tablet quality throughout the batch. That
> in itself is a big paradigm change for the industry. We\'ve also
> designed a 21 C.F.R. 11 data management system to go along with it,
> because with all this data on all these spectra, compliant data
> management is clearly of the essence. And through that, we believe
> that we have real-time continuous quality assurance.
>
> This is the actual architecture, and it\'s so complicated on this
> small screen I can\'t see it, so I\'m going to have to just talk to it
> up here. If you look at this, you\'ll actually see that the analyzers
> we\'ve used are by Brimrose, because of the OTF. You\'ll see there are
> four Brimrose analyzers which run the plant.
>
> If you then look on each analyzer, you will see a panel PC and you\'ll
> see actually a bar code reader also on there, which is attached to
> each measurement. And these are managed by an NIR server on the top
> there, and all the data is reflected to what we call the PacMan
> server, which is a system for storing this data in a correct forum
> which was developed by our colleagues in Astra.
>
> So to give you an example, in the dispensary for instance, the
> operator would come along. He would log onto his panel PC, using his
> password, because it\'s 21 C.F.R. 11. Having done that, he would then
> take the bar code reading, so the batch attributes, hence the panel
> PC, so it has the operator\'s name, all the batch attributes.
>
> The panel PC then contacts the NIR server, which enables the analyzer
> to do the correct measurement and puts any models, etcetera, down into
> the analyzer. He takes the measurement, the panel PC gives him the
> result, and then all the data is automatically transferred from the
> analyzer via the NIR server into the PacMan system, so it\'s in there
> for inspection by regulatory authorities or anyone else, for that
> matter.
>
> The way we have designed this system, by the way, it\'s also capable
> of being inspected remotely through modem. So someone could sit in
> Washington, connect to the modem, with our permission, of course, this
> is complete openness, and actually look at that plant as it\'s running
> to check the compliance, which could be a thing for the future.
>
> Okay, just moving along, you\'ll see we have our fluid bed drive
> analyzer there, which is a dryer end point control. That\'s actually
> the one multiplexed analyzer. We then have the blender analyzer, which
> sits in a base station, comes off the base station, is mounted onto an
> IBC which is spun, and looks through the sapphire window, tells you
> when the blend is finished, stops the blender. When you put it back on
> the base station, the data, the spectra, automatically again transfer
> through the system into the PacMan system. That\'s all for regulatory
> authorities or anyone else to inspect.
>
> Okay. And, moving on to the tablet analyzers\--I\'m trying to watch
> the time here and keep this down\--there are two tablet analyzers, two
> tablet presses. We have only put one in at the moment because nobody
> really believes all this will work, and that\'s the problem with the
> industry, I think. But I come from ICI Petrochemicals, and was very,
> very used to doing all this sort of work, so it\'s second nature to me
> and my team.
>
> Again, the tablet analyzer, it\'s using transmission and reflectance,
> and all the data is transferred up and stored in PacMan, the same as
> with the other systems.
>
> Okay, now I\'m not too sure what other slides I\'ve got in here. I\'ll
> just try them. Oh, yes, that\'s just a schematic, obviously, of the
> plant, and that\'s a solid dosage facility, which you\'ll all be aware
> of. That\'s an example of an IBC with the blend monitoring unit
> actually mounted on it. This only 120 kilograms. That\'s why the IBC
> looks so small. The whole system just spins together there.
>
> A tablet analyzer. That particular one I think is the one in the lab.
> You need to have them in the lab also, because you need to model, and
> it\'s much easier to model with it in the lab. But it\'s connected up
> to use on that system just the same, and is the analyzer that actually
> sits in the tablet press. And that\'s it actually in the tablet press,
> I bit difficult to see, I think, but the box here is actually the
> analyzer, the tablets coming off and going down to be analyzed as they
> pass.
>
> Okay, that\'s what I wanted to say to you. As you see, that plant does
> exist, so the industry is moving forward. In terms of the actual way
> forward, our intention would be, listening to this morning\'s
> presentations, our own intention would be to obviously start talking
> to regulatory authorities. I\'m a bit premature here. The opportunity
> arose.
>
> We would chose one of our existing products that we make, which we
> have five years say operating experience of, so we have lots of means
> of comparison. We would model with that. It would be our intention
> then to run parallel dossiers, because we can run the plant with or
> without the system. So we would run near infrared and run all the
> existing registered systems, and compile parallel dossiers, and then
> bring that to regulatory authorities who we should have been talking
> to, will talk to all the time, as a means of comparison. So if you
> like that as the sort of pilot project that I think someone mentioned
> this morning, then that would be our intention.
>
> So that\'s all I have to say. I\'ve cut it down, obviously. That\'s
> normally a one-hour presentation. But hopefully I got enough over to
> let you know what we\'re doing. Okay? Thank you.
>
> CHAIRMAN LANGER: Thank you. Are there any questions or comments? Any
> other comments from anyone here? Yes?
>
> MR. WOLD: Yes, Svante Wold from Umetrics. I just want to emphasize one
> thing, and that is that we see a lot of very nice technologies, and
> that is essential. You have to measure the right data. But one also
> has to tie everything together. You have to have, as in the last talk
> we heard, a data-based system, and you have to have tools to follow
> all these data. Otherwise, it just becomes a data cemetery. And there
> exists technology for that, too, and that is what we presented. Thank
> you.
>
> CHAIRMAN LANGER: Any other comments?
>
> Okay. Well, thank you all very much. We\'ll move on now, and we\'re
> going to get an update on the CDRH External Science Review. At the end
> of this, we need to vote on acceptance of the report at the end of the
> presentation, and Dr. Nerem, who was Chair of this, will lead the
> discussion. Bob? This will be about a two-minute thing?
>
> \[Laughter.
>
> DR. NEREM: Actually I was going to use this time to sell coming to
> Georgia Tech to do your educational program.
>
> \[Laughter.\]
>
> CHAIRMAN LANGER: We\'ll make sure that\'s on the next Science Board
> agenda.
>
> DR. NEREM: Well, it\'s a pleasure to be here and to represent the
> committee which produced this report, which we ended up titling
> \"Science at Work in CDRH: The Role of Science in the Regulatory
> Process.\" The next slide actually shows the members of this
> committee. I\'m not going to go over it in all the detail, but I do
> want to recognize and introduce Alexa Canady, who was my Co-Chair and
> who is here to make sure that I\'m honest, I think. But it was an
> amazing committee, and I believe FDA and CDRH really owe a vote of
> thanks to all of these people who just performed in a marvelous way.
>
> In addition to a note of thanks to my committee members, I want to
> thank the CDRH staff members who worked closely with us. Of course
> that was at a variety of levels. There were people that really made it
> happen, and that includes Toni Marie Nearing who is sitting over here.
> Toni, thanks for all you did. I see Sandy Weininger out there, who
> helped\--I was going to say helped write the report, in fact should be
> listed probably as a co-author, but he really was very neutral in his
> approach to what we did. I see Mitch Shein back there. And there\'s
> another person, I don\'t know if he is in the room. Is Heini in the
> room somewhere? I don\'t think Heini is here, but he was also
> extremely helpful through the entire process.
>
> And of course we want to thank the entire management of CDRH and the
> staff who participated in the internal/external reviews. I think all
> told there must have been somewhere on the order of at least 150
> people, and maybe there was more than that, David. I don\'t know.
>
> Our objective was really to assess the quality of science across the
> organization and its relevance to the organization\'s regulatory
> mission. We were not put together as a committee to evaluate the
> research going on within CDRH, but really to look at how science was
> playing a role and how it could play an even more effective role in
> regulatory decision-making in CDRH.
>
> This is an outline of the report. I won\'t go over this in any detail.
> I\'ll talk a little about process. I\'m going to come back to process
> at the end; talk about the findings under these three categories; our
> recommendations; and then some concluding comments.
>
> There was an internal review process. I think one of the key issues
> was that it was decided early on by CDRH that electrostimulation
> devices would be chosen as the representative technology. That is
> really where we focused most of our work, although we believe that in
> fact much of what we found can be generalized to other parts of CDRH,
> in fact can perhaps be generalized to all of FDA.
>
> The ground rules are indicated here, and I\'m not going to go over
> that in any detail, but I do want to take this opportunity to commend
> CDRH for the substantive nature of the internal review and the spirit
> in which it was conducted. I really believe that internal review,
> which was a time-consuming process for CDRH, provided the foundation
> for them to move forward as an organization and for us to come in as
> an outside group and get some insight into what could be done in the
> future.
>
> In terms of the external review process, I have already indicated that
> built on the knowledge provided by the internal review. There were
> really three different meetings, all of which were important, in my
> opinion. The first was a preparatory meeting held in Atlanta, where
> the External Review Committee came together and where we really sort
> of sorted out what we were about, and in fact we made some assignments
> at that time in terms of some of the case studies that we would be
> involved in.
>
> There was then the three-day review held in Rockville, July 24, 25,
> 26, and then finally a good part of the committee came together for a
> one-day report writing session on August 8th. At the three-day
> meeting, we began to put together the outline of a report. We made
> assignments for different sections of the report, but the report
> really came together at that August 8th meeting, and then we had a
> final draft this past month.
>
> In that July 24-26 review, there were the case studies; there were
> role-playing session, both for pre-IDE and post-IDE; there were omsbud
> reviews; industry interviews; and in fact international interviews.
> The international interviews being, number one, we had Beth Pieterson
> from Health Canada on our team, so we could talk to her directly. But
> we also were hooked up by video conference with David Jefferies in the
> U.K. to get a perspective on what was going on in Europe.
>
> Now, under scientific expertise we break down our findings into these
> different areas, and I\'m just going to highlight some of the
> findings. The complete report is available, as well as a copy of this
> presentation. So let\'s move to the next slide, John.
>
> And in terms of the findings, I mean, to start with we certainly
> wanted to go on record as reaffirming that good science is critical to
> good regulatory decision-making. Furthermore, as I think we all
> recognize, the complexity of applications requiring review has
> increased and will continue to do so.
>
> What was evident to us was, in general, the overall high quality of
> reviewers, medical officers, scientists, engineers. Even so, the
> expertise across fields is uneven, and that\'s something I\'ll come
> back to. We also felt that perhaps the level of expertise among staff
> about the clinical environment, at least in some cases, was limited.
>
> Continuing with the section on scientific expertise, we felt that
> there was not enough emphasis placed on the quality of decision-making
> as compared to the timeliness and volume of review, and I\'ll come
> back to that in the recommendations. Furthermore, there appeared to be
> a strong tendency for the Office of Device Evaluation to operate
> primarily in-house, and as indicated there, we felt that was at least
> what was happening in fact, whether it was not by plan, but certainly
> that was our perception of the way day-to-day business was being
> conducted.
>
> We were very interested in learning about the use of third parties in
> other countries, for example, the notified bodies in Europe. And as we
> look to the future, we have a concern as a committee whether CDRH or
> even FDA as a whole has the right expertise for the evaluation of
> combination products, those products that will be a combination of a
> device and a drug, a combination of a device and a biologic, or
> whatever.
>
> Moving to the next section of the report, which is the human resource
> issues, it\'s organized by these different categories, and let\'s go
> to the first slide of findings, John.
>
> Again, I want to note that we were impressed with the quality,
> professionalism, and dedication of the staff we encountered. However,
> it\'s clear that there is a gap between the scientific expertise
> needed and the competencies of the current staff. There also is a
> woefully inadequate investment of resources and providing of
> opportunities for staff training and development. There are clearly
> too few staff to carry out the necessary activities as CDRH now
> functions.
>
> And for CDRH scientists, people who not take the track of management,
> it seemed to us that there was a lack of promotion opportunities, at
> least opportunities that could be somewhat rapidly taken advantage of.
> The process apparently to be promoted as a scientist was a rather
> long, extensive one.
>
> Moving to the organizational and process issues, again the report is
> structured along these lines, and let me just say a few words about
> our findings.
>
> To start with, we characterized CDRH as an organization that was
> basically \"semi-porous silos.\" I suppose the good news is, they\'re
> semi-porous. We\'re not quite sure how large the pores are. But there
> needs to be attention paid to that.
>
> There also needs to be attention paid to metrics about quality, for as
> far as we could tell, there appeared to be no quality metrics about
> CDRH as an organization or even necessarily the decision-making
> process. Certainly there seemed to be no system of retrospective
> measurement and analysis of specific CDRH decisions.
>
> Now, in the case study that took place as part of the internal review,
> in fact that\'s one of the things that took place. There was some
> reflective looking at things, but that does not appear to happen on a
> regular basis.
>
> Also consistent with the semi-porous silos is the fact that there is
> no effective interoffice communication and coordination. Furthermore,
> external experts are seldom used beyond those who sit on existing FDA
> advisory panels.
>
> And in the case of combination products, there is no clear pathway or
> guidelines for the regulation of these products. There is really no
> single entry point for these products.
>
> So moving to the recommendations, recommendation number one is that
> CDRH needs to communicate, both internally and externally, a clear
> vision of the fundamental role of science in the regulatory process.
>
> Secondly, it really needs to rethink, in our opinion, how it carries
> out its mission, prioritizing its activities, outsourcing those
> functions it can, while still maintaining oversight, and reallocating
> its resources so as to expand its investment in science. And as part
> of this, CDRH should examine its existing organizational structure as
> well as other regulatory models.
>
> As part of its restructuring of activities, recommendation three is
> that to enhance the fundamental role of science, CDRH should assess
> and reconsider the structure of the Office of Science and Technology,
> to focus that office on emerging science and technology. This will
> probably require a separate review of OST, but we believe in fact that
> OST should be that part of CDRH that is really leading CDRH into the
> technologies of the 21st century, and that we believe requires some
> restructuring, but since we did not have a chance to look in depth at
> OST, we feel a separate review is in order.
>
> CDRH should develop a plan for enhancing cross-office and interagency
> communication and collaboration.
>
> The next two recommendations, five and six, really come to information
> technology, and that may be a problem for FDA as a whole. Certainly
> there should be an electronic database for liaison functions and an
> internal and external expertise inventory. Furthermore, we believe
> that CDRH should develop and implement a formal process for capturing
> institutional knowledge, so that when a decision is reached it does
> not remain in the mind of the reviewer.
>
> I think an important recommendation is that with the large staff
> turnover anticipated in the next five years, and in order to fill gaps
> in scientific expertise, CDRH should expeditiously perform an
> assessment of the current level and breadth of expertise so as to
> develop a long-term strategic staffing and recruitment plan. As an
> organization, it really should be looking at where it needs to be five
> years from now, what kind of expertise is going to be required, and
> develop a staffing plan that is going to allow that to take place.
>
> There also needs to be the development of procedures and staff
> development opportunities to ensure that reviewer mandates for such
> issues as sample size or randomized trials are shaped by realistic
> clinical perspectives and relevant ethical considerations.
>
> Recommendation nine goes back to a comment I made earlier, but that is
> that CDRH needs to streamline processes that encourage scientific
> growth within the staff and provide for a more inviting career path
> and reward structure for scientific personnel, people who are not
> moving into management but are valuable as scientists within the
> organization.
>
> There also should be an encouragement and the facilitation of ODE
> using internal but non-ODE expertise, and also external expertise,
> including the development of policies that promote a more liberal use
> of external experts.
>
> As part of this, CDRH should expand its outreach to and scientific
> interactions with both industry and universities.
>
> The final three recommendations are that CDRH should develop a plan in
> collaboration with other Centers for the evaluation of combination
> products. This plan in fact may require changes in organizational
> structure and operational procedures.
>
> Number thirteen and fourteen really go together, really relate to
> quality improvement. Thirteen is really more at the regulatory
> decision-making level. CDRH should implement a quality evaluation
> improvement program, and as part of this develop metrics for the
> assessment of quality as well as the timeliness of results.
>
> Fourteen is, at the organizational level CDRH should implement a
> quality system with a focus on CDRH as an organization, and on
> development of activities that contribute to high quality decisions
> and the most productive use of resources.
>
> With this, let me say a few words about the process itself. These may
> have a bias of my own. David Feigal and his office actually sent out a
> survey form, and I think they are reasonably consistent, but this is
> my take on the process.
>
> I believe that the review, in focusing on the role of science in
> regulatory decision-making and not on scientific laboratory research,
> that that was the right focus, and we recommend it to the Science
> Board for use in future reviews. The deliverable of an organization
> like this is not good research; the deliverable is good regulatory
> decision-making, and I think that needs to be the focus of these
> reviews.
>
> The internal self-study not only provided a foundation for the
> external review, but was a significant learning experience in its own
> right. The external review, as I noted earlier, had three separate
> meetings, and I believe that each of these meetings was critical. The
> pre-meeting in Atlanta really allowed the review team to get organized
> into how they were really going to conduct their work in a three-day
> period. The three-day meeting in Rockville allowed us to carry out the
> review, and the final meeting on August 8th allowed us to complete a
> reasonable first draft of a report.
>
> In terms of the components of the process, I thought the case studies
> were important to our success, and also the fact that we assigned at
> the initial preparatory meeting small teams to investigate each case
> prior to the three-day review.
>
> The role-playing, my own view was that the role-playing was not as
> effective as it might have been. I don\'t really feel like the
> committee ever got into the role-playing. I don\'t know how Alexa
> feels, but I just didn\'t feel that we really put ourself in the roles
> we were supposed to.
>
> The on-the-spot reviews, that was basically where we could get any
> information on any kind of a review decision that had been made, and
> it was difficult in a way to intervene in that and get something. At
> the same time, CDRH was offering us everything and anything, and just
> that gesture by itself was a very clear signal that they were open to
> us looking at any aspect of the operation, and I think that was an
> important signal.
>
> The industry interviews were important. Unfortunately, they weren\'t
> all face-to-face, and I think in the future if this kind of model is
> used, it needs to be clear that these need to be face-to-face, these
> discussions with industry people.
>
> The international interviews, we thought that was quite useful, both
> having Beth Pieterson on the committee as well as the teleconference
> with David Jefferies. The CDRH management and staff meetings are
> equally important, and we did, particularly in the case of the case
> studies, during each of those meetings we asked senior management to
> leave so we could meet with working staff without management in the
> room, and we believe that was important in terms of creating an
> environment where there would be a totally honest conversation.
>
> We also had a meeting with the union management. I think that meeting
> could have been much more useful if it had been organized well in
> advance. The fact of the matter is, it was only at the last minute
> that we asked for the meeting, and there wasn\'t the same preparation,
> both on our side as well as on the union management side, and so
> therefore I don\'t think it was as useful as it could have been.
>
> Some concluding comments. I again want to commend CDRH for the
> dedication, integrity, and commitment to excellence exhibited by this
> effort. In many ways CDRH is doing an excellent job. Even so, with new
> products arising out of the biological revolution, with breakthrough
> technologies which will be increasingly complex, CDRH is facing a
> significant challenge.
>
> We felt that this review was conducted in the spirit of trying to be
> of constructive help to CDRH as it faced up to these challenges. From
> the viewpoint of the committee, there clearly are changes necessary if
> CDRH is to significantly increase the role of science in regulatory
> decision-making.
>
> This slide really has what I think are, of all the recommendations,
> what I think are the three key things. First, I really think there has
> to be a rethinking as to how the business is conducted. Again, what do
> you do in-house, what do you farm out, what are the priorities, how do
> you get your hands around science and technology, which every day
> expands further and further.
>
> Secondly, as part of this, as part of this reinventing of CDRH is a
> reinventing of the staff through strategic recruitment, the continuous
> professional growth of existing staff, and policies that reward staff
> for the quality of scientific expertise. And that goes back to really
> creating a long-term strategy for recruitment over the next five
> years.
>
> CDRH must reach out to external resources to create partnerships that
> will accelerate making new technologies available that are both safe
> and effective, and so as to enhance patient benefit in America. No
> organization can have all the expertise, and I think CDRH needs to
> more and more use external expertise.
>
> Finally, the subcommittee review team appreciates the fact that these
> recommendations, even if accepted, cannot be put into place overnight,
> and certainly the way to go would be to incorporate these in some
> active way into the strategic plan of CDRH.
>
> I think that may be it. Is there another slide?
>
> Okay. Thank you for this opportunity to present the report, and again,
> thanks to everybody who worked with us. And I don\'t know if you want
> to open it to questions or whether you want David to have a chance
> to\--
>
> CHAIRMAN LANGER: What do you prefer?
>
> DR. NEREM: I\'m easy. But I\'m glad you asked about Georgia Tech, Bob.
>
> \[Laughter.\]
>
> CHAIRMAN LANGER: Maybe I\'ll let David present. There will be many
> questions about Georgia Tech later.
>
> DR. NEREM: Well, particularly since we\'re trying to get David\'s son
> to come down to Georgia Tech and be a student. Right, David?
>
> DR. FEIGAL: Well, I need to begin by thanking Bob and Alexa and the
> other 10 members of the committee that joined them for the tremendous
> amount of time and the thoughtfulness of the effort that they put in,
> and I think you probably all appreciate how busy Bob is likely to be,
> but part of the reason we met in Atlanta for the kick-off meeting was,
> that seemed to be the only way to accommodate Bob\'s schedule, and we
> were interested enough in getting this to move along and get things,
> that we were happy to travel down there and begin with the
> orientation.
>
> This report comes at a very important time for us, because it\'s
> coming at a time when we have been working on a strategic plan to ask
> how do we meet the challenges of the future, and I have presented bits
> of that to the Science Board before. Part of that is a vision that the
> Center has, that medical devices have a life cycle; that the whole
> life cycle is informative in the scientific decisions we made; that in
> fact it\'s a pipeline of multiple generations of products.
>
> There is a regulatory structure that surrounds that life cycle, but
> what we really were asking the team to do was to come in and look at
> this. And what this is, it\'s the underlying science that we think is
> necessary to do science-based regulation at the different parts of the
> life cycle, for all the different regulatory tasks that we have. And
> our focus and our interest was not as much about asking how we got
> here or why we were the way we were, but really looking forward and
> saying how do we need to go from where we are now into the future, and
> I think that we appreciated the very constructive approach that the
> committee took in helping us think about that.
>
> Let me pause just for a second to show you, somebody had said
> something about the Center. The room was pretty full this morning but
> it wasn\'t the same people. Would everybody who works for the Center
> stand up? This is a group that\--you can sit down now\--we are very,
> very interested in where we\'re going and the help we have getting
> there and the comments, and it\'s a process I think that, Bob and
> Alexa, you realize we take very seriously.
>
> As you pointed out, this began with a planning process that began in
> November of \'99. It was helpful to me as a new Center Director. I had
> started about six months earlier than that. Unfortunately, now I\'ve
> been there long enough that many things are my fault. If we had had
> these recommendations just as I arrived, I would have felt even
> better, but that\'s all right. We\'ll move forward.
>
> And where we are today is near the bottom of this chart, and the
> important thing, part of what I want to show to you is our strategy
> for implementation. But before I do that, I actually want to share
> some of the things that we did, that you alluded to, with our internal
> report process. It will give you an opportunity to see whether or not
> we were on sort of some of the same tracks that you were, because
> I\'ve taken the documents, unedited, that we provided to the committee
> when it first began to meet.
>
> As you pointed out, we really were interested in the scientific
> decision-making process. We think that is our most fundamental
> product, our decisions. In fact, if you hear complaints about us,
> it\'s that we haven\'t decided something, and then the second
> complaint is what we did decide. But we\'re in the decision-making
> business, and it\'s important that we understand the impact, the
> resources that are required for this to be a science-based process,
> how well those decisions are integrated with all the different
> processes that we\'re responsible for, and how the organization learns
> from the way that it does its work, and our preparedness for future
> issues.
>
> I\'m a little sorry that Dr. Skulnick isn\'t here, because you
> remember at the last meeting he said, \"Why don\'t you give us the top
> 10 list of the best things about the Center and the worst things about
> the Center?\" We in fact actually provided a slight modification of
> that to the committee as a product of the internal review, and I\'m
> presenting this as one way of summarizing some of the work of the
> internal review.
>
> We presented a top 10 list of the greatest challenges and problems for
> science-based regulation at CDRH, and then we also made
> recommendations of what we thought we had to do to address some of
> these. And it may be interesting for you, having heard the External
> Committee\'s recommendation, to take a look and see how self-aware the
> Center was or was not about some of these issues. In the notebooks I
> have presented these just on one page, and I\'ve broken these out and
> organized them so that the challenge is met with our own
> recommendation.
>
> And so our first observation was that we\'re not always recognized as
> a science-based organization, sometimes not even by parts of our own
> structure in FDA. It certainly is not a novel experience to have
> Health and Human Services organize a scientific group and leave us
> off. When they organized the task force for the Biomedical Engineering
> Institute at the NIH, they put together a Public Health Service
> Advisory Board, and FDA, CDRH was not included in the PHS group that
> was to advise the NIH on the scientific needs. Congress at times
> really is very\--well, they\'re always very aware of the freight that
> we need to move, but they\'re not always as aware of the scientific
> basis of that, and at times that\'s true of industry as well.
>
> So where we began with our first challenge\--and these are in rough
> priority order\--was that we need to communicate our scientific vision
> and the scientific business for our regulatory actions. It isn\'t
> adequate to simply say we\'re doing something because of precedent or
> level playing field or because we said so. We need to make it clear
> that these are science-based. We also need, and this is a request from
> you, we need advocates for our scientific role in medical devices and
> radiological health, and there are ways that you have been doing that.
>
> The second comment that we made when we were being self-critical of
> ourselves is that the Center leadership, meaning me and the senior
> people in the Center, do not always communicate science as a priority.
> I think we\'re always quite clear about meeting performance deadlines
> in some of the goals, particularly the ones we report to Congress or
> with a trade press or an industry track.
>
> But we miss opportunities to create the resources and time for our
> scientists to have the training. We don\'t create the expectation in
> our own staff that part of their job is to stay at the top of their
> game and stay current. And the budget in our resource planning has
> often been reactive and short-term, and we need to walk the talk and
> show that science is really a priority to us. Our recommendation sort
> of is the mirror of the observation.
>
> We are also very aware of the fact that the CDRH\'s scientific staff
> is graying. This year we actually saw the retirement of the employee
> who was the longest working employee for the agency. He has worked for
> the agency for 62 years, and I hope he\'s enjoying his retirement in
> Florida. But one of the real challenges for us is that there are time
> when we go through waves of hiring and long periods without hiring,
> and that gives us waves of retirement, and this is both a challenge
> and an opportunity.
>
> And one of the elements of our strategic plan is one that we call
> Magnet for Excellence. We borrowed that concept of being a magnet from
> the magnet school system. We really want to be able to attract the
> type of employees that want to help us accomplish our public health
> mission. And I really resonate very well, Bob, with your phrase
> \"strategic recruitment.\" We really need to not just think when we
> lose someone, even though that person was doing valuable work and had
> built up an in-box that now needs to be taken over and a specific area
> of expertise, we really need to look and say \"What do we need now?\"
> That person was hired at a time when we needed that. And we need to
> think about what the process is, because if we just backfill position
> by position by position, we will be configured the same way in five
> years that we are now, so we need to think about how we\'re going to
> do that.
>
> The budget policies of the last eight years markedly reduced our
> operating dollars, as we were absorbing the salary increases, and the
> good news that you heard last night from Jeff Weber is that in this
> year\'s budget in fact we don\'t have to absorb 4.6 percent of our
> staff in order to pay for the appreciated pay raise, but it\'s even
> more appreciated when they give us the money for it.
>
> But I think the concept for us is that it really doesn\'t matter if
> we\'re rich or poor, we have to have the same scientific values and
> the same approach to scientific problems, whether it\'s a year where
> we have some budget flexibility or some budget challenges. And we need
> to really look at how to take care of our existing employees to make
> them as effective as they can.
>
> There was a very nice comment by one of the members of the Science
> Board who couldn\'t be here today. Earlier this week there was a
> meeting at the University of Maryland. I think they beat Georgia Tech,
> didn\'t they this year, Bob? But there\'s always the basketball
> season. We\'ll see how this goes.
>
> DR. NEREM: We\'re even better in basketball.
>
> DR. FEIGAL: But the comment that was made is that art is \"I\" and
> science is \"we\", and we really train people almost as artisans, as
> apprentices. They work with a small team. They learn what that team
> does, how it works. We really need to take the strength of the
> scientific method, which is really a group process, a process where
> everyone learns from each other, we need to identify much more
> systematically, particularly with employees whose jobs are changing,
> to identify the core competencies and the type of experiences that
> will develop them as scientists and create flexibility in our
> scientific work force to meet future challenges.
>
> Our current system actually tends to have a system where people almost
> need to burrow in to get promoted. If you\'re not going to be a
> supervisor, then you need to become an expert, and an expert often is
> someone who\--it\'s more of that \"I\" model, where you are the
> expert. You are the one that has the knowledge and doesn\'t share it.
> And one of the things that has happened as part of the strategic plan
> and part of our grappling with this, is that we have actually created
> and gotten approved a program called the Master Reviewer that
> supplements the expert path, that rewards breadth, and a different
> type of experience for promotion. It\'s a program that Janet Woodcock
> had in CDER, and then we have actually crafted our own version of it
> which is just now being launched.
>
> There is the very real fact that premarket deadlines, acute problems,
> squeaky wheels, meaning any type of, sort of contentious situation,
> often dominate resource allocation in a way that can leave programs
> disconnected and sometimes out of balance. One of the hardest things
> for us to figure out is, what\'s the right size for different parts of
> the unit, because everyone is busy and everyone could do more with
> more resources. And are we just putting it where Congress squeaks or
> where a group of manufacturers create a lot of public attention?
>
> We need to have our own vision of sort of the public health mission,
> and be able to balance and prioritize even through that. Even though
> we must meet these deadlines and must deal with these problems as they
> come up, we need to more deliberately prioritize our work proactively,
> rather than just being reactive.
>
> Scientific communication opportunities are under-utilized, whether
> this is with our scientific peers, whether it\'s medical device users
> or the general public, and this hides what we know. It hides the
> knowledge that we in fact manage, and limits our mission
> effectiveness. And so one of our real goals is to understand better. I
> really appreciated the earlier public presentation on risk management
> and risk communication. That\'s something we think a lot about. And
> the public\'s hunger for knowledge is illustrated by the fact that
> nearly a million people will read the Lasik web site this year.
>
> We solve many problems too slowly in a rapidly changing world. Some of
> our decision-making is timely, particularly the ones where the rules
> are set out in advance that say, \"You send us this kind of
> application and we\'ll review it in that many days.\" But there are
> other kind of problems that are much more difficult, and we need to
> really be able to set goals, choose important problems, assess how to
> measure the impact in those areas, create the team needed, and then be
> accountable for timely results of the efforts. And we\'re going to
> need to learn to prioritize and do that.
>
> We agree with your comments about the way that people\'s work is
> reviewed, whether it\'s the quality or the impact of the decision.
> Peer review is under-utilized as a method for prioritizing our efforts
> for evaluation. And usually when we do evaluation, it\'s through the
> usual hierarchical supervisory structure, and I think this actually
> misses an opportunity for people to be reviewed by their peer, to look
> at the incorporation of science into the decision-making.
>
> I think that this is all the more important as we make the results of
> our decision, not just the decision itself but also the logic behind
> it, as we start publishing our summary basis of decisions. You know,
> the science is laid out there bold for everybody to see, and we need
> to take advantage of that.
>
> And then finally, and again I think is very concordant with one of
> your recommendations, scientific partnerships with the NIH, the
> National Academy of Science, universities, professional societies.
> Many of these exist, but they are under-developed. We could do much
> more with them than we currently do.
>
> And so that was our top 10 list and our 10 recommendations that we
> gave last spring. We put together sort of a different structure for
> this review, and we were sort of making it up as we went along. And so
> one of the things I would be happy to show you is the survey that Dr.
> Nerem alluded to. All 12 members would have responded, but one was on
> travel and couldn\'t be reached. And this is in your packet, in a
> handout we gave at lunch time in a tabular form that I\'ve reformatted
> for the slides.
>
> One question was, was it the best thing to open the scope of the
> review to be the entire Center and not, for example, just to limit it
> to the research programs. And that, after the fact, after the review
> was over\--this was a five-point scale where the green at the end is a
> five and blue is a four and yellow in the middle is a three and so
> forth\--and so you can see that actually that was a concept that
> resonated well with the committee. They agreed with you that the
> meeting in Atlanta was useful, and a complement to many of the people
> here in the room, that the background materials on the mission and
> organization that helped jump start that process were useful.
>
> Case studies. We asked separately about the concept because we
> weren\'t\--we also, particularly as we looked at the different ones,
> there were different levels of execution. I think the committee got a
> little better into the pre-IDE one than the post-marketing one. And
> the most useful thing, and you\'ll see this theme again, was being
> able to have access to interview them about the process. Materials,
> they are, I mean these are complementary marks, but clearly the staff
> interviews were the most valued. And the concept by and large seemed
> to work, whether or not\--you know, I think we could have improved the
> execution, and some of the problems at times was trying to get it all
> crammed into three days.
>
> On-the-spot concept didn\'t work as well, and the committee agreed
> with you. And again, the thing they liked the best was having access
> to staff, to talk to them about specific decisions that came up. The
> role-playing didn\'t score as high as some things, but still
> complementary. The interviews, and the importance of having a session
> to come back and collect your thoughts about a month after the three
> intensive days, and not try and do the writing in that same session, I
> think was a strategy that the group liked.
>
> We asked four open-ended questions, and we\'ve given you all the
> responses to that in the handout, and I won\'t\--they are on slides
> but I\'m actually going to skip them, partly because the slides are
> unreadable, but also so we can have some discussion.
>
> DR. NEREM: Your time is about up.
>
> DR. FEIGAL: Oh, is my timer going to go off? Okay.
>
> So what are the next steps for us? One of the things that we did is,
> we established a CDRH Recommendations Committee, a committee to go
> over the Science Review Board recommendations and to make
> recommendations to the senior management and the team that\'s
> developing and continuing to develop and implement the strategic plan,
> to really look at how we incorporate these recommendations into our
> other activities. And let me just acknowledge this group.
>
> You will notice this group has, if you know our alphabet soup, which
> Bob and Alexa now have memorized, there is someone from all six of our
> offices. And because of the emphasis on quality and quality systems
> and peer review, we actually have quality systems experts because
> it\'s one of the things we inspect industry on, and we\'ve actually
> asked them to take a look at us. One of our one-liner goals for
> ourselves sometimes is, \"Gee, we\'d like to be good enough to pass an
> FDA inspection.\"
>
> We have scheduled a go-away for our division directors in December,
> and one of the real focuses there is going to be to particularly look
> at the human resource issues and the kinds of things that we can do
> already at a local level. And the focus of that day will really be to
> ask the division directors, what can I do in my own shop now? If I
> were to say things that I could take and implement all by myself for
> the family of staff that I\'m responsible for, what is it that I think
> I can accomplish for the next year? And then, of course, they can also
> lean on the rest of us, to let us know what kinds of resources and
> support are needed for that.
>
> And as of this afternoon, we\'re posting this report. We really
> welcome the report, and we even had a preview, you know, because Bob
> was kind enough to come up and present this to the office directors
> two weeks ago. We knew what we were posting. And we have arranged to
> have videotapes of your presentation and this afternoon\'s comments
> replayed in the Center, and will be available for people. What we will
> ask the CDRH Recommendations Committee to do is to prioritize the
> recommendations, to identify which are things that are short-term and
> which of them are longer term goals, as I mentioned, to make these
> recommendations on how to merge into the strategic plan.
>
> I think one of the themes that you developed, I would just like to
> sort of comment a little bit about at a high level, sort of how I see
> the strategy. And I think in some ways it begins to change the way
> that we think about doing the business, even though many of the
> elements are there, and many of the things that you ask us to do are
> not things that we don\'t do at all, but we do them as you describe,
> in groups that sort of work more or less autonomously. They actually
> pull together quite nicely in a crisis, and I think you saw evidence
> of that when we presented some of the cases, and there is quite a bit
> of interaction, and when they need to get together, they know, the
> staff knows how to do that.
>
> But I think one of the things that your recommendations make clear is
> that we would be more effective and much more powerful as a scientific
> group if we could knit it all together. And one of the issues is how
> do we deal with new technology. We\'ve had several on the horizon. One
> that gets mentioned sometimes, very often, is the revolution that\'s
> going to occur for genomics, and our part of that will at least be
> diagnostic testing. Over 1,000 diagnostic tests for genetic diseases
> are under investigation and are available now that weren\'t available
> five years ago, so it\'s really an area that is exploding. And ask us
> if we could do 1,000 PMAs in a year.
>
> Well, part of the process, this is sort of\--you know, I think what
> your challenge to us would be is to get down to the nitty gritty to do
> this, is to have a process that scans the horizon. We have done that,
> and some of the responsibility for that actually has been OST, to
> identify the kinds of technologies that are coming along.
>
> One of the first things industry always wants to know from us, though,
> is what\'s the regulatory path, and that\'s sort of one of the
> complaints often, is that there is this down time while they try and
> figure out how they\'re going to get this product to market, and whose
> product is it? It is going to be Kathy? Is it going to be us? Heaven
> forbid, both of us? And they probably haven\'t come up with
> four-Center combinations yet, but I think we\'ve had a couple of
> three-Center combinations.
>
> And this is the time, shortly after that, to begin identifying the
> external expertise and using external expertise. That is the best way
> to actually build that expertise into our own staff and our own
> workings, at a time before we have much action. So while I mentioned
> that we actually are at the point where we have work for geneticists
> on the staff, but for a long time it was on the horizon, it was
> coming, but there weren\'t any products, people weren\'t talking to
> us.
>
> But I think this is something we often don\'t do, and we haven\'t done
> aggressively, is to really identify how do we find the external
> experts and really build them and make them part of the team, and then
> at a point when a product area becomes busy and begins to pan out, to
> build internal capacity and develop our own staff. Some of that
> initially would logically be retraining of people that have done
> similar types of things. That is how we have had to deal with many of
> the issues of bioterrorism, is to look at the skills mix of existing
> staff who really weren\'t doing bioterrorism before and say, how do we
> now turn you in this way?
>
> And then, finally, I think we need to begin to consolidate a team that
> works across the whole life cycle. We\'re often actually not too bad
> at taking a new technology and getting it to market. But if it\'s a
> brand new technology, we may not have thought yet about the human
> factors, about the post-marketing problems, about how rapidly the
> generations of that product are going to change, what the issues are
> in terms of risk communication and communication about the products.
> And I think that we are beginning to pull together a conceptualization
> of sort of how we need to do business in a way that explicitly takes
> on new technology, and doesn\'t just put us in the reactive mode of
> waiting to see what comes in and what gets filed.
>
> As you know, we have presented before in a brief form the theme areas
> that we developed about 15 months ago for the strategic plan, and one
> of the good questions you can always ask of strategic goal areas is
> whether they serve you when you get a new challenge and have something
> that you need to do. And actually I think that many if not most of
> your recommendations fit well into groups we have organized to work on
> these issues.
>
> The semi-porous silo issue is a quote I liked enough that the staff
> have already heard me repeat it as the characterization of the Center.
> It\'s something that we are aware of, as we look at the need to work
> the Total Product Life Cycle, and are aware of the fact we don\'t
> quite do it yet. We do it with handoffs now, more like a relay team
> than a team all pulling together.
>
> The Magnet for Excellence to really develop our staff and human
> resources is an issue not just for recruiting new people but
> developing the very talented and dedicated people that we have.
>
> Knowledge management, and where these two things meet or how to
> develop expertise databases, there are some very interesting tools and
> technologies out there now that may make this more helpful.
>
> And then the final area is meaningful metrics, which is that we really
> want to be able to measure the impact that we have when we take
> something on, not just do it because we think it would be a good idea,
> but actually to be able to say, what is it that we\'re hoping
> accomplish with this? So, for example, if we have a mentoring program,
> it\'s good to have mentoring programs, people in them like being in
> them, but I would like to then ask the question a step further: What
> are we trying to accomplish with that, and how do we know if we have a
> successful mentoring program? In my mind, one of the things it needs
> to help us do is transfer some of that institutional knowledge and
> help us with succession planning, because a lot of our retirement will
> be with our more senior people in the Center.
>
> So, you know, in short I think the other way to come back and ask
> whether or not our efforts to do the internal review and the advice we
> got with you really stayed focused on the core thing about the Center,
> which is our mission, which is really pretty straightforward: promote
> and protect the health of the public; safe and effective medical
> devices; safe radiological health products.
>
> And I think both of us are actually on that, on that mark. I think
> that there are things that, as you said in one of your slides, were
> not things we would accomplish overnight. There actually I think are
> some things that we should be able to start on very quickly, and I
> think one of the things that we need to do is to really identify where
> we want to go and what we think the challenges will be to do that.
>
> And we need to do that without saying, \"Well, we\'ll do it if we get
> a good budget,\" or \"We\'ll do it if we get these new things
> funded,\" or whatever. These are things that are so fundamental to the
> way we do business, we have to take a look at our resources and say,
> \"Hey, we\'ve got 1,000 people in Rockville, 1,400 people nationwide,
> a budget of about \$140 million. We ought to be able to do something
> with that.\"
>
> Let me just close with a thank-you for all your time. I hope you will
> expect a progress report from time to time, and we will\--we are
> starting on this activity already. So thanks very much.
>
> CHAIRMAN LANGER: So, comments or questions for David?
>
> DR. NEREM: Alexa, did you want to make any comments?
>
> DR. CANADY: I just think that, sitting here this morning, many of the
> issues that we discussed this morning are directly applicable here. So
> I think it\--but the key issue I see is the need to support with
> education and training the existing staff, as well as the new staff.
> That, like in most places, loses out to number counting and just
> budget deteriorations, and I think it is critical in a time of
> technological advance like we\'re in now.
>
> CHAIRMAN LANGER: Comments from people on the Science Board, or from
> the audience?
>
> DR. KANTOR: Can I make a comment? I am Gideon Kantor, Adjunct
> Associate Professor of Biomedical Engineering, Catholic University,
> and as I said before, until \'95 part of FDA.
>
> These are excellent reports, but I would like to draw attention to a
> point that I think was part of the report but maybe not as emphasized
> as I like to do it, and that is linkages. Linkages are extremely
> important. Now, for that purpose I have mentioned briefly before that
> you need a meta search engine, and what I\'m talking about is that the
> different offices are looked at from the keyword point of view. What
> are the keywords that identify the differences in their subdivisions?
> Then all the computer does is link those keywords together.
>
> Now, let me give you an example. For example, medical device panels,
> they are the categories of medical devices in terms of clinical
> applications. At the Office of Science and Technology there are
> breakdowns in terms of science and technology. Obviously the medical
> devices contain some of the components of the Office of Science and
> Technology, so that\'s just one example.
>
> For example, you have an implanted defibrillator. You are concerned
> about particular technical issues, say interpretation of signals, say
> safety of equipment. If you have these keywords, you could easily link
> them.
>
> So what I\'m proposing is the following: that each office and
> subdivision looks for some keywords that are common to other entities
> of the organization, and then when you have established these
> linkages, establish a panel of experts that validates these linkages.
>
> I know it is a new idea, and a lot of people are opposed to it for
> many reasons. I think many of them are good reasons, but when we look
> into the 21st century with the information explosion, we need to put
> some order in the complexity that surrounds us. And just looking
> individually at issues is a very good idea, but it is beyond sometimes
> our capability of our brain, that which decision scope has not been
> increased.
>
> So I very strongly believe in this, and I hope that people tell me if
> they do not believe in it, because at least I can learn from these.
> Thank you very much.
>
> MR. BENSON: I\'m Jim Benson with Avimed, and I think this is not on
> but that\'s probably okay if you can hear me.
>
> DR. NEREM: You have to lower yourself, Jim.
>
> MR. BENSON: I have to lower myself? I thought I was raising myself
> when I came to this meeting.
>
> \[Laughter.\]
>
> Just for the record, I went to Georgia Tech and the University of
> Maryland.
>
> \[Laughter.\]
>
> Also, I didn\'t know whether to stand up when David asked for people
> in the Center to stand. I was a little torn there.
>
> I want to just say a couple of things. One is compliments to this
> Board for establishing this look, and specifically to the subcommittee
> which Bob chaired, and also very much to the center, to David and the
> folks in the Center, because from my own experience at FDA,
> introspection, organizational introspection isn\'t always a fun
> process, and so I think everybody should be complimented for that.
>
> A couple of specific comments, if I may. One, I think the emphasis on
> looking at new technology, the exploding, I think that\'s a critical
> step. The concept of OST looking at, paying maybe perhaps more
> attention to new technology, perhaps along with that letting go some
> of the ongoing projects, I think can be a challenge and a very
> exciting one. I think looking to the outside for help for the existing
> expertise in the Center is terrific. I think that budget is a problem
> there, but I think there are ways that the budget can get increased,
> as well as under existing budgets to be able to enhance that.
>
> I noticed in Bob\'s report, you included industry, scientists in
> industry as part of that. I would encourage David to include that in
> his outreach slide. And I\'m not nit-picking here, I just think the
> concept is important.
>
> If the agency wants, for example, to really take a look at new
> technology and some of the problems associated with that, probably if
> you look to the industry as well as to academia and other
> institutions, that combination I think can be enormously helpful, and
> we really need to figure out a way to accomplish that. Thank you.
>
> CHAIRMAN LANGER: Other comments? Anybody on the Science Board, any
> questions?
>
> Well, then we are supposed to decide whether we want to accept this
> report, I guess.
>
> DR. FENNEMA: I would move acceptance of the report.
>
> DR. PRINCIPE: Second.
>
> CHAIRMAN LANGER: So why don\'t we vote? It has been moved and
> seconded, so we\'re going to vote on it.
>
> DR. SCHWETZ: I did have a question, but Bob and Alexa, I want to thank
> you very much for all of the work that you obviously put in, and you
> took this very seriously. You were innovative in responding to what
> David came up with as an innovative approach. So on behalf of the
> agency, if we have a good review of a component, it helps the agency
> broadly. So I thank you for all of the work you did as well as the
> rest of your team, and we will get thanks out to the rest of the team
> as well.
>
> My question is this: These reviews were not meant to be the end, they
> were meant to be the beginning of a process. Having taken this
> innovative approach of taking one product line from top to bottom, as
> opposed to the horizontal approach that we\'ve taken in other Centers,
> what do you recommend as a follow-up? Do we go in greater depth to
> this, or do we go horizontal, or do we pick another piece and go
> vertical?
>
> DR. NEREM: My own view, and Alexa may wish to comment also, but I
> think, I really believe that the most important part of what happened
> was the internal review that took place. And I think that somehow
> needs to be brought into, if you wish, business as usual. It\'s part
> of one of our recommendations of taking a reflective look, not to
> criticize people for decisions that may or may not have been made but
> simply to look at what has been done and use that as a learning
> experience so as to do things better in the future.
>
> And certainly there are other areas of CDRH where the report card
> might not be exactly the same as in the electrostimulation device
> area, so it\'s important to look at these other areas. I don\'t think
> that requires an external team to come in. I think that\'s something
> that can be built into a regular internal review process, and maybe
> each year look at a part of what\'s going on.
>
> DR. CANADY: I really agree with everything Bob said. I would add one
> piece. I think that it was valuable for the members of the CDRH to
> have an opportunity to talk without management present and make
> arguments, and that you can\'t really get with the internal review
> process, but I agree that the internal review process was critical. We
> could never have gotten this far. We would have spent a lot more time
> trying to understand things if we did not have the internal review
> process.
>
> DR. SCHWETZ: I just want to give credit where credit is due. Dr.
> Fennema was the one who had the idea that this was an essential and
> critical part of the review process, and we have used it since he
> provided leadership in a review team of CFSAN. And when that was
> brought back to the Science Board, it was approved as an
> institutionalized process.
>
> So I have always felt that the internal review is the most beneficial
> part of any of these reviews, and what you get from the external
> reviewers is additive to that. But the reality is getting your own
> people internally to recognize what they\'re doing and what they
> haven\'t done and to deal with it. And I would say that we are going
> to continue to have these internal reviews as we go through the rest
> of the Centers, and I would encourage that, to the extent that they
> are useful internally in the absence of an external review, that we
> would look at that as well.
>
> So, Owen, thanks for an idea that has become very beneficial to us.
>
> DR. NEREM: But in addition to this being used as part of the Science
> Board review structure, it also could be built into the business as
> usual of the Center.
>
> CHAIRMAN LANGER: One question I had\--go ahead.
>
> DR. FEIGAL: I was just going to comment on some of the processes that
> we plan to take forward. We actually appreciated the suggestion to
> actually now do a review of OST. We think actually this larger view
> now actually gives a context to look at the research efforts both in
> OST and in some of the other areas like epidemiology where we have
> specific research projects, and we can actually look at them.
>
> Another effort which has been going on, and actually has an external
> component as well, has been for us to look at the Radiological Health
> Program, since this Center is the merger of two different programs
> with different authorities and different laws, and we didn\'t really
> try and do the Rad Health Program, except there was some overlap. And
> so those are two activities that will be extensions or continuations
> of that, in addition to tackling some of the explicit issues from this
> report.
>
> The internal review was definitely something that we did get from Dr.
> Fennema. We actually hadn\'t initially planned to do it. We had an
> internal group preparing for the external review, but we actually
> pulled a separate team together that was more senior than that group
> and asked them to actually prepare the internal review report, and it
> was the right decision to do that.
>
> CHAIRMAN LANGER: Any other comments or\--yes?
>
> DR. ROY: Suva Roy, Otsuka Maryland Research Institute. I have never
> worked at the CDRH, but I have worked in the Center for Devices. One
> of the things I would like to see perhaps this meeting address, and
> that is the qualification and experience requirements for reviewers.
> Many of the job descriptions, at least I can speak from the Center for
> Devices, many of the job descriptions were written 30 years ago and it
> has really not changed, or the experience or qualification
> requirements. But if those things are not updated, the Centers may not
> be able to attract or retain the best possible people. So you can
> retrain people, but it\'s like somebody said, you cannot buy a
> Volkswagen Beetle and expect to run it like a Porsche. You have to
> have something underneath to work from. Thank you.
>
> CHAIRMAN LANGER: Bob?
>
> DR. NEREM: Yes. On that comment, I mean, I think as part of really
> doing an in depth look at the kind of staffing needed five years from
> now and strategic recruiting, you really have to look at how different
> positions are defined.
>
> The other thing I wanted to comment on was Jim Benson\'s comment. I
> mean, we specifically included industry, and I noted it was left out
> of your slide, David. I realize that industry on the one hand is
> what\'s being regulated. On the other hand, for certain technologies,
> the expertise is actually out there in the industry, and if you\'re
> going to learn about those technologies you have to take advantage of
> that, and you have to somehow walk that balancing act.
>
> CHAIRMAN LANGER: Okay. Well, thank you very much. I think that\'s an
> excellent review.
>
> The next thing is emerging issues and FDA\'s oversight of clinical
> research, and David Lepay will discuss that.
>
> DR. LEPAY: I\'m going to change the focus of attention a little bit
> here. What we\'re going to talk about for the next 20, 25 minutes are
> clinical trials, the conduct of clinical trials and the oversight of
> clinical trials, and some of the events that are taking place here
> within the agency and in our interactions with the department.
>
> I think first and foremost, though, when we start off here we have to
> give ourselves a very large round of applause for the progress that
> has been made over maybe the past 25, 26 years in the area of clinical
> research. If you look back, it really is very much since the mid-\'70s
> that certainly most of the infrastructure that exists today for the
> oversight of clinical trials, for IRBs, has been put in place.
>
> The Belmont Report, which specified many of the ethical underpinnings
> of our current models, is less than 25 years old. The true
> implementation of evidence-based decision-making at the agency
> probably has taken place within the last 25 years, even though it was
> put in place with the Kefauver-Harris amendments to the FD&C Act. And
> even our standards for research conduct, 10 years ago we hadn\'t
> really defined what good clinical practice was in the agency, and it
> was only when we began moving internationally into harmonization that
> we began to move forward in that direction as well.
>
> And, similarly, we have seen a lot of attention to quality
> improvement, quality assurance systems in this period of time, and
> ultimately a very significant improvement in the quality of clinical
> research as FDA has viewed this in the course of our own oversight, in
> the course of our own inspection system.
>
> In 1977, the first year that we began looking at clinical
> investigators and clinical trials, we were seeing certainly quite a
> number of problems, and the percentage at least\--granted, we didn\'t
> do very many inspections back in the \'70s\--the percentage of what we
> are seeing now in terms of major problems, the red there on the graph,
> is down on the order of about 2 to 3 percent where FDA has to come in
> and take official action in clinical trials. But that is a percentage
> change.
>
> We certainly know that the clinical trial landscape has changed
> markedly over the past 25, 27 years. We may see fewer percentage
> problems, but we know there are more sites, there are more special
> investigators. We know that from the standpoint of trying to get good
> clinical data on populations that will be using our products, we have
> needed to go forward and encourage the enrollment and recruitment of
> subjects from more vulnerable populations than we ever have: children,
> the elderly, ethnic groups.
>
> We have had to face changes in the whole clinical trial system, the
> way it\'s conducted, the outsourcing of trials, new technologies, not
> only from the standpoint of how information is acquired and
> transmitted by electronic means, for example, but certainly also new
> technologies, as science has advanced to the point where basic science
> moved into clinical research, and we have certainly a more
> sophisticated level of applications that we\'re seeing now for review
> at both the research permit, the IND stage, and at the NDA stage. This
> is very much an area of global expansion.
>
> Well, we certainly know over the past few years we\'ve seen a large
> number of calls to action in the area of clinical research, a great
> deal of press attention. I can\'t say that the IG report back in June
> of \'98 was by any means the first, nor had we not recognized some of
> the problems that the IG reported back in \'98, but it began to
> certainly consolidate thinking and bring a great deal of public
> attention to this area, to the concept that institutions were having
> difficulties in their oversight of clinical research. Resources
> weren\'t adequate at the institutional level. IRBs were overworked.
>
> In reports in the New York Times, the concept that we still have cases
> of very, very marked clinical investigator fraud. We still have deaths
> in clinical trials. Some we would like to think perhaps are
> preventable, and indeed a death in a gene therapy trial in September
> of \'99 certainly got a great deal of attention. Problems that we\'ve
> seen abroad have gotten a great deal of attention in the press, the
> Washington Post series this past December, and even very recently, a
> death in what one would consider an academic research trial, certainly
> a trial that was not being forwarded for purposes of
> commercialization, but nonetheless a trial that used an
> investigational product, a drug by our definition, in a clinical
> investigation.
>
> We are certainly trying to answer these calls, and I\'ll talk a little
> bit about how we\'re going about doing this in just a moment.
> Ultimately, in answering these calls we really are very much based on
> our mission, and it is certainly a very broad public mission. We have
> to be out there ensuring the safe use of all of the products we
> regulate, 25 percent of the U.S. economy, or close to it, and make
> sure that those products themselves are safe and efficacious.
>
> And to do this we need the information that comes from clinical
> research. We need the science that\'s underlying our decision-making,
> much of what has been talked about all day today. We need the
> accuracy, the completeness of information from good clinical trials.
>
> Our mission is very broad, even from the standpoint of what we have to
> oversee in the clinical trial arena. We call it Good Clinical
> Practice, but it is very all-encompassing, very all-embracing. It\'s
> not simply domestic, it\'s very much a global issue.
>
> But fortunately we have colleagues in this process. GCP is, as it has
> been developed, very much a system of shared responsibilities, and
> that is the system that in fact we want to keep as vital as possible.
> We think it has done a very good job of protecting human research
> subjects over the past 25 years.
>
> And in fact when we look at those few cases that I mentioned in the
> earlier slide where we\'ve had deaths, we can actually look at this
> list of responsibilities and say in those cases we\'ve lost some of
> the control points in each of those cases that would otherwise ensure
> the appropriate oversight of clinical trials, either by the
> investigator and the sponsor becoming one, the IRB simultaneously
> failing, the failure to bring these to the attention of government
> regulators to be able to interact in these clinical trials.
>
> We have been very lucky, as well. Not only do we have the built-in
> colleagues that come from the shared system of responsibilities in
> GCP, we also have a number of colleagues in government and a number of
> new government entities, if you will, or new people coming into
> government entities to revitalize this process. We\'re working very
> closely right now with the Office for Human Research Protections in
> the department to try to develop human subject protection as a unified
> entity, working as a single voice across government.
>
> We\'re even extending that beyond the department, working with the
> National Science and Technology Committee\'s Subcommittee on Human
> Subject Research. This is a group of representatives from all the
> agencies that are involved in human research, behavioral, social, as
> well as biomedical. And we\'ve seen a lot of new infrastructures
> coming into play, the VA putting in its own series of systems, again
> for research compliance, for research assurance, for furthering the
> oversight of clinical trials. New advisory committees coming down the
> line, as well as advisory committees to our own department, the
> National Human Research Protection Advisory Committee.
>
> But at the end of the day, though, we have all of these colleagues to
> work with, but we are still in some measure left on our own because
> FDA certainly has very unique responsibilities, responsibilities that
> ultimately play on decision-making in applications.
>
> So what are we doing to address the issues that we\'ve seen, the
> problems that have come to public attention, the problems that are
> threatening the ability in fact to even conduct clinical research
> because they\'re scaring off subjects from enrolling in clinical
> trials? We obviously have to address these concerns and make sure, in
> fact, that FDA is out at the forefront assuring that these protections
> are in place.
>
> So we\'re looking at this from the standpoint of broad initiatives,
> initiatives to further protection of human research subjects,
> initiatives directed at defining and improving the responsibility of
> those who are involved in the clinical research process, looking at
> reporting to FDA, trying to pull in and trying to enhance the
> reporting of problems to FDA so that in fact we can help work toward
> creative solutions in dealing with them. Ultimately, as well, issues
> in education and outreach.
>
> And I\'ll talk also a little bit about how we\'re moving in these
> directions through an infrastructure that we put in place, the Office
> for Good Clinical Practices, and the collaborations out of there.
>
> Well, first of all, protection. We know that there are a number of
> areas that we certainly have to strengthen and that we are working to
> strengthen. These aren\'t the level of the IRBs and institutions,
> looking at issues in real-time oversight of safety. It\'s not simply
> enough to come in after the fact, after the damage has been done.
> Looking at effective sponsor monitoring, not simply rote sponsor
> monitoring but mechanisms that will make the clinical trial process
> better. Strengthening our system with regard to clinical investigators
> and site staff, as well as our own responsiveness to subject concerns
> and complaints.
>
> Well, let\'s talk a little bit again about how we\'re moving to
> strengthen the IRB system. One very fundamental criticism that was
> brought our way by the Inspector General was that we don\'t even know
> the entire spectrum of IRBs that are out there, involved in FDA
> regulated research. So we have taken to heart the concept of moving
> toward IRB registration, not simply just to define an inventory but
> because now we have information technology capabilities available
> that, as we do put in place an IRB registration, it can be a two-way
> system that gives us the ability not only to know who is out there
> doing our work, but to be able to tell them what is new in that area,
> what we can come to expect in this area.
>
> We\'re working with the Institute of Medicine and with OHRP, the Human
> Subject Research Subcommittee, toward at least piloting accreditation
> of IRBs. The goal is to raise the floor above our minimal regulatory
> requirements, and we think the best way to do that is to move to an
> accreditation system that will largely be outside of government, where
> the standards in fact will help to promote improvements in the
> process.
>
> And I think very much the third point is one we have to take into
> account, and that is to start reducing unnecessary burdens on IRBs and
> institutions where these are adding little to human subject
> protection, or indeed where they are already covered, covered by
> industry, covered by us, or otherwise better covered by systems that
> we perhaps have to still think about but put in play.
>
> So, again, the challenges for us are still, one, we have a whole
> series of human subject protection functions that we need to cover. We
> know that this includes a review of the ethics, a review of consent,
> scientific review, general monitoring of studies, specific safety
> monitoring of studies and real-time safety monitoring. We have to make
> sure conflict of interest isn\'t at issue, and we still have concerns
> about maintaining privacy and confidentiality.
>
> All of these functions are necessary to keep the process vital, but we
> have to now take a look back and say the IRB cannot do all of these.
> We have to look again at the system. Say these all need to be covered,
> but who best to do these? We have to sit down and have very clear
> dialogue about how to define roles, how to redefine roles, and how to
> clarify roles.
>
> GCP works because there is some reasonable level of redundancy. We
> have to keep some reasonable level of redundancy, but too much becomes
> ineffective and bogs the entire process down, and this is what we have
> to work to avoid. Ultimately it\'s not simply a question of putting in
> place structures, putting in place systems. We all know that the real
> key is ensuring that these systems are performing, that they are
> providing protection for subjects, that they are providing the quality
> of science that\'s going to be important to FDA decision-making. And
> for us to do this, of course, we need to ensure through education, and
> through an emphasis on quality assurance and continual quality
> improvement, that we are making strides in this whole process.
>
> We are working as well in the area of real-time oversight of safety.
> Part of this we know. The only group that can effectively, or the only
> individual that can effectively ensure the safety of a subject,
> outside of the subject his or herself, is going to be the person with
> direct contact, and that\'s the clinical investigator or site staff. I
> think we\'re all fooling ourselves if we think that parties very
> remote to the subject and the investigator are going to accomplish
> this.
>
> So we have to spend time on education and on changing institutional
> culture to ensure, if we have cases where an investigator is also the
> sponsor of a study, they understand that that doesn\'t mean they have
> to do less because no one is monitoring them. Rather, it means they
> have twice the responsibility and twice the need for education in what
> they need to do properly.
>
> We\'re moving from the standpoint of oversight of safety in looking at
> other structures, though. I mentioned this earlier, and one of these
> is certainly the Data Monitoring Committee. And I am actually very
> pleased to say FDA\'s guidance, our draft guidance on data monitoring,
> issued on our web sites this morning. It is a fortuitous time because
> in fact we had long ago planned to have a public workshop on data
> monitoring committees scheduled for the 27th of November here in
> Bethesda, and we are pleased to see that the guidance document is
> available, such that it can be discussed in time for that meeting.
>
> And we\'re working as well with NIH, with OHRP, in discussion of
> safety databases. We\'re also working in the area of protecting
> vulnerable populations. As I said, part of the goal is for FDA to
> speak with one voice across government, and one of the ways we have
> done this is by starting to look at those regulations, those areas
> that we can promote protection, that are otherwise part of government
> regulation, such as the PHS regulations for children, and have moved
> to adopt these. And so Subpart B of the interim rule, which looks at
> safeguards at the level of the IRB, is now part of FDA regulation as
> an interim rule we put into place in April of this year.
>
> We are starting to look down the line in other ways to look at
> consistency, looking at Subpart B, for example, another PHS subpart
> dealing with protections for pregnant women and neonates. We are
> looking also to enhance our bio research monitoring program. It\'s
> always difficult. Our Office for Regulatory Affairs, our field force,
> has always had to suffer from continual declines in resources, from
> continual pulling away of resources from the bio research monitoring
> arena, but I think now we can say we may have some success in moving
> toward more resources in this area.
>
> But again, like with our other strategies, we have to use these
> resources very wisely. We have to use them in a strategic planned
> fashion, and part of this means we need to take on a balance between
> how we look at clinical trials. We need of course to keep looking at
> trials as they are submitted for purposes of FDA decision-making, to
> ensure the integrity of the information that we get, but we also need
> to use those resources to be responsive to the public, to the
> community, by following up on real-time complaints, and also to
> promote the science of what we are doing in our bio research
> monitoring program.
>
> It\'s important to know at some level the state of affairs in areas
> that are coming to the forefront scientifically or that are involving
> vulnerable populations. We started this with gene therapy, doing a
> more systematic statistical look. Certainly we\'re going to move down
> this row in other areas. I put pediatric trials up here because
> that\'s one area I certainly would like to see focused upon. I\'m not
> sure we have yet made our decisions entirely where we are going to
> next prioritize.
>
> But in any case, as we are moving forward, we are moving forward with
> other groups as well. We have started information sharing with OHRP,
> with the VA, with others, to make sure in fact that we are not simply
> preventing compliance information that\'s important to all of us from
> going forward.
>
> And you\'ve heard a lot about quality. Quality assurance is going to
> be part of our system. We know we need to look not only externally and
> promote to industry that they should have quality assurance programs
> and quality improvement programs. That\'s kind of a hollow advice to
> industry, if we ourselves are not doing the same with FDA, such that
> we can assure industry and the community are getting consistent advice
> from us.
>
> Well, I said before, part of this also is responsibility. We have to
> be out there ensuring understanding. Right now, of course, based on
> issues I had mentioned with recent deaths in an academic setting, we
> have to reiterate what in fact our law, what our regulations currently
> state. Our law defines \"drug\" very broadly, and in fact it is, as
> indicated here, one of the definitions is \"articles (other than food)
> to affect the structure or any function of the body of man.\"
>
> So you can see, I mean, our coverage, what we are responsible for in
> regulating these products under the law is very broad, and similarly
> clinical investigation in our regulations is defined very broadly.
> It\'s essentially, for an approved product, any use in medical
> practice, any experiment that involves a drug or a test article. And
> indeed, under our regulations, when an unapproved drug or product is
> used in a clinical investigation, there is a requirement for FDA to be
> part of the regulatory scheme. That\'s how it currently exists.
>
> So the challenge for us, of course, is now we have to reiterate that
> message, that challenge studies, physiology studies of unapproved
> drugs, biologics, and significant risk devices certainly meet the
> definitions for FDA jurisdiction. But we also need to be cognizant of
> how that\'s going to impact science and how that\'s going to impact
> the community, by understanding the nature and scope of these
> activities in the community, and ultimately coming to work with the
> community to define how we can balance our level of oversight with the
> level of risk in these studies.
>
> We also know that for a long period of time we have had a lot of
> ambiguity in what the FDA definitions read, such that this has created
> loopholes and confusion in the clinical trial arena. I don\'t think
> any of us in FDA ever thought of the concept of a subinvestigator or,
> excuse me, an investigator being 3,000 miles removed from any physical
> or verbal contact with a patient, but simply an administrator in an
> office, while everyone else is a subinvestigator. That\'s certainly
> not what ICH, the International Conference on Harmonization, has put
> forward, and I don\'t think that that\'s what any of our thinking
> would be, but that\'s not clear from our definitions.
>
> We have those intrinsic problems, as I said, with
> sponsor/investigators. If GCP is a system of controls, what happens
> when the sponsor and the investigator are the same? They are silly
> questions in some ways. I mean, the sponsor is responsible to provide
> the investigator with an investigator brochure. What does this mean,
> that the person gives it to themselves? The sponsor is responsible for
> monitoring the investigator. What does that mean in a
> sponsor/investigator study? The person is supposed to monitor
> themselves without any additional oversight?
>
> These are real problems for us right now. And similarly there are the
> problems of what are the responsibilities of institutions? We said
> IRBs can\'t do it all. FDA certainly regulates institutions. We have
> to talk a little bit with the community about what institutions can
> and should do.
>
> It\'s certainly an issue as well of conflict of interest. We are
> working as part of a broader group with OHRP, with the National Human
> Research Protection Advisory Committee, the Human Research Subject
> Subcommittee, to develop guidance that will help promote minimization
> and managing of conflicts of interest, not simply payments but any
> kind of potential conflict of interest, and not simply for the
> investigator but also at the institutional level.
>
> We also have to look again at non-U.S. trials. The Inspector General
> has just told us that we\'ve seen a 16-fold increase in the number of
> non-U.S. clinical investigators submitting data to FDA applications
> over the past 9 to 10 years. That\'s certainly a very large increase,
> but one that you would expect with the globalization of the industry.
>
> We have to look back at our criteria for accepting these studies. We
> didn\'t have standards, we didn\'t have GCP defined when we put most
> of these regulations in place, and we rooted our acceptance in very
> vague ethical principles such as those in the early versions of the
> Declaration of Helsinki. We\'ve moved a long ways in that area on an
> international level. Certainly much of the world, even China, is now
> adopting GCP standards, ICH GCP standards. I think it\'s time we
> update our own expectation. You know, we expect more than just vague
> ethical conformance. We want good science, we want good quality, and
> we also want good human subject protection.
>
> And we\'ve made a great deal of progress in GCP harmonization. We\'re
> looking toward GCP as a more concrete standard, and as we do that,
> we\'re looking also toward venues in which we can further globalize
> these standards. The World Health Organization is interested in this.
> They have recently convened a consultation that we were part of. Pan
> American Health Organization as well, in the device area they\'re
> moving forward through ISO. And as well we\'re looking at mechanisms
> for supporting capacity building.
>
> We also need to deal with issues of misconduct. We\'ve talked with
> various of the trade organizations about this, because in fact we
> worry that there are loopholes in the current regulatory schema. The
> concept that in fact only the clinical investigator is subject to
> termination with regard to falsification, this is a matter that takes
> place only if the sponsor can\'t correct. And if the trial is over,
> what does that mean? You obviously can\'t correct when the trial is
> over, but yet that is a loophole in terms of reporting.
>
> So we\'re looking back at what we expect to keep scientific validity
> in an appropriate position, and we\'re looking at this even from the
> standpoint of regulation.
>
> Well, there is no question education is ultimately going to be the
> key. We need to target all who participate. We\'re looking at
> technology. We\'ve moved into web sites that are going to provide
> access to GCP information in consolidated spots.
>
> This is our new office\'s web site, and I\'ll say a little bit more
> about that very briefly. One of the things that certainly we have
> decided to do within the agency, and I certainly thank our leadership
> council for that decision, is to establish an umbrella office, a new
> office to coordinate GCP across the agency as well as beyond the
> agency.
>
> We had a few abortive attempts at naming this office. Those of you who
> have followed this perhaps in the trade press, we started off as an
> Office of Clinical Science. I think we all agreed that this embraces
> perhaps more than clinical science, embraces all aspects of Good
> Clinical Practice. We tried Office for Human Research Trials, with the
> hope that this would give the impression of our coordinated work with
> Office for Human Research Protection at the department. Unfortunately
> it created a great deal of confusion instead, so we settled on the
> Office for Good Clinical Practice. It is a very small office. We\'re
> going to remain it as a very small office, but it is strategically
> located within the Commissioner\'s Office and our Office of Science.
>
> The key positions are the directorship and two other positions that we
> certainly moved forward with. Stan Woollen\'s position is Associate
> Director for Bio Research Monitoring. Stan has had some 25 years of
> experience or 23 years of experience in the bio research monitoring
> arena, at all levels from field to ORA management to Center level and
> now to our umbrella office. And Bonnie Lee, who has been involved with
> FDA in the area of ethics issues from the time of the National
> Commission and the Tuskeegee studies, again a very long-experienced
> person in the area of human subject protection policy.
>
> So our role here, we\'re taking on a centralized role as a small
> office, to largely try to bridge the Centers and ORA in the
> development of GCP policy, in developing those quality systems for our
> own bio research monitoring program and promoting quality in clinical
> trials externally, in many of the initiatives I\'ve indicated earlier,
> in our agency international harmonization efforts in the GCP arena,
> and coordinating GCP education and outreach.
>
> In remaining small, we have to rely on leveraging, and so this
> affects\--again, I am very thankful for the cooperation of our senior
> management, our leadership council, by providing our group with the
> resources of the key medical policy-makers and key compliance
> policy-makers within the agency to come together in steering
> committees, roundtables, and working groups to deal with these
> problems. So we don\'t have to manage them from a top-down
> perspective, but we can actually pull in operational knowledge from
> the strongest people in all of the Centers. We\'re leveraging with
> OHRP and ultimately leveraging with our stakeholders.
>
> So in conclusion I would like to say we are moving forward, but there
> are certainly a lot of opportunities where we need to work together as
> an agency and we need to work together with all of our constituency
> groups. The reforms are underway here, but the only way we are going
> to make these systems improve and get the best possible systems is to
> get our broadest possible participation.
>
> So I thank you very much for your time and attention, and I will be
> taking questions.
>
> CHAIRMAN LANGER: Questions or comments from anyone? Okay, thank you
> very much.
>
> Comments in general from the Science Board?
>
> Another comment? Yes.
>
> MS. MOENCH: Yes, I would like to ask a question if you don\'t mind.
> Liz Moench from MediciGroup, and I really want to thank Dr. Lepay for
> an excellent presentation. I think there are a couple of things, as I
> listened to this presentation, that I\'d like to ask for consideration
> on.
>
> Number one is, I think that we have to give very careful consideration
> to the role of the PI. The PI is, I think needs to be redefined, not
> as a physician investigator but actually as practically invisible or
> partially involved. In a study that we just completed, I can tell you
> that out of 100 PIs, only two were actually actively seeing patients.
> So what we\'re seeing is a very concerning trend where it is the study
> coordinator who is playing a much more involved role in clinical
> research today, and not the PI.
>
> So I think that that is an issue that is certainly going to rear its
> head in clinical litigation, because we\'re certainly seeing more and
> more law firms getting into this, and maybe then sponsors will play a
> more active role in setting performance standards. But I think that
> maybe FDA, in collaboration with the AMA, could play a role in more
> certification. I like the idea of IRB certification, but I would
> certainly like to see greater certification of physician investigators
> who actually really realize what their role should be and what the
> consequences are.
>
> I think the other point I would like to raise also is that we really
> need to look at overhauling the informed consent process. I can tell
> you when we do comprehension testing, many patients have no idea
> really what they\'re signing. And there is some marvelous literature
> now out there that actually shows how few patients really comprehend
> in fact that they are even participating in a clinical trial. So I
> would really like to see that and some more comprehension testing,
> that sponsors in fact have to demonstrate that the patients really do
> understand. I know Lou Morris did so much work looking at
> comprehension testing of labeling of OTC products. Really this is
> comparable, I think, to that process.
>
> And finally, I would really like to see that we get more in terms of
> quality check, in terms of patient feedback. I know that we have
> played a role with some sponsors in actually doing satisfaction
> testing, where we actually get feedback directly from patients and
> their experience in clinical trials, and I can tell you it has been an
> eye opener to some of the clinical teams.
>
> So those are some points that I would like to raise, and I thank you
> very much.
>
> DR. LEPAY: Just briefly.
>
> CHAIRMAN LANGER: Very briefly.
>
> DR. LEPAY: I was just going to say those are three certainly very good
> points, and from the perspective of clinical investigators, this is
> something that we have targeted as an issue for the past two or three
> years. We\'re working with the AAMC. We\'ve worked with a number of
> medical schools and medical colleges that have come forth and within
> their own institutions have put into place, or tried to put into
> place, certification programs or certification requirements. We
> thought that that was a good use of FDA resources in contributing to
> educational programs.
>
> On the realm of IRBs and informed consent, I think you\'re absolutely
> right, and I think the only way we are going to achieve a better
> informed consent process is to pull IRBs back to basics, to say in
> fact the informed consent is one of the leading roles of the IRB, and
> we would much rather focus some level of time and attention on quality
> assuring and quality improving the process of informed consent, and
> maybe less on some of the less important, less protective issues that
> they have come to acquire over the years, and we have to move forward
> in restructuring that aspect of the system.
>
> DR. LEPAY: Thank you. So just briefly, a summary, I think what we
> concluded today is that the pharmaceutical manufacturing issues that
> were raised this morning were very important. I want to encourage the
> FDA to move forward on that and to keep us informed. And we certainly
> accept the CDRH\'s External Science Review. It\'s very positive. So
> thank you all very much, and we\'ll look forward to the next meeting.

\[Whereupon, at 4:00 p.m., the meeting was adjourned.\]