> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> PUBLIC HEALTH SERVICE
>
> FOOD AND DRUG ADMINISTRATION
>
> SCIENCE BOARD MEETING
>
> 8:08 a.m.
>
> Friday, October 25, 2002
>
> 5630 Fishers Lane
>
> Room 1066
>
> Rockville, Maryland
>
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> [FDA Science Board]{.underline}
>
> Robert Langer, Sc.D., Chair
>
> Susan M. Bond, Executive Secretary
>
> Martin Rosenberg, Ph.D.
>
> Michael Patrick Doyle, Ph.D.
>
> Robert Nerem, Ph.D.
>
> Harold Davis, D.V.M., Ph.D.
>
> Jim Riviere, D.V.M., Ph.D.
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> Josephine Grima, Ph.D.
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> Lester Crawford, D.V.M., Ph.D., FDA
>
> Norris E. Alderson, Ph.D., FDA
>
> [Presenters]{.underline}
>
> Joseph Levitt, Esq.
>
> Andrea Meyerhoff, M.D.
>
> Margaret Miller, Ph.D.
>
> Philip Noguchi, M.D.
>
> Kathleen Uhl, M.D.
>
> Susan Wood, Ph.D.
>
> Janet Woodcock, M.D.
>
> Kathryn Zoon, Ph.D.
>
> [Also Present:]{.underline}
>
> Daniel Casciano, Ph.D.
>
> David Feigal, M.D.
>
> Steven Galson, M.D.
>
> John Marzilli
>
> Betsy Natz
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> Bernard Schwetz, D.V.M., Ph.D.
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> Stephen Sundlof, D.V.M., Ph.D.
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> [AGENDA ITEM]{.underline} [PAGE]{.underline}
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> **Call to Order** - Robert S. Langer, Sc.D.,
>
> Science Board Chair 5
>
> **Introductory Remarks** - Lester Crawford,
>
> D.V.M., Ph.D., Deputy Commissioner, FDA 7
>
> **Introductory Remarks** - Norris E. Alderson,
>
> Ph.D., Senior Associate Commissioner for
>
> Science and Health 13
>
> **Counterterrorism Initiatives at FDA** - Andrea Meyerhoff, M.D.,
> Director, Counterterrorism Programs, Office of the Commissioner 17
>
> **Food Safety - Counterterrorism Initiatives** -
>
> Joseph Levitt, Esq., Director, Center for
>
> Food Safety and Applied Nutrition 38
>
> **Discussion** - Science Board Members 66
>
> **Office of Cellular, Tissue, and Gene**
>
> **Therapies (OCTGT)**
>
> \- Kathryn Zoon, Ph.D., Director, Center
>
> for Biologics Evaluation & Research
>
> (CBER) 92
>
> \- Philip Noguchi, M.D., Director, OCTGT 107
>
> **Open Public Comment** 156
>
> **Pregnancy Labeling/Research & Study Design on Medications Used by
> Pregnant Women**
>
> \- Susan Wood, Ph.D., Director, Office of Women\'s
>
> Health (OWH), Office of the Commissioner 164
>
> \- Margaret Miller, Ph.D., Manager, Science
>
> Programs, OWH 178
>
> \- Kathleen Uhl, M.D., Medical Officer,
>
> Pregnancy Labeling Team, CDER 171
>
> **Discussion** - Science Board Members 192
>
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> (Continued)
>
> [AGENDA ITEM]{.underline} [PAGE]{.underline}
>
> **Pharmaceutical cGMPs Initiative (Update)**
>
> \- Janet Woodcock, M.D., Director, Center
>
> for Drug Evaluation & Research (CDER) 234
>
> **Discussion** - Science Board Members 257
>
> **Science Board Closing Remarks/Future**
>
> **Direction** 266
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> DR. LANGER: Good morning. My name is Bob Langer. We\'ll just call the
> meeting to order. I just want to make one announcement and then have
> people go around and introduce themselves.
>
> The announcement is, if you looked at the original schedule that was
> posted, there\'s going to be one change. Dr. Lumpkin can\'t be here
> today. So the schedule will be\--there\'s a new handout that people
> hopefully have, so there will probably be a little bit earlier break
> for lunch so people can eat more.
>
> So, with that, why don\'t we start and we\'ll just go around and
> introduce ourselves.
>
> DR. RIVIERE: Jim Riviere, North Carolina State University.
>
> DR. LANGER: And you\'re a member of the Science Board.
>
> DR. RIVIERE: Member of the Science Board.
>
> DR. GRIMA: Josephine Grima. I\'m the consumer representative for the
> Science Board. I am now with the National Marfan Foundation.
>
> DR. NEREM: This is Bob Nerem. I\'m from Georgia Tech, a member of the
> Science Board.
>
> DR. DAVIS: Harold Davis from Amgen, member of the Science Board.
>
> DR. ROSENBERG: Marty Rosenberg. I\'m also a member of the Science
> Board, and I\'m on sabbatical, teaching at the University of
> Wisconsin.
>
> DR. DOYLE: I\'m Mike Doyle with the University of Georgia, and I\'m
> also a member of the Science Board.
>
> DR. SCHWETZ: Bernard Schwetz, Senior Advisor for Science at the FDA.
>
> DR. LANGER: I\'m Bob Langer, Science Board. I\'m from MIT.
>
> DR. ALDERSON: I\'m Norris Alderson, Senior Associate Commissioner for
> Science at FDA.
>
> MS. BOND: Susan Bond, Executive Secretary to the Board.
>
> MR. MARZILLI: I\'m John Marzilli. I\'m with the Office of Regulatory
> Affairs.
>
> MR. LEVITT: I\'m Joe Levitt, Center for Food Safety and Applied
> Nutrition, FDA.
>
> DR. ZOON: Kathy Zoon, Director of Center for Biologics.
>
> DR. CASCIANO: Dan Casciano, National Center for Toxicologic Research.
>
> DR. SUNDLOF: Stephen Sundlof, Director of the Center for Veterinary
> Medicine.
>
> DR. GALSON: Steve Galson. I\'m the Deputy Director of the Center for
> Drug Evaluation and Research.
>
> MS. NATZ: Betsy Natz. I\'m with the Office of External Affairs.
>
> DR. LANGER: Thank you all. I did want to make one other announcement.
> Kathy Zoon, who introduced herself a minute ago, was elected two weeks
> ago to the Institute of Medicine of the National Academy of Science.
>
> \[Applause.\]
>
> DR. LANGER: Anyhow, with that, let\'s turn it to Dr. Crawford for
> introductory comments.
>
> DR. CRAWFORD: Thank you, Dr. Langer.
>
> We have four members of the Science Board that have served long, well,
> hard, and painfully who will be retiring from the Board. All of them
> have to be recognized, and must be, starting with Owen Fennema, Ed
> Scolnick; Rita Colwell actually has called from Stockholm. We can only
> imagine what she\'s doing in Stockholm. She may be trying to one-up
> Dr. Zoon. \[Laughter.\]
>
> And, finally, the long-suffering but brilliant Chairman of the Science
> Board, Dr. Bob Langer, and all of you who are devotees of Time
> Magazine may recall on August 20, 2001, that our man Langer was
> featured. And there is a very large picture of him, which I\'m going
> to embarrass him with, and it does not show a defective ocular
> situation. It shows him looking for the optimal drug delivery system,
> and it indicates some essentials which I am going to embarrass him
> with. You may not leave the room. It says he was born August 29, 1948,
> in Albany, New York. What got him started was a Gilbert chemistry set,
> which he received when he was 11 years old, that he still has and
> plays with most evenings. \[Laughter.\]
>
> The turning point in his life was a post-doctoral fellowship with
> cancer researcher Judah Folkman, which took him off the
> chemical-engineering career track. And his modus operandi, he looks at
> problems upside down and inside out. And that\'s why he\'s so
> comfortable working with FDA.
>
> So I have the honor of presenting the award, which I hope you will
> enjoy and hope you will open now. At the University of Georgia where I
> worked for about 20 years, we got a Gruen watch. This is a Gruen
> watch. This is a big one.
>
> \[Applause.\]
>
> DR. LANGER: Thank you very much.
>
> DR. CRAWFORD: Take a moment.
>
> DR. LANGER: It\'s not going to blow up, I hope.
>
> DR. CRAWFORD: No, no.
>
> DR. LANGER: It does look a little something like a watch. Well, thank
> you very much.
>
> DR. CRAWFORD: Well done.
>
> \[Applause.\]
>
> DR. CRAWFORD: Now, at this point I would also like to announce the new
> Chair for the Science Board beginning with the term of January 1st of
> next year, and it will last longer than that, depending on his
> performance, Dr. Michael Doyle of the University of Georgia. Mike?
>
> \[Applause.\]
>
> DR. CRAWFORD: All of us are a bit\--we have a couple of changes to the
> program. First, Dr. Mark McClellan is unable to be here. As some of
> you know, he is still doing his White House duties as one of the three
> members of the Economic Council that advises the President on the
> nation\'s economy. Dr. McClellan will be sworn in probably on November
> 8th and will show up here, we all hope, and especially me, within a
> few minutes after that. His replacement at the White House\--actually,
> that is his starting date, so we believe that things will happen at
> that point. He\'s already been confirmed by the Senate and, therefore,
> is called Commissioner Designate until President Bush swears him in.
>
> Let it be said for the record that Dr. McClellan, if he does make it
> by November 8th, will be the youngest FDA Commissioner ever at the age
> of 39-plus, but 40-less. But if it goes as late as November 12th,
> David Kessler will still maintain that honor.
>
> \[Laughter.\]
>
> DR. CRAWFORD: So we\'re working with POTUS to get him sworn in before
> then because that is a notable distinction, and Dr. McClellan has
> begun his process of getting oriented to FDA, and we are all very,
> very impressed.
>
> He has been our primary White House liaison during the time that I\'ve
> been here, which is now eight months, and he will be very familiar
> with all of FDA\'s matters. Anyhow, I think it is going to be a little
> bit dangerous to orient him, and I\'m trying not to be involved in
> that process because he\'s already oriented, I can assure you of that.
>
> Now, one other thing we want to mention, and that is that Dr. Lumpkin
> is with Dr. McClellan and, therefore, both of them are unable to be
> here. If that makes sense to you, then I\'d like to speak to you after
> this meeting. But big things are happening, so we had to take off\--we
> had to change the program both to reflect Dr. McClellan\'s inability
> to make opening remarks and also for Mack\'s inability to talk about
> the CBER/CDER switch.
>
> Dr. Lumpkin has been Chairman of the Implementation Team that has put
> that into place. I now have before me the recommended approach. This
> has been shared with CBER, and we are now in the process of discussing
> with them the fine-tuning of that.
>
> Last night at the dinner, I discussed some aspects of that, and also
> the idea that there would be some other organizational considerations,
> and the Science Board, at least one of you and hopefully two or three,
> have agreed to form a subcommittee to look at future changes, and we
> may need a permanent subcommittee, Mr. Chairman and Mr. New Chairman.
> So we\'ll be looking forward to working with you on that. And this
> kind of input would be very useful to us for future changes.
>
> So, with that, I will turn the meeting back over to Norris Alderson to
> make other comments, and I look forward to being with you until the
> lunch, where I have to also go to the White House. And I have not been
> told what it\'s about, so that\'s life.
>
> DR. ALDERSON: Thank you, Dr. Crawford.
>
> I would like to second Dr. Crawford\'s comments regarding Dr. Langer.
> It\'s been a real pleasure for me to work with Bob since I\'ve been in
> this position, and I really appreciate, Bob, the guidance you\'ve
> given us over that period.
>
> As Les mentioned, we are in the process of getting four new Board
> members beginning in January. They\'ve been selected. They\'re going
> through the clearance process, and as soon as they\'ve made the
> clearance, we will be making an announcement of those individuals.
>
> I do want to point out that the FDA Science Forum for 2003 has been
> scheduled. There are copies of the announcement outside on the table.
> It\'s scheduled for April 24th and 25th at the Washington Convention
> Center. We encourage Board members to attend that if they can.
>
> This is one of the premier science activities of FDA. It\'s becoming
> of more significance in the science arena for FDA than ever before.
> Last year we had over 1,200 registered for it.
>
> This year\'s theme will have three areas: one, risk management;
> second, novel science initiatives at FDA; and, third, public health
> initiatives post-9/11. So we think we\'ve got an outstanding program
> planned with outstanding speakers, and we certainly encourage everyone
> to attend.
>
> As a note of follow-up items to the April meeting, you\'ll remember we
> had considerable discussion regarding the development, or lack
> thereof, of antibiotics that is going on in the industry. Dr. Crawford
> is pursuing with us the additional time at the April meeting of this
> Board to pursue that further, and I\'ll be talking with many of you in
> the next few months about your view on how we need to address that as
> a program for the Science Board. But I just want to alert you to that.
>
> That\'s all I have, and I think Sue has some administrative
> requirements she needs to tell everyone about.
>
> MS. BOND: I have to make comments for the public record, if you\'ll
> bear with me here.
>
> The following announcement addresses the conflict of interest with
> respect to this meeting and is made part of the record to preclude the
> appearance of such at the meeting. The Food and Drug Administration
> has prepared general matter waivers for Drs. Nerem, Davis, Grima,
> Riviere, Langer, Rosenberg, and Doyle. A copy of these waiver
> statements may be obtained by submitting a written request to the
> agency\'s Freedom of Information Office in the Parklawn Building, Room
> 12A30. The waivers permit them to participate in today\'s discussion
> of counterterrorism initiatives, the new CBER Office of Cellular,
> Tissue, and Gene Therapies, Pregnancy Labeling Study issues, and the
> agency\'s Pharmaceutical Manufacturing Initiative.
>
> The topics of today\'s meeting are of broad applicability. Unlike
> issues before a committee in which a particular product is discussed,
> issues of broader applicability involve many industrial sponsors and
> academic institutions. The participating committee members have been
> screened for their financial interests as they apply to these general
> topics. Because the topics impact so many institutions, it is not
> prudent or practical to list all of them at this time.
>
> We acknowledge there may be potential conflicts of interest where,
> because of the general nature of the discussion before the committee,
> these potential interests are mitigated.
>
> Now, to the important other housekeeping things, just for the public
> we invite everybody to have coffee and Danish up in front of the room
> here. There are phones outside behind the guard station. The rest
> rooms are right outside the door. We\'ll be breaking for lunch\--well,
> Bob will call the lunch. We may be breaking a little bit early. And
> there\'s a list of restaurants outside on the table for those of you
> that want to go somewhere.
>
> Public comment will start at 1 o\'clock, and remember to push the
> microphones on when you talk. And that\'s all.
>
> DR. LANGER: Thank you very much.
>
> So now I guess we\'re ready to start, and the first discussion will be
> counterterrorism initiatives at the FDA, and Andrea Meyerhoff is going
> to lead that.
>
> DR. MEYERHOFF: Good morning. Thank you very much for asking me here
> today. Can you hear me?
>
> \[Pause.\]
>
> DR. MEYERHOFF: Thanks. Good morning. I\'ll say again thank you very
> much for asking me here today. What I\'d like to do is provide
> something of an overview of our counterterrorism programs and
> then\--it went off and on here. I\'ll stay away from the
> microphone\--and then present something of a sampling of scientific
> issues that have arisen in this area for the consideration of the
> Science Board.
>
> The way I\'d like to proceed is to make some very general comments
> about our mandate in counterterrorism or what does FDA do in this
> area. I\'d like to go over our strategic plan, which has been updated
> and made comprehensive in the past year. I\'ll talk briefly about how
> we\'re organized across the agency, and then proceed to talk about the
> scientific issues that I\'ve selected for discussion this morning.
>
> If we take a step back and look at the sort of big picture of the
> agency, I think we can see FDA responsibilities in counterterrorism in
> the context of our dual identity in both public health and law
> enforcement.
>
> On the law enforcement side of things in counterterrorism, FDA seeks
> to basically assure the safety and security of our regulated products.
> And this is the whole range of products we regulate: 80 percent of the
> nation\'s food, animal feed, the blood supply, radiation-emitting
> instruments, and the wide range of medical products that are used in
> this country\--drugs, vaccines, and devices\--as well as other
> biologics, I should mention.
>
> On the public health side, we are looking specifically at our role to
> facilitate the availability of safe and effective medical
> countermeasures across the three risk areas in counterterrorism, and
> that is, to respond to the care of individuals who have been exposed
> to biological, chemical, or nuclear agents.
>
> FDA regulations apply across the board to both the civilian and
> military populations, and I think when we think globally about these
> two groups in our country, there are some generalizations we might be
> able to make when we look at the public health needs of these two
> groups.
>
> As I put this slide together over the last few weeks, I really had to
> question some of these statements. I would say these are general
> trends, and I\'m sure we can find exceptions in both of these areas.
> By and large, civilians carrying out the activities of everyday living
> operate in areas of lower risk than do active-duty military. The
> civilian population includes special groups\--children, the elderly,
> pregnant women\--who may represent special medical needs.
>
> Public health actions in counterterrorism are most likely to follow a
> sentinel event, such as a disease outbreak, as we saw last fall with
> the occurrence of the anthrax outbreak in this country. Again, I
> don\'t think a hard and fast rule, but something to keep in mind when
> we look at the needs of the military population, and that is, they
> have the potential to operate in the areas of highest
> risk\--deployment to theaters of operation where there may be
> knowledge of or high risk for exposure to weapons of mass destruction.
> The population medically tends to be more homogeneous. These are
> generally healthy young adults. And in certain instances, the need for
> public health actions may really precede any sentinel event, but be
> more preventive measures.
>
> Let me turn now and talk a little bit about just what the program
> areas are in counterterrorism. What are we doing?
>
> One way to look at this is to contrast the agency\'s level of
> involvement and breadth of programs before the 11th of September last
> year compared to after that date.
>
> These side-by-side bulleted lists give a sense of the changes that
> took place at that time. Before the 11th of September, our budget for
> counterterrorism was somewhere on the order of \$8 million. The
> activities were largely focused on the availability of medical
> products for biological events, that is, an adequate supply of drugs,
> vaccines, and biologicals; and much of the activity was focused in the
> Centers for Drugs and Biologics.
>
> In the wake of the attacks of September 11th, the anthrax outbreak in
> this country, and the deployment of military forces to Central Asia,
> the agency really took a very broad look at all of the different
> activities that needed to come under counterterrorism and how those
> were going to be organized.
>
> Our budget grew substantially. In 2002, that was somewhat in excess of
> \$159 million. Counterterrorism became the new name of what we were
> doing. It was recognized, I think, about the 12th or 13th of September
> that we needed to drop the bio and understand that there were many
> categories of threat agents out there beyond the biological. And it
> encompassed now the full range of products regulated by FDA and
> certainly necessitated total agency involvement.
>
> It was during this period that the agency\'s Strategic Plan in
> Counterterrorism, as it came to be named, underwent a substantial
> review and was an attempt to bring in this total agency involvement.
> And these are the four general areas that encompass what came under
> the rubric of counterterrorism, and it still does.
>
> Goal Area 1 is the safety and security of our regulated products. It
> also gets referred to by the traditional law enforcement activities
> that are encompassed by that: deterrence, detection, investigation,
> and interdiction\--happily referred to usually as DDII.
>
> Goal Area 2 is the availability of safe and effective medical
> countermeasures.
>
> Goal Area 3 refers to the agency\'s activities in emergency
> preparedness and response.
>
> And Goal 4 really was set off by itself more because it has elements
> of each of the three preceding goals, and that is radiation safety.
>
> I\'m now going to talk a little bit about each of these goal areas to
> show how we have set various strategies within them.
>
> The safety and security of FDA-regulated products may be looked at
> from three different angles: how we regulate imported products, how we
> assure their safety in domestic commerce, and how we integrate our
> information systems to assimilate this very large body of data that we
> collect on the vast array of products we regulate.
>
> A very large component of these efforts is our food safety and
> security programs, and I think because I\'m going to be followed by
> Mr. Levitt, I am going to defer to him to talk more extensively about
> that subject.
>
> The medical countermeasures area I think we can look at in three very
> broad strategies in which FDA gets involved. The first of these is
> research and development. As an agency, we provide substantial
> regulatory guidance to those sponsors of products, be they drugs,
> biologics, or devices, that are seeking an indication for a
> counterterrorism-related need.
>
> Secondly, we have a substantial role in assisting in the stockpile and
> inventory of these products. This was illustrated very graphically to
> us during the anthrax outbreak last year. We were in very close
> communication with the manufacturers of the various drugs that were
> being given out as post-exposure prophylaxis\--ciprofloxacin,
> doxycycline, and some of the penicillin products\--in order to assure
> that there were adequate supplies, that manufacturing was understood,
> the available quantities in inventory were known to us and
> communicated to the various other parts of the government that needed
> to know that.
>
> Lastly, in the medical countermeasures area is the issue of
> deployment. When a number of our regulated products would be used in
> this setting, there can be the need to collect data on how they were
> used and what the outcomes were regarding both safety and efficacy in
> the patients who received them.
>
> Some of the regulatory mechanisms that make these products available,
> such as the accelerated approval regs, the new animal efficacy rule,
> or the investigational new drug regulations, warrant that outcomes
> data be collected, and much of our planning in counterterrorism looks
> at how we will go about doing that in what is likely to be a
> large-scale and rapidly evolving public health emergency.
>
> Emergency preparedness and response encompasses a broad array of
> activities here in the agency, including our crisis management, what
> we do in emergency operations and exercising to prepare for terrorist
> events; our security programs for our personnel, our buildings, our
> documents, our communications; and I think that\'s the bulk of those
> categories. I\'m just trying to think if I\'ve left anything out.
>
> No, I think that\'s pretty much it for that.
>
> Lastly, I\'ll move on to radiation safety, which, as I mentioned
> earlier, encompasses the three areas I\'ve already described. We have
> responsibility for the safety of radiation-emitting instruments of all
> kinds, and this again was illustrated to us when FDA got involved in
> discussions of what was a safe and effective way to irradiate the mail
> that had been potentially contaminated by anthrax spores last fall and
> winter.
>
> We participated in the discussions of what would be appropriate doses
> of radiation to use in order to accomplish the task at hand and at the
> same time not overexpose the operators of the equipment to excessive
> radiation.
>
> There\'s a broad array of medical countermeasures that are needed in
> the event of a radiological or nuclear attack. A number of those are
> under development, and those developers or sponsors receive
> substantial regulatory guidance from the agency in manufacturing
> issues, safety and effectiveness, much as any other product does.
>
> Lastly, FDA has certain responsibilities in emergency response in a
> radiation event, and those two are subsumed under the Counterterrorism
> Strategic Plan.
>
> The breadth of our counterterrorism activities is clearly handled
> across the agency, and our office is responsible for coordinating
> those and serving as a point of contact for those outside of the
> agency who have any kind of counterterrorism-related inquiry.
>
> We are in the process of beginning to form our Office of Crisis
> Management. I mention it here simply to point out the three functional
> areas that are coming together to work, and that is our Office of
> Security Operations, Policy and Planning, our Office of Emergency
> Operations, and Counterterrorism.
>
> I thought perhaps one way to illustrate how we assemble ourselves in
> counterterrorism is to take a look from first the outside and then the
> inside. Counterterrorism-related queries that come to the agency can
> come from a very, very broad array of sources. Certainly industry,
> academic investigators, foreign governments, our own government
> agencies, state and local governments, and the occasional concerned
> private citizen may bring to our attention issues relating to product
> development, new ideas in technology, issues regarding the security of
> our regulated products, and any of those are appropriate to bring to
> our office.
>
> Some of the more common questions we handle are whether or not FDA is
> truly involved\--is this a matter of FDA jurisdiction or does it
> belong to another agency?\--whether or not we are funding any of these
> initiatives or can we assist people in finding where they might do
> that; and then if the product does belong in FDA, we serve as a guide
> to assisting in it getting placed in its appropriate regulatory home.
>
> Inside the agency, counterterrorism operates through a steering
> committee. There are any number of points of contact across the agency
> that are part of this steering committee. The five product centers,
> the Office of Regulatory Affairs, and the National Center for
> Toxicological Research all have ongoing scientific presences on the
> steering committee. In addition, there are a number of other functions
> across the agency that are needed and also serve on our steering
> committee.
>
> As I put together my remarks for this morning, I tried to choose a
> sampling of scientific issues that I thought illustrated both the
> breadth of what is going on and also a common theme, and that is, the
> need for us to develop standards in a new arena, building on
> regulatory precedent as a guide. And I think one of the messages that
> is repeatedly driven home to me when we think about the risks posed by
> terrorist activities is they introduce the element of the unknown.
> They introduce agents to which we do not have a lot of experience
> responding, and they introduce new needs for regulatory action for
> which we may not have a lot of precedent. And I\'ll describe a few of
> those now to try and illustrate this. I\'d like to look at certain
> questions in the area of medical countermeasures, in food security,
> and in radiation safety.
>
> This is a list that has been making its way around a lot recently. It
> is the Category A list of biological agents. It was compiled in 1999
> and published by the CDC. It represents the efforts of a number of
> government agencies looking at biological agents that are capable of
> causing serious disease or death, and for which there seems to be some
> information that there is capability somewhere out there for someone
> to use them.
>
> The diseases they cause\--smallpox, anthrax, plague, botulism,
> tularemia, and hemorrhagic fevers\--have very much been in the news, I
> think, some represented more than others. But one of the things I take
> home from looking at a list like this is that these are rather exotic
> agents when we think about disease. These are not commonly encountered
> agents in human disease. I think a couple of them may be more common
> in animal disease. But, nonetheless, up until the relatively recent
> past, we were not really thinking about what we had in our medical
> countermeasure armamentarium to deal with them.
>
> So when we think about the development of drugs and biologics, one of
> the first things we recognize is that we\'re looking at the need to
> understand efficacy and safety of products that will have indications
> for which there is very little regulatory precedent. Up until last
> year, there had been a total of, I think, 18 cases of inhalational
> anthrax in this country. We still have had experience now with less
> than 30. That is a substantial paucity when we think about the kinds
> of information we need when we want to understand how a product works.
>
> Similarly, the last case of smallpox in this country was in 1947. The
> antibiotic era was just getting started then. The antiviral era had
> not even begun. These are diseases with which we have very little
> regulatory precedent for development of products.
>
> The understanding that these are rare diseases, and certainly
> unethical to introduce into human populations for the purpose of
> study, turns us to the use of animal models to better understand the
> products that do need to be developed. And one of the biggest
> questions that we are wrestling with now, both in drugs and biologics,
> is what are appropriate endpoints, what are appropriate animal models
> in which to develop these endpoints to understand how these products
> work.
>
> These types of experiments raise fairly quickly two other fairly
> important issues. One of them is the availability of non-human
> primates for the conduct of these studies. While a primate model is
> not required by the animal efficacy rule or for the study of product
> efficacy, primates are often the most appropriate animal to use, and
> certain species of them are in limited supply and warrant that we
> think strategically about how to use those resources in order to get
> the most information and the most useful products.
>
> Similarly, the laboratory space that\'s available to conduct these
> experiments needs to be a fairly specialized environment with certain
> safety features and certain laboratory expertise among its personnel
> that is not really widely distributed. And, again, building this up
> and understanding how we bring together laboratory facilities,
> experimental animal availability, and then getting the right models to
> do this in are substantial tasks.
>
> I\'m actually going to skip over this particular example in the
> interest of time and, rather, move on to a discussion of some of the
> issues about the development of diagnostic devices. I think I\'ve made
> the point repeatedly now that we are looking at a new range of
> biological agents to assay.
>
> If we take a step back and look at the evolution of the outbreak of
> disease caused by the intentional use of a biological agent, one of
> the things we will readily recognize is making an accurate diagnosis
> is a very, very important step and a very early step in the evolution
> of the outbreak. There are clearly public health and infrastructure
> and economic consequences linked to the information we would get from
> the diagnosis of such a disease and, therefore, putting an especially
> bright light on the need for good diagnostic tools.
>
> As we look at our needs in this area, we need to ask ourselves: What
> is an appropriate level of sensitivity and specificity for these
> tests? How often can we be wrong at the expense of being right?
>
> There\'s a need to validate these assays, make sure that they\'re
> reproducible. And in many ways, the parallels between good diagnosis
> and good prevention and treatment show us that there is a substantial
> amount of work to be done in both of these areas of the development of
> medical countermeasures.
>
> I\'d like to touch on certain issues in food security because they are
> so closely\--they\'re similar to what we have seen with the
> development of clinical diagnostic assays, and that is, we need to
> understand how to detect these biological agents in various food
> matrices which are numerous and varied. How well do these pathogens
> survive in a given food matrix? Can such a pathogen cause human
> disease following oral ingestion in this food matrix? What\'s the
> relevant inoculum causing clinical disease?
>
> Again, these are questions that are currently of great interest and
> the subject of a fair amount of activity that we need to develop.
>
> Lastly, I\'d like to touch on some issues in radiation safety. This is
> a little bit different because this is an area where, as a public
> health community and as a government, we have decades of experience.
> In fact, decades ago, this was an issue of tremendous interest and
> tremendous public health preparedness.
>
> In FDA, we maintain expertise in radiological public health. We have
> experience with population dosimetry studies from one of the largest
> sources of radiation to the general population, that is, medical
> X-rays, and as I mentioned earlier, we have a role in radiation
> response.
>
> The maintenance of a workforce with these kind of skills requires a
> combination of scientific credentials and on-the-job training. There
> is some recognition that these kinds of individuals who were very much
> in demand decades ago are starting to retire. It\'s not clear that we
> have identified the sources and the means for maintaining this
> workforce. And we need to start looking at where this kind of resource
> is being trained, what are the programs out there, how are we going to
> identify our next generation of radiation safety workers.
>
> The expertise that the country has had in nuclear and in radiological
> events may serve us very well, and at the same time we need to be
> positioned to think very broadly about how radiation exposure might
> come about when the element of the human imagination is introduced
> into these kind of risks. What we had traditionally thought were the
> categories of risk to think about may need to be expanded depending
> upon what someone might think is an appropriate medium in which to
> slip a radiation-emitting material.
>
> So, again, we are looking at a strong regulatory precedent, but a need
> to maintain that and stay light on our feet when we try to understand
> the breadth of problems conveyed by new risks associated with
> terrorism.
>
> By way of conclusion, I think what I\'d like to show is the balance we
> seek to strike in our efforts in counterterrorism. As an agency, we
> have a mandate to see that any of our regulated products meet a
> standard of purity, of safety and effectiveness, and are available
> when they\'re needed. In a public health emergency, such as would be
> presented by a terrorist attack, it\'s imperative that there be a
> rapid availability of these regulated products for large-scale use.
>
> The agency\'s role in counterterrorism is to see that this
> availability need is met for pure, safe, and effective products
> consistent with our legal responsibilities as a regulatory agency.
>
> Thank you very much, and I will be happy to take any questions.
>
> DR. LANGER: Would you like to do questions now or after Joe Levitt?
> What\'s your preference?
>
> DR. MEYERHOFF: I am happy to wait if that\--
>
> DR. LANGER: Anything is fine. So we\'ll wait. Good. Thank you very
> much.
>
> So Joe Levitt will talk about food safety and the counterterrorism
> initiatives.
>
> MR. LEVITT: Thank you very much. A pleasure to be here. Let me begin
> by thanking the Chair for your distinguished service as Chair of this
> panel and welcoming the new Chair. We look forward to the seamless
> continuity that we know will occur.
>
> I reflect back to the first time I addressed this Board several years
> ago following the Science Board\'s review of our Foods Program. We
> provided a lot of good suggestions, and today we are well on our way
> to making a lot of progress there.
>
> Understandably, that review did not really address counterterrorism,
> that not being broadly on our agenda at the time, and so we have a lot
> of new information this year.
>
> I think probably my first main point is that today, about a year after
> the terrorist attacks, while a lot has been done\--and you\'ll see a
> lot has been done\--we also now have enough distance to really see how
> massive an undertaking this really is and needs to be.
>
> Interestingly, in today\'s Washington Post, for those of us that had
> time to get past the detailed description of the sniper apprehension
> and so on and so forth, on the front page there is a report of a major
> bipartisan panel on counterterrorism. This panel, for those that
> didn\'t see the article\--and I didn\'t know anything about it until I
> saw the article, so don\'t worry, you\'re forgiven\--was chaired by
> former Senators Gary Hart and Warren Rudman. It had such distinguished
> membership as George Shultz and Warren Christopher, former Secretaries
> of State; former Chairman of the Joint Chiefs of Staff, William
> Webster, former FBI and CIA Director; and Harold Varmus, former NIH
> Director. And the major conclusion from that report is that, \"The
> task of protecting the nation is so complicated and expensive that the
> government\'s multi-billion-dollar efforts will barely dent the
> problem.\"
>
> That\'s kind of a staggering statement and a sobering statement, but I
> can tell you, for somebody who has lived it from a inside-the-FDA
> standpoint, it rings true.
>
> My third point is that\--and I will periodically come back to this
> only because I can\'t help myself. While we have done a lot of
> planning, a lot of exercises, a lot of laboratory work, we had our own
> little version of on-the-job training during the anthrax episode of a
> year ago, not because of the fact that food was affected but the fact
> that our building was affected. And when we were downtown at
> FDA\--we\'ve since moved up to College Park. Because of our proximity
> to the Brentwood mail facility and the triage of testing mailrooms, we
> were among the first mailrooms in Washington to be found to be called
> \"presumptively positive\" for anthrax. That was on a Sunday night.
> Because that was the front end of what we\'re now calling the need for
> surge capacity, it took almost an entire week before we found out on
> Saturday, confirmed from the Centers for Disease Control that, in
> fact, it was negative. But it was one hellacious week, and during that
> week, in retrospect, I can tell you, we learned a lot about what it
> feels like to be a victim as opposed to just somebody on the
> scientific end, learned a lot about risk communication, and in
> retrospect, I think it\'s been a valuable part of our emergency
> preparedness.
>
> With that, let me go to what I want to talk about. I\'ll describe some
> of our general main messages, the activities we\'ve undertaken, some
> areas of special attention, and some conclusions.
>
> I think, first of all\--and this was one of our first insights about a
> year ago\--was that we\'re not starting from zero; that, in fact, we
> have a good start; that the systems that have been put in place to
> reduce foodborne illness, those systems being the surveillance system
> through CDC, the FoodNet and so forth, the prevention systems we\'ve
> put in place, HACCP, good agricultural practices, the emergency
> response system that\'s been drastically improved, including the
> advent of the PulseNet and the DNA fingerprinting\--those are the same
> systems that will help us preventing and responding to a terrorist
> attack.
>
> Indeed, when you think about it, if there is an outbreak of foodborne
> illness, you don\'t know in the beginning whether or not it is
> accidental or intentional. We\'ve always assumed that it\'s
> accidental, but now we realize it could be intentional as well. But in
> the beginning, you\'re not going to know, and those same systems are
> going to be the ones that we\'re going to need to depend on.
>
> We\'ve already realized that especially critical is we need to do what
> we do best. We need to continue to rely on science-based approaches to
> solving these problems. And if we do that, we do feel we can make a
> lot of progress.
>
> Now, let me describe what we\'ve done. We very quickly put together
> what we call a short-term, medium-term, long-term plan that divided
> our activities into three simple notions. One is anticipation. To what
> extent can we do risk assessments, threat assessments, to anticipate
> what is the highest areas of likelihood that food could be used as a
> terrorist vehicle? You know, nothing is for sure, but to the extent
> that we can anticipate, we should.
>
> Second, we know we can\'t anticipate everything, and we\'re going to
> have to be sure if something happens we can respond effectively and
> immediately. But over the long haul, just as with food safety
> generally, the more we can put in place prevention/deterrence systems,
> the better off we will be in the long run. And so we have gone through
> and tried to flesh these out, so let me do that for you here.
>
> Starting with anticipation, one of the first things we found
> out\--it\'s interesting, the things you learn in times of unexpected
> occurrences. While Dr. Meyerhoff is right we\'re dealing here with a
> lot of exotic agents that we\'ve not been talking a lot about
> recently, nevertheless, we have a lot of people with a lot of
> experience. And all of a sudden you hear, you know: I worked on
> anthrax 20 years ago; people told me stop working on its because it
> wasn\'t relevant. But we found we have people with a lot of
> experience, a lot of expertise, and we put together special teams to
> do a series of risk or threat assessments across the food supply.
>
> We used a model that we obtained from the Air Force, you know, under
> the good slogan, \"Good luck beats good planning any day.\" In the Air
> Force Reserves is a gentleman named Larry Barrett, who also is in the
> Department of Public Health in California. He got called up in the Air
> Force to put together a food security plan for the Air Force. Pilots
> eat, too, and they want to have safe food. And immediately because of
> his civilian work, he realized that the applicability of what he was
> putting together would have direct applicability to us. So he
> immediately went to his Surgeon General and his superiors and figured
> out how to declassify or sanitize, whatever the right verbiage is, and
> shared with us the system known as operational risk management, which
> basically looks at a combination of severity and probability and tries
> to match where is the greatest chance for the greatest harm and really
> focus there.
>
> We used that system, and we used a three-part process looking at the
> food, the agents, and the place in the food chain.
>
> Now, it sounds kind of silly, I will confess, but the way we all
> remember is to think back to the board game Clue. Everybody remember
> Clue? Colonel Mustard with a wrench in the kitchen? Well, you got to
> know your food. Are you you\'re dealing with mustard or plums? You
> need to know your weapon. Are you dealing with anthrax or are you
> dealing with smallpox or what? And you need to know the place,
> especially in the food chain with so much food processing, what agents
> are going to be killed by pasteurization and which aren\'t. What
> happens at the end of the system is different from what happens at the
> beginning.
>
> And what we found is that it\'s also a good triage system, because
> almost any food can be tied to some agent, and almost any agent can do
> some harm somewhere. But once you start putting all those three
> together, you can start refining what are the greatest likelihoods.
>
> And we put together a panel of experts from FDA, from the Center and
> from the field, and we came up with a series of threat assessments
> internally. That process is now being validated externally by a group
> through IFT.
>
> Interestingly, one of the things we\'ve learned\--there\'s also
> reference in this news article\--and that we\'re not used to is the
> fact that a lot of this information, while really sought after, also
> needs to be really carefully protected. The watch word is don\'t give
> the terrorists a road map. And so those threat assessments, no sooner
> were they written and we presented them to the department leadership,
> they were immediately classified. And you know what that meant? The
> people who wrote them could no longer read them. But don\'t worry, the
> safe had them, and they were safe. They were safe from the terrorists
> and safe from all who could use them, beneficially or un-beneficially.
> I saw that obviously sarcastically. It was an area of major internal
> debate and frustration.
>
> A year later, I can tell you we\'ve put a lot of people through the
> clearance process, and so now the people who wrote them can read them
> and can use them to our benefit. But one of the things that is new
> that we are not used to is the notion of secrecy versus the need for
> openness. And it presents major challenges, I can assure you.
>
> At the same time, or actually before\--and we actually had this going
> before September 11th, although not by much\--we had a contract
> scheduled Battelle to do a similar kind of threat assessment from the
> outside. We got a progress report on that in the spring. We made some
> additions and adjustments, added our own experiences, and that final
> report is due out in December. And so we\'ll have the benefit of that.
>
> Also under the area of anticipation is better intelligence gathering.
> You know, I now say all the time, because it just seems so odd to me,
> that, you know, as CFSAN Director, I never thought I\'d stand up
> before a group and say we need a closer working relationship with the
> CIA. I mean, who can imagine such a thing? And yet obviously that\'s
> now true. FDA is fortunate, through our Office of Criminal
> Investigations, we do have very close ties through to the intelligence
> community, the FBI, and, again, once you get the right security
> clearances, we can get that kind of information. And yet I can tell
> you even from the intelligence community, this is not the kind of
> information they\'re used to collecting. And so this is some new areas
> for them as well.
>
> So, number one, anticipate what we can.
>
> Number two, respond to what we must. This is probably where FDA
> historically is at its best. We have a lot of history of responding to
> emergencies of all kinds. In this area, I\'m thinking back to the
> Tylenol tamperings. We have applied that. We have conducted under Alan
> Morrison\'s leadership a number of emergency exercises, and some the
> FDA leads, some the department leads, some USDA leads. But there is a
> lot of effort going into it. I can tell you they are sobering
> exercises. Each time you learn a lot, but you also realize how many
> things can happen.
>
> One thing that we learned from the anthrax episode, I can tell you
> both internally and just watching, is the laser-like focus by the
> media. You know, when you have a foodborne illness outbreak, while, as
> I said and it is correct, we\'re responding quicker than ever,
> nevertheless, it takes time to do the epidemiology. By and large,
> these things are, you know, subterranean. Nobody knows they\'re really
> going on, and only at the end when we announce the recall, ah, you
> know, the government did its job.
>
> Well, if the media were following us hour by hour, like they were
> during anthrax, like they were during the sniper episode the last
> three weeks, you know, it\'s an entirely different story. And so when
> you go through these exercises, it is a sobering experience of how
> much there is to do and how important the work is. But we benefit each
> time.
>
> A second point that is getting a lot of attention now, as it should,
> is the whole area of lab capacity and what we\'re calling surge
> capacity. Again, going back to the anthrax episode, it boggles my mind
> that during those several weeks across the country there were over
> 100,000 samples taken and tested and screened for anthrax. You think
> back to that time, everybody saw white powder. Everybody collected it,
> called the hazmat team, sent it in. But the labs couldn\'t handle it,
> and, of course, the labs also, as we found out later, didn\'t have the
> right test for it. And that was a big problem.
>
> And so the CDC has worked hard through their laboratory response
> network, through clinical laboratories, to learn from that experience
> and build on it. And we\'re also realizing that those labs are not
> really equipped to deal with foods, to deal with testing of the food
> matrix. They don\'t have the methods, don\'t have the experience,
> don\'t necessarily have the know-how, and that is presenting a major,
> major challenge for us.
>
> Finally, informing the public. As I\'ve referenced a couple of times,
> these are the kind of events that will get attention like we have
> never seen before, and the importance of good communication, of
> constant communication, of knowing who your spokespeople are, I can
> tell you what we learned internally from just dealing with our own
> employees. And if you go back to your risk communication manuals it\'s
> all there. It just doesn\'t sing out to you until you\'ve really
> experienced it as such. You know, especially a scientific agency like
> ours, we want to have the facts. We want to know the answer. We want
> to be up there standing\--we know Listeria in this product, and these
> people shouldn\'t eat it, and we\'re recalling it, and the thing is
> taken care of. That\'s what we like to say. But the problem here is
> we\'re not going to know. For a long time we\'re not going to know.
> And at that time, it\'s not about conveying information. It\'s about
> building trust. It\'s about building trust with the public, that
> you\'ll be open with them, that you\'ll be honest with them, that
> you\'ll tell them where there is a problem, because basically they
> think we will not.
>
> You know, think back to alar in apples. All the government people said
> they\'re safe, apples are safe, apples are safe. Meryl Streep stood
> up, took an apple out of the refrigerator, threw it in the basket, and
> everybody in the country did the same thing. And so the importance of
> the right kind of public communications is critical.
>
> Finally, most importantly, but also most long term, is the whole issue
> of prevention and deterrence. Imports is an area that all government
> agencies involved with that are critically worried about.
> Interestingly, it\'s highlighted in the report I just referenced this
> morning, across the board, not focused on foods at all. And a major
> part of the resources FDA provided are geared to strengthening our
> role at the borders, and that\'s needed. There\'s also increased
> emphasis on laboratory testing, but really an important area that is
> only starting to receive\--I can\'t say enough attention; it\'s
> starting to receive some attention\--is the whole need for broad
> research agenda. And Dr. Meyerhoff covered a number of the points, but
> as a lot of things, we don\'t know basic stuff. We don\'t really know
> what the\--in anthrax, for example, what GI anthrax really is, you
> know, what its likelihood is, what its severity is. We know more about
> inhalation, more about cutaneous. We kind of jump through quickly to
> GI anthrax, but when, in fact, in a survey of the literature, not as
> much is known as people thought.
>
> We need to know more about how these agents act, what diseases they
> cause, how to detect them, what medical countermeasures are needed to
> respond to them. This is a whole enormous area. In our kind of smaller
> world of FDA and laboratories is the area of methods development.
> There is a massive task to be done, and, unfortunately, in the world
> of research, it\'s boring stuff. You know, methods development is not
> where the Nobel Prize is won, but we need to be able to devote enough
> of the research dollars and interest so we can do our job, so that if
> there is an event we don\'t have presumptive positive on Monday that
> the milk supply is unsafe, only to find out six days later that it was
> all a mistake and all for nothing, didn\'t have a good test. That is
> not going to wash, I can assure you.
>
> The areas of special attention. Number one, we have been fortunate.
> During this time it was quickly recognized that large parts of FDA,
> but especially the food section, the chronic under funding that has
> been circulating in Congress, really came to the fore. People
> understood why we should be worried, and as Dr. Meyerhoff pointed out
> in her slides, roughly two-thirds of the supplemental appropriation
> went to the food area. Almost all of that, appropriately again, went
> to the field, and most of that has gone to the border. We now have
> more people at more borders. We doubled the exams at the border this
> year. We\'re doubling again this year. The Office of Regulatory
> Affairs is truly to be congratulated for being able to hire over 600
> people in just a few months, get them trained, up and running, working
> productively. It\'s really something of historic nature in the FDA.
>
> In the food area and in the field, not since the early 1970s and bon
> vivant have we seen this kind of hiring and new blood brought into the
> FDA. Obviously, not only will it help us for this immediate issue, but
> the leaders 20 years from now will be from the class that was hired
> this past year. And they are a good class and we are very proud of
> them.
>
> Second, legislative authorities. We received the benefit of new
> legislation, and I\'ll go over a little more of that in a minute. We
> also devised a guidance for the industry, what steps they can be
> taking in their own establishments to reduce the risk. And finally,
> strengthening communication and coordination of other federal
> agencies. That\'s always an issue. Even an article like this that
> doesn\'t mention our Department or the FDA, does manage to say there
> is not a single food agency. And so we\'re used to seeing that and
> reading that everywhere, but I do want to assure you, we do talk
> regularly, we meet regularly. There was a lot of coordination among
> the federal agencies, but like so many issues, it does take work and
> it does need constant nurturing.
>
> Let me focus a little on the new legislation. The areas, while there
> are five major title areas of the legislation, only one of which deals
> with food, and in the food area there are over a dozen provisions. The
> four areas that are getting the most attention because they need new
> regulations from the FDA have to do with these four areas. Number one,
> registration of food facilities. Many people are surprised. \"You mean
> that didn\'t always occur?\" In a drug area you have to register with
> the government. In many other areas you have to register. Not in the
> food area, so that\'s new. And that covers all the products we
> regulate, food, animal feed, dietary supplements, the whole shebang,
> and also includes for establishments. The challenge is for a place
> that didn\'t have any registration, now we\'re looking at registration
> of upward to 300,000 facilities. And so that itself is a major
> challenge, not just the right regulations, but to have the IT systems
> in place so we can pull that off.
>
> Second is the establishment and maintenance of records. This has
> always been a major bone of contention with the food industry. Again,
> in the drug industry it\'s relatively accepted because it\'s been part
> of the law for so many years. In the food industry they\'re my
> records. They\'re my records, they\'re not yours. And you know,
> basically when you get a criminal search warrant, you\'re going to get
> it and see records.
>
> But recognition, the time for that has come and gone. If we are to
> have rapid containment of an outbreak, we need to quickly be able to
> trace back where the food came from, and if it\'s a problem at a
> facility we need to be able to trace forward where it went to. And so
> there is new legislation to require a step-wise maintenance of
> records, of what they\--it\'s basically described as one up, one down.
> You need to keep a record where you bought it from, where you sold it
> to. And then the next person along the chain has to do the same thing,
> so that there ought to be a chain back and forth. It will not be
> foolproof. There are lots of areas that are not so susceptible, where
> products are commingled. You may know where you see it, but at the end
> you\'re not going to know which one started from where, and
> ingredients are commingled at manufacturing sites. So it is not a
> foolproof system, but it is a system that will be significantly
> improved over what we have now.
>
> Third, imports. Again, major interest in imports, a system for prior
> notice of imported food and shipments. We\'re getting now, what, John,
> 5 million, 6 million entries a year. That\'s a lot of food coming
> across the border. And the notion is if we had prior notice we could
> better triage and decide what we really need to look at, and finally
> be able to detain goods, an administrative detention mechanism, so
> that if there is a problem\--and this is largely domestic, because we
> do have that authority at the border, that we could, instead of
> running to the state officials, which we do now, and say, \"Can you
> put a hold on this while we go to court,\" We would be able to do that
> ourselves. We have that authority in the medical device area, so FDA
> has some experience with how to do that. All of these regulations are
> on a\--for lack of a better phrase, a really fast track. The reason is
> not just because the law tells us to do them, for better or for worse,
> there\'s a long history of statutory deadlines. Some get met, some
> don\'t. But the ones that get met, I can assure you, are the ones that
> have a hammer, meaning if you don\'t meet it, something even worse
> happens. And under registration, if we don\'t have regs out on how to
> register, they still have to register or the food can\'t be sold or
> imported, and that\'s a pretty heavy hammer. So we will have a
> registration system in place I can assure you.
>
> Same with prior notice. There will be a prior notice system. Both of
> those December 12th, 2003. That\'s only a little more than a year away
> from now. There will be one in place because they are required by law,
> where they may not import their goods. So I sure hope, since they
> can\'t import them, and we don\'t want to have a line at the Mexican
> border all the way down to Argentina, which is where it would be in
> about 5 hours I think. We are going to have to be sure we have that in
> place. So a lot of effort is going on into that.
>
> Guidance to the industry. I reference this quickly. This is one of the
> things we\'re able to do early on, and have gotten a lot of positive
> feedback on. We have guidance both for domestic producers as well as
> for importers. They are designed to be preventive measures. One of the
> areas we got a lot of feedback on was retail area is really different
> in many ways from a manufacturing establishment, the most obvious of
> which is, when you think of intentional contamination, the most
> important thing is access, who can get in. Well, in a food
> manufacturing plant, you want to keep out people you don\'t know. But
> think about your local food store. You want people you don\'t know
> coming in. How else are you going to sell your products? And so there
> are some significant differences, and so as we go through the next
> round of guidance, we\'ll be doing something specific with year two,
> the retail community, and we\'ve had a lot of meetings with them on
> that.
>
> I want to pause here, and let my energy level go down a little bit.
> When we first started, I guess the first presentation of this type I
> gave last December, and that was\--I mean last fall was such crunch
> time, I can\'t even describe it because I don\'t think my mind would
> be clear enough to be able to try and describe it. It was just
> constant overload. And you know, the period it looked like, when you
> start seeing how much there is to do, the food system is so wide open,
> it is not geared to protection of this type, that it almost feels, I
> mean, it almost felt overwhelming, and you wonder, should I just give
> up? Should I just say we can\'t do this. Go and create and Department
> of Homeland Security, staff them up, let them do the right thing.
>
> And so we kind of paused and took an inventory, if you will, what are
> our assets or what do we have going for us? And we realized we
> actually have a fair amount. Number one, we have a lot of capability
> and know-how, as I mentioned earlier. Not only do we have a lot of
> good microbiologists and toxicologists and chemists, but we have
> people that have varying backgrounds. You find the people that have
> been to the military, people that have gone parts of their career
> through CDC, infectious disease areas, and when you take that, you add
> what\'s known in academic institutions, you add what\'s known in the
> industry. There\'s a lot of capability and know-how in this country.
> And realizing that, I think was positive point number one.
>
> Positive point number two is that we do have nurtured and believe we
> have a positive relationship with the industry we deal with. To be
> honest, I was a little worried that the legislation would become so
> acrimonious that might pull away. We\'re able to keep that under
> control. But by and large, this is an area you have to be able to work
> with the industry on. This is something we have a joint problem, a
> joint enemy, and indeed they had joint resolutions, and we feel good
> about that.
>
> Third, the FDA has a long history of successfully responding to
> challenges. Part of our culture, part of who we are, part of why we
> work here, part of our heritage, if you will, is we do rise to the
> occasion. There\'s lots of examples of that dating back to 1906, most
> recently successes on food safety that I ascribed earlier.
>
> And finally, there is a lot of public trust in the FDA. I talked
> before about credibility and public communication. The public does
> believe the FDA and we\'ll need that, and the FDA does have a very
> strong esprit d\'corps and ability to rise to challenges. So this is a
> little bit of true confessions, but once we kind of catalogued these,
> we said, \"Well, wait a minute. We can do this. We can do this too.\"
>
> In conclusion then how do we kind of reflect on this? I think number
> one, food safety and food security, while there are differences
> certainly, they are closely related. As I said, the same kinds of
> systems and approaches that have worked well in food safety are going
> to help us here too. Number two, FDA is certainly increasing its
> vigilance. I think that by now that\'s an understatement. Three, this
> is under-anticipation. We need to be prepared for what is reasonably
> foreseeable, and we spend a lot of time trying to understand what
> might be reasonably foreseeable. But, four, we can\'t figure
> everything out in advance. We have to recognize that unexpected things
> happen, and the way I think of it is, you know, you have your forward
> sight for what you\'re looking at, but you also have peripheral
> vision. And when something happens out of peripheral vision, you need
> to turn to it, and now that\'s in your central sight. We need to
> realize unexpected stuff is going to happen, and that\'s when you rely
> back to what are your assets, what are your tools, what are your
> underlying capabilities. And then finally that means is we need to
> have the flexibility to respond swiftly and effectively to anything
> that does occur. God forbid that it does.
>
> With that I am happy to, I guess, welcome Dr. Meyerhoff back up here
> with me to help answer questions across the spectrum of our issues.
> Thank you very much.
>
> DR. LANGER: Thank you. Why don\'t we open it up for questions,
> comments?
>
> MR. DOYLE: Thank you very much. I really appreciate the comments. I
> thought that whole presentation was very well done.
>
> Mr. Levitt, for you, I continually hear and agree that imports are
> probably one of the our real soft spots. Is the Agency taking a
> holistic size-based approach to inspection of imports? Are we
> profiling, based on science, the greatest foods of risk? Are we
> determining, based n science, the best sampling methods, as well as
> the best testing methods and taking advantage of science to do all
> this?
>
> MR. LEVITT: Obviously a good question. The answer is, that\'s a work
> in progress. That\'s certainly our goal. And you need to also add in
> there what you know in terms of triaging from where the food is coming
> from in terms of what are hot spots. This goes back a little to the
> threat assessments that I described that we did that were actually
> designed to do that. When we locked them in the safe, it became harder
> to do it. We now have more access to the safe, and so you\'re going to
> see more of that rolling out. And because even though we have
> increased\--this will be confidence inspiring\--we\'ve increased the
> sampling from 1 percent to 2 percent. That\'s why we say we doubled
> and doubled again. It does sound better.
>
> \[Laughter.\]
>
> MR. LEVITT: But we\'re never going to have high percentages. That\'s
> why targeting, triaging, stratifying is the key to be able to do this.
> I think in its first phase, to be honest, more effort has been gone
> just getting more people out there, getting them trained to know how
> to do this. As we gear up there will be more triaging. As more
> intelligence information comes in, we\'ll feed that into the system.
> Part of the new IT systems I describe for registration and prior
> notice are really part of an ongoing upgrade across FDA through ORA,
> through Regulatory Affairs, to upgrade our OASIS system, which is the
> historical import system we\'ve had that itself tries to triage our
> internal, our domestic information that we have. We\'re trying to get
> that all brought in together so we have, if you will, a centralized,
> computerized brain of information that can help triage.
>
> In terms of the laboratories, the ability to follow up on the threat
> assessments will depend on having the right methods, the right
> laboratories, the right capabilities. So we will phase that in based
> on what we do have. But it will be some time before we have all really
> the right tools so that the work at the border\--that\'s really the
> bigger picture. I think last year while we were putting together the
> appropriations, during that time of enormous intensity, I guess what I
> learned in retrospect, in times of enormous intensity, you get one
> message. And the one message that got out was FDA doesn\'t have enough
> people at the border.
>
> The concomitant, which were I to do it over again, I would have found
> a way to package two halves of one message, is you\'ve got to have the
> people, you\'ve got to give them the tools. And the scientific tools,
> which is what you\'re referring to, is something that the funding was,
> you know, not proportionate by any means, and something that we\'re
> really trying to focus on in coming areas.
>
> There is some opportunity, assuming the 2003 budget goes through. The
> National Institutes of Health have received, from an FDA perspective,
> an enormous amount of increased bioterrorism funding. Some of that may
> be an opportunity for us, because they do have an area\--we were just
> briefed a couple weeks ago\--they have an area for diagnostics. And
> while they were thinking originally human diagnostics, as we talk to
> them, they understand the point that you need to be able to have the
> diagnostic for the food as well as for the person. And so those of you
> from academic institutions, the FDA cannot apply for those grants, but
> it\'s something we\'ll be working on getting the word out that that is
> an area to try and tap into.
>
> DR. LANGER: Yes?
>
> DR. DAVIS: You mentioned Category A agents in particular, but of
> course, as far as the food supply and certainly for things by the oral
> route, Category B and C have the agents that are actually of far more
> concern perhaps than even Category A if you\'re going to swallow
> things. Can you comment on where you are in terms of the full spectrum
> of those categories?
>
> DR. MEYERHOFF: Sure. I would say two things. First of all, the entries
> on Categories B and C are lengthy, and as you very appropriately point
> out, are often more of a threat to food than some of the really high
> visibility organisms I put in Category A on the slide. And truly what
> we know historically about what has been introduced into food
> intentionally in this country has been the more garden variety good
> pathogens. I think particularly of an event each with salmonella and
> shigella.
>
> The second comment I would make is currently we in the federal public
> health agencies that are looking at this, are starting to work through
> Lists B and C, and they are getting a lot of attention right now, both
> in what belongs on the select agents lists and how we\'re going to
> approach dealing with those bugs. So they haven\'t been neglected, but
> rather left off of my presentation more for the sake of showing what
> are some of the highest threat agents.
>
> MR. LEVITT: If I could just add to that. From the food perspective,
> what we\'re calling the traditional agents like salmonella, E. coli,
> listeria and so forth, we\'re more comfortable simply because we have
> more experience, we have the tools, and we\'re more just better
> prepared to deal with that. But one area, now that we think back to
> the food safety activities over the last several years, one of the
> areas that was really missing was medical countermeasures. There
> really was not a lot of interest or attention to medical treatments
> for food poisoning, and I think that may be one positive side effect
> of this now that people are thinking of medical countermeasures.
> Before it was simply find it, bring them in, give them antibiotics and
> go home. Now there may be more interest in dealing with some of the
> medical countermeasures that weren\'t really in the medical arsenal
> before.
>
> DR. DAVIS: That\'s somewhat, you answered one of the questions that I
> was going to pose. \$159 million didn\'t seem like a lot of money as
> you listed out all of the things that FDA was going to be involved in,
> et cetera. It seemed like a drop in the bucket. And even though NIH
> may be getting a lot of money that you say you may be able to
> piggyback off of. Obviously, when it\'s other people\'s money they get
> to drive the program, and their interest and yours may not lie along
> the same length. So that was one thing.
>
> But the other thing that was mentioned about the availability of
> nonhuman primates to potentially do some work, clearly, that takes a
> lot of money. My business in drug development, we\'re always scuffling
> now with the availability of primates to do normal drug development.
> So to have someone like FDA out there using those same resources,
> that\'s not something that\'s going to be doable in a quick fix kind
> of thing. And so you\'d have to be a sustained user in order to
> increase the supply, and that again will take I think a lot of money.
> And so my concern was that 159 million, sounds like most of it is
> going over to people to do the border work, which I\'m sure is
> necessary, but how do you get the rest of that done, and what do you
> sacrifice? What else isn\'t being done in order to do this new work?
> It just sounds like there are a lot of activities that you have been
> engaged in in the last year, so what hasn\'t been done?
>
> MR. LEVITT: Well, let me kind of go back to, for better, for worse,
> the world of the federal budget. And I guess one I\'ve learned is that
> it is very difficult to break out of historical norms. The FDA is, by
> federal agencies, is a small agency. And a lot of budget talk is in
> percentages. And so while we joke and say we\'ll just take 1 percent
> of the NIH budget, we\'re not allowed to talk in those terms. You
> know, a 10 percent increase in the FDA budget is like what more could
> you possibly want? And so the FDA, that\'s part of our world. As a
> second part of that world, in the food area, there was a GAO report,
> by now a couple years ago, that pointed out that the FDA has 80
> percent of the responsibility in food regulation, but 20 percent of
> the resources. So along comes the Bioterrorism Bill. They do
> appropriations. The FDA got \$100 million for foods. My gosh, you
> broke out of that mold. Well, USDA got 400 million. You know what that
> is? 80/20.
>
> And so somehow the system does not break out of traditional modes. We
> constantly fight against that. If you have any ideas, but I would just
> tell you, that is a nature of the system. I was\--I guess even I took
> a step back when I heard a presentation from NIAID, where a lot of
> bioterrorism money has gone, appropriately. Their increase, increase
> at one institute, a big institute for \'03 if it\'s passed in the
> President\'s budget, is 1.75 billion. The FDA budget, not the
> increase, the FDA budget for everything we do is less than that, a
> little less than that. It\'s the same ballpark. What are we at now,
> 1.6 maybe, 1.6 billion. So an increase is greater than our entire?
> What that tells us is that one, we have to keep making the case, but
> we also have to realize we have to really go to leveraging. We have to
> be good at working with programs that are elsewhere. We cannot think
> of it simply as the FDA is an isolated island. And a lot of our work
> is based on working with USDA, with the research that\'s done
> internally at ARS over there, extramurally through CRES \[?\] and
> tapping into NIH funding and working with universities. That is part
> of who we are and how we work, because I think the other, if we think
> we can do it all by ourselves, I don\'t think we\'ll ever get there.
> In terms of what is not getting done, we worry about that all the
> time. I can tell you that we all feel that the food safety work that
> had increased for several years, has\--I would say that momentum has
> paused. We haven\'t lost the momentum, but it has not continued to
> accelerate as it might otherwise have done. We do need to respond and
> are doing incrementally more work in areas like food allergens. The
> TSEs is an area that is getting more attention.
>
> But you are absolutely correct, at some point there is only so much in
> that box to give. And what we keep looking for are areas that we get a
> two-for out of. When we put somebody at the border, they\'re not just
> looking for anthrax. They\'re looking for additional agents. They\'re
> looking for the same work we\'ve also looked for, so a lot of it does
> go for both, but you raise important points
>
> DR. MEYERHOFF: I\'d just like to add a couple of things to Mr.
> Levitt\'s remarks. On the issue of leveraging on the medical
> countermeasures side, I think recognizing that NIAID has been very
> well recognized as a place where the research dollars are going to go
> for the development of research and new products, we work very closely
> with them developing criteria for animal models and looking at what
> needs to happen to study these new products, vaccines,
> immunoglobulins, drugs.
>
> Yesterday I was listening to some remarks from Dr. Fauci, and was very
> interested to hear what a large proportion of their efforts are going
> to go towards product development. They are looking for deliverables
> that I think we, as the regulatory agency, will be deeply involved in.
>
> Your comments about the primates I think are very well taken. One
> point I want to make explicitly because I\'m not sure I did in my
> remarks, is that we are not so much seeking to have animals on which
> to work in our laboratories, although we do do some of that, but
> rather, I think because we think see the breadth of product
> development, we understand how many different products are going to
> need primates. And I think we need to collaborate with the academic
> community, with industry, with the other federal agencies that are
> working on this to recognize we have a limited resource, we need to
> figure out what comes first and what comes next, and make sure that we
> deploy it in a way that serves all of these needs. So, yes, there\'s a
> shortage of those animals and it\'s going to take a lot of
> organization to figure out how to use them best.
>
> DR. LANGER: Yes?
>
> DR. RIVIERE: Mr. Levitt, following up on this increased vigilance at
> the border, did you find out anything with that? I\'m curious because
> the sampling has always been so low and now that you have an increased
> presence for non-bioterrorism type of problems, have you come up with
> anything that was a surprise or\--
>
> MR. LEVITT: I guess I\'ll ask John to see if he has more specifics on
> that.
>
> MR. MARZILLI: Yes. The first thing I want to mention about the
> increased vigilance on the borders, I know a lot of people probably
> came in through National Airport or Dulles Airport this morning when
> they arrived here, and they were greeted by folks from the TSA.
> That\'s not the kind of employee that we have at the border.
>
> First of all, the folks that we hired in the counterterrorism hiring
> and in our additional hiring, are all folks with science degrees. Most
> of them have experience. Just f.y.i, the average age of these 600
> employees that came in was 36, so we have a lot of people with a lot
> of experience. These folks are not strictly deployed at the borders.
> That is their home station. That\'s their home office. But these folks
> will and are also conducting domestic inspections at the plants where
> these products are further manufactured in the United States, and
> going overseas. So they will be going overseas to do inspections at
> overseas that manufacture products for here.
>
> Yes, we have had a number of very interesting cases this year in terms
> of folks that were familiar with products, and just having hundreds
> more people on the border as a border presence, looking at these
> products come across, could be things as simple as the person
> conducted an inspection at pharmaceutical plant X and new what the raw
> ingredients were that were going into that firm. Yet, they saw an
> entry coming into the country that didn\'t look anything like the
> drums of raw materials that were destined for that firm. That makes a
> completely well rounded investigator that we have there on the border.
> And as I said, all of these folks are folks with science degrees, and
> we have had a number of interesting cases this year, and even things
> as bizarre as crates of product coming in with something sprawled on
> the side that says \"Osama is our hero.\" I mean things like that,
> having people there has made the difference, and having product
> testing done at the border is additional work that we\'re doing as
> well.
>
> DR. RIVIERE: Well, I guess the question is, is the sampling before was
> relatively sparse, and I\'m wondering if that\'s increased now because
> there\'s increased testing going on pretty much to those predictions
> that were holding before as to incidents that carry through. In other
> words, were there any surprises? Were you all of a sudden finding an
> increased level because of more people looking in say a specially
> specific commodity area, an increased presence of either bacterial
> contaminant or chemical contaminant? Are there increases again of
> chlorine pesticides coming in?
>
> MR. MARZILLI: Actually, that is a very good point because we have\--as
> Joe has pointed out, these efforts are dovetailed with our domestic
> efforts, so we have had more, quote, \"hits\" in terms of some of the
> pesticide problems that we\'ve found and some of the pathogens, not
> only natural pathogens but the foodborne pathogens that we
> traditionally look at. So we are getting a lot more surveillance. As
> we\'re implementing these counterterrorism efforts we\'re getting a
> lot more surveillance on the front in terms of food safety and safety
> of other products as well.
>
> So, yes, we are finding\--we\'re getting more information. We\'re
> honing in on more products. We\'re able to do more blitzes as a result
> of it, just because of the intelligence that we\'re gathering.
>
> But, yes, we have had increases in pesticide residues, increases in
> finding products with some contamination from heavy metals that we may
> not have had a chance to look at before because we simply didn\'t have
> people out there collecting the samples.
>
> Our sample examinations this year, as we cranked out the numbers, went
> from about 10 or 12,000 last year to I think it was 34,000 sample
> exams at the border this year. So, obviously, what that is helping us
> to do is to better target products as well as things are progressing
> along. And we have a system for doing that through importer lists, et
> cetera. So it has given us a lot more information.
>
> And it\'s been good fortune for us that some of these systems, as Joe
> mentioned, the OASIS computerized system for import entry that was
> developed a dozen years ago to facilitate product entry into the
> country with more people tuning in to their computer screens and
> taking a look at the products as they\'re coming across, and being at
> the border with that information, querying other data systems, has
> really given us an opportunity to do a lot more surveillance, and
> we\'re going to be cranking that up again next year, so it\'s been a
> dual win for us, actually.
>
> MR. LEVITT: There\'s also, I would just add, an intangible element as
> well, and that is having enough presence, enough show of force that
> this does not come across as the weak link. And when we\--when you
> stand up and say there are 300 ports of entry and the FDA has 150
> import inspectors, how do you say that to the public if you\'re really
> worried? You know, the FDA had always seen the import program as a
> check, a small little check as opposed to a first line of defense. And
> so that difference, it\'s hard to measure exactly how much\--what the
> impression is on the other side, but they\'ll see if it\'s harder to
> get through, if there is more scrutiny, then they are less prone to
> just think it\'s an easy mark.
>
> DR. RIVIERE: Would the creation of a Department of Homeland Security
> impact any of what you just presented?
>
> MR. LEVITT: I don\'t think so. One of the things that we have a done a
> lot over the last 5 or 10 years is work more closely with Customs
> Service, and while the U.S. Customs Service is to be part of the new
> Department of Homeland Security, I suspect they will remain much as
> they are, and therefore, our connections with them will remain much as
> they are.
>
> DR. RIVIERE: Thank you.
>
> DR. DOYLE: NIH has a major request out now for proposals addressing a
> foodborne and waterborne network, which I guess would try to line up
> several universities and perhaps other facilities throughout the
> country. Is FDA an integral part of this program?
>
> MR. LEVITT: That really was part of what I was referring to before,
> and we have met with them. Actually some of the people working at NIH
> came from FDA. One of them actually came from CFSAN. And so I think
> they\'ve made real overtures to try and understand what the needs are
> so they can respond properly. But as somebody said, it\'s not the same
> as having your own. We have to learn how to work within that system.
> We in the food area are not as familiar with the NIH system, the study
> sections, how they review the grants and so forth, as other folks may
> be, so it\'s a learning process for us.
>
> DR. DOYLE: Following up on that, it seems to that FDA ought to be a
> highly important player in this approach, because as I read it,
> there\'s going to be kind of like an oversight, an overseer, whoever
> that may be\--it didn\'t indicate in the grant proposals\--but
> they\'re going to determine what additional testing may need to be
> done in the case of an event, and who would get involved in
> development of methods for detecting foodborne pathogens. This all
> seems to fit very closely to what your needs and interest would be. So
> I would hope that FDA could be a primary player, not only in the end
> product, the end results of all this, but also in the developmental
> stage in identifying besides the key players.
>
> MR. LEVITT: I agree.
>
> DR. LANGER: Are there other questions anyone in the audience or FDA
> would like to ask, or comments?
>
> \[No response.\]
>
> DR. LANGER: I guess not. Thank you very much. That was really very,
> very helpful. Is there anything that we can be helpful to you on?
>
> MR. LEVITT: I think for us your words of encouragement on the research
> side and the method development side, as I said, funny things drive
> budget allocation, and while we like to think there is some cosmic
> risk based thing, that\'s there in part, but in part, certain projects
> require certain sums of money. You\'re going to put in an automated
> food registration prior notice system, that is going to take a chunk
> of money. But it has a definable amount. And so you can say, \"This is
> what I need and I\'m done.\" The area of research, methods
> development, is a little more amorphous. You can\'t say, \"Give me \$5
> million and you will never see me again.\" In fact, the worry is
> there\'s a never-ending need, and so whatever I give you is okay
> because I can\'t satisfy you anyway.
>
> Any help or advice you can give in how to help us frame research
> needs, relative importance to other things, so we can keep that high
> on the radar screen, I think would be very useful to us.
>
> DR. DAVIS: That sort of goes back to my concern about the vast array
> of things that we put up earlier that the FDA saw it should be
> involved with around this topic, and the fact that there was only
> \$150 million. Any organization has a mission, and people always look
> to see where they can be involved and have a real impact. So I think
> one of the things that FDA\'s going to have to do in the absence of
> being able to get real dollars, as you describe them, you\'re really
> going to have to prioritize the programs because there are a lot of
> things to do, as you put up in your list, but \$150 million are not
> going to go very far unless you start to cut into programs that were
> already ongoing. And maybe you have to do that with something like
> this, but again, I simply say what last year, what was very important
> is no longer important, that you can get rid of it to carry out this
> program. And that\'s of concern.
>
> MR. LEVITT: Just to give you some sense of the portion, in CFSAN\'s
> research program, we consciously decided we would redirect 15 percent
> of our research program to methods development for these areas. So
> from an inside viewpoint that\'s a lot, because it\'s not 1 or 2
> percent, that it affects a number of different people in our center,
> but it also means 85 percent we didn\'t redirect. That will give you
> some sense of proportion that way.
>
> DR. MEYERHOFF: If I could just make a couple of more comments on that.
> You\'re right, there is a lot to do, and I think there\'s a number of
> different tools we can bring to that. Some of these tasks are built
> into what we already do. We do a lot. If we had more, we could do
> more.
>
> Secondly, we leverage across the government and other sectors of
> society, with industry, with academia, to get some of these jobs done.
>
> Lastly, and probably what I think is really one of the most important
> things in counterterrorism, is understanding the need to be light on
> our feet. We are never going to be able to predict exactly what the
> next event is going to look like, but we need our systems to be
> elastic enough and moveable enough that we can respond, knowing what
> our job is but not knowing what the exact threat is going to be
> perhaps until very close to the time it happens or when it does.
>
> But your points are very well taken. Thank you.
>
> DR. LANGER: Other comments?
>
> MR. LEVITT: I\'m sorry. Could I add one other thing in response to
> your question.
>
> DR. LANGER: Sure.
>
> MR. LEVITT: Another area that you could help us with, and maybe it
> might be a topic for the next meeting, is how we can better capture
> the expertise out in the many universities in the country. We are\--I
> can\'t say starting because it started\--to receive a series of visits
> from University X with their new Center for Food Safety and Security,
> and University Y with their Center for Food Safety and Security, and Z
> with, guess what, their new Center for Food Safety and Security. And
> while they\'re all coming hoping to get funding and are sorely
> disappointed when I describe our funding capabilities in the area,
> nevertheless, there are a lot of established universities with
> established expertise, which if there is a way to get that banded
> together\--NIH often likes the phrase \"Centers for
> excellence\"\--into a series of Centers for Excellence in Food Safety
> and Security devoted to these things, so we\'re not duplicating, so we
> can tap into the right people, and so we have more of a real
> forward-looking effort, that\'s something that I think would be worth
> further discussion.
>
> DR. LANGER: I think that would be very useful to a future meeting.
>
> Along those lines, one thought is\--this is really only a partial
> answer to that\--but is giving talks at scientific meetings in
> universities. I don\'t know to what extent that happens, and I would
> think that if there are scientific talks on these topics, they would
> probably make you much more visible and people would be interested in
> sharing things with you. I don\'t know if there are really programs
> aimed at that or not, but that\'s just like I say, one thought.
>
> I\'m sure the people here are all at universities and would certainly
> be happy to help. But if you let universities know, I mean I\'m sure
> that there\'s some interest on the FDA\'s part. I\'m sure that they\'d
> be happy to invite you.
>
> MR. LEVITT: Thank you.
>
> DR. LANGER: Other comments?
>
> \[No response.\]
>
> DR. LANGER: Well, thank you very much. What we\'re going to do is take
> a break and then come back at 10:15, where we\'ll be discussing the
> Office of Cellular, Tissue and Gene Therapies at that time. Thank you
> very, very much.
>
> \[Recess.\]
>
> DR. LANGER: The advice I\'m getting is that when people want to speak,
> they need to press the button and make sure the red light\'s on, and
> then they can speak, reasonably close to the microphone.
>
> With that, let me introduce Kathy Zoon, and she\'s going to discuss
> the Office of Cellular, Tissue and Gene Therapies. I\'ll let you lead
> the next discussion, Kathy.
>
> DR. ZOON: Thank you.
>
> I just want to say it\'s a pleasure to be here today and have the
> opportunity to discuss the Office of Cellular, Tissue and Gene
> Therapies and some related topics, and in doing so, before I get
> started, yesterday CBER had the wonderful opportunity of having a
> number of you from the Science Board visit our center, and we had just
> a great afternoon. For those of you who didn\'t get a chance to come
> this time, we\'re happy to have you all the next time, and we\'ll
> certainly be happy to host other visits to CBER, but we had a great
> discussion, a lot of very good input onto the programs that were
> presented, as well as some of the specific projects and initiatives
> going on in CBER. So thank you.
>
> My presentation here today actually is a reflection of a lot of
> thinking that you all have done with respect to cell tissues and gene
> therapies, and the discussions we\'ve had previously with this group
> on combination products. And CBER has taken to heart the discussions
> of this body. We\'ve had a number of open public workshops regarding
> cells, tissues and tissue engineering with Dr. Feigal, David, and have
> spent a lot of time thinking about this.
>
> And one of the fruits of our discussions and with the support of Dr.
> Crawford, has been the creation of the new Office of Cell, Tissue and
> Gene Therapies. And in saying this, one of the things that we are
> currently doing is working with David and CDRH on tissue engineered
> products, and we are currently working on a schema that we will
> hopefully have an opportunity to present to the Board at the next
> meeting that will look at the issues and how we are going to manage
> these as a seamless process between the two centers, so that these
> products of tomorrow can actually reach patients in a timely way.
>
> So, David, I thank you and all your team, and we look forward to
> continuing to work together on this important area.
>
> I just want to spend the time this morning discussing several issues,
> to talk about the regulation of biological products in general, and
> some of the philosophy which I think is really important for products
> of new technology, including the products that are in the new Office
> of Cell Tissues and Gene Therapy.
>
> As you know, the regulation of our products is based on science, law
> and public health impact, and this has really been afforded us by two
> main laws. It\'s the Public Health Service Act, and the Food, Drug and
> Cosmetic Act. And I think one of the things that CBER has looked at
> over the years is the importance of science underpinning our
> regulation of these products as well as making sure they\'re safe and
> facilitating them to the public.
>
> At the core of this you\'ll see research. Research I think of,
> there\'s two pieces of research. One is a laboratory based science and
> another is the research that one gives intellectual freedom to our
> scientists to think beyond the boundaries and to contribute to new
> ideas and new processes. So in our center this has been the core of
> our mission with the review process and our surveillance in policy and
> compliance.
>
> In doing so, I think it\'s important for people to realize we have
> four main product offices within the Center for Biologics. We have the
> Office of Therapeutics Research and Review, the Office of Vaccines
> Research and Review, the Office of Blood Research and Review, and now
> the new Office of Cellular, Tissue and Gene Therapies.
>
> While CBER is constructed on an office level, the dynamics and the
> interplay between our organizations is intense. We feed the science
> across our organization. We\'re not a stovepipe organization. We\'re
> actually a very cross-cutting organization with respect to sharing
> science among our agencies. We have focus groups. We have cross
> support for all our products, and I think I will come back to this
> because I think some of the reorganizational changes that have been
> proposed that we are working with Dr. Crawford on have raised grave
> concerns with me. And I think I will discuss those to some length
> during the course of my presentation before I turn it over to Phil,
> and perhaps this is something that the Committee will discuss with me.
> So with that, I will go on and talk about why we actually went in and
> established this office.
>
> The first question is why did we actually create this new office, and
> one of the main reasons was because there was an increasing number of
> regulatory activities in this area of cell, tissue and gene therapy.
> In addition, we were looking at stem cells and tissue engineering, and
> how to incorporate these important products into our organization in a
> way that we could facilitate science.
>
> Now, clearly in the area of stem cells, we have been working with stem
> cells for quite a while. We have had peripheral blood stem cells, cord
> blood stem cells, mesenchymal stem cells, a lot of different stem
> cells. However, most recently back in August of last year, President
> Bush allowed that embryonic stem cells created before August 9th, 2001
> could now be used in the public forum to do research. So the
> opportunity to look at tissue engineering in a global sense, and
> really to try to understand the science and how we were going to move
> this area forward became a major new program for our center. We were
> also seeing that these products are getting more and more complex. Dr.
> Noguchi, who will be the Acting Director of the new office and will
> speak to you, will give you some examples. We\'re just not talking
> about a cell. We\'re talking about how these cells are grown, how
> they\'re manipulated, what are the factors that cause their
> differentiation, how do you stabilize these, how do you actually
> understand what the characteristics of these cells are that you can
> make products consistently? All of this requires a lot of science and
> a lot of direction in this new area.
>
> And clearly, there\'s an evolution likewise within the Center for
> Devices, where new matrixes are being developed and new science is
> being developed that has to interdigitate where there are combination
> products. And so we recognize that this is an important area and needs
> serious attention and work by the FDA. And we are committed to do it,
> which leads to the seamless and transparent coordination and
> communication. I think we have heard loud and clear from our advisory
> boards, from the public comment, that we need to develop a process
> that is clear, transparent, logical, that imparts the best from CDRH
> and CBER to get these products reviewed in a timely way, and that we
> give timely guidance and instructions.
>
> And as part of this reorganization in CBER, our commitments in working
> with CDRH in developing this process are currently under way, and we
> look forward, as I said, to sharing that with you soon.
>
> This just gives you a sense of the products that have been coming to
> this area. We have literally over 1,000 types of cell and gene
> therapies applications, INDs, into the agency. While there is still
> not a lot of licensed products available, they are advancing in their
> clinical investigation. There\'s also a great advance in the science,
> so it\'s an iterative process, and it\'s extremely important that that
> CBER keep up with the science, i.e., our research review model, and I
> think it\'s really clear for us that you need to have people that
> understand the science that actually do the science that can help lead
> the way in developing policy and guidances, not only to ensure safety
> but to further the science along.
>
> So clearly over the past six years there\'s been a large increase in
> this area, even in spite of some major issues that have been raised.
> Clearly in gene therapy, the death of Jesse Gelsinger \[ph\] has
> raised issues. The science is there. It needs to be actually
> augmented, basic research in this area that feeds into the FDA that we
> could use working with our colleagues both in government, such as NIH,
> where we have a lot of our laboratories, as well as with the industry
> and academic institutions that are developing these products. So I
> think we\'re looking at a very interactive development process.
>
> So what is this new office going to do? Well, this new office is going
> to be responsible for conventional tissues. These are banked human
> tissues. And ultimately, as our tissue rules go forward, these will
> probably encapture reproductive tissues as well. We\'re looking at
> assisted reproductive technologies which is the complex manipulations
> of eggs and sperm and how they\'re going to be used in the future, as
> well as i mentioned, the tissue engineered products and stem cells. It
> will have all the cellular-based products that are currently regulated
> by CBER in these tissue-based products, gene therapies,
> xenotransplantation, which is the use of animal tissues, cells and
> organs. This is a particular area where we have now an advisory
> committee under the Secretary of HHS to deal with the unique zoonotic
> agents that might be of some concern.
>
> We have, as I mentioned, the assisted reproduction area. To give you
> an example of this and some of the things going on in this area that
> raised FDA\'s attention to being manipulated in a way that we consider
> has important safety issues as well as in many ways looking at the
> success of these processes, where people are taking older women\'s
> eggs and actually taking out the cytoplasm and putting in the
> cytoplasm of younger women\'s eggs. And in fact, as many of you know,
> there\'s mitochondrial DNA in the ooplasm of these eggs, and in fact
> you\'re doing essentially gene transfer in some of these activities by
> introducing new genes.
>
> So I think there\'s a lot of issues going on here. Clearly, the
> combination products is a big area that we are concerned about, and we
> think that this is really important, and are anxious to move this area
> forward. Obviously, we want to assure the safe identity, purity and
> potency of these products.
>
> The expertise. We\'ve had a lot of input from you on the Science
> Board. We thank you for that input. Many of you have contacted us with
> your ideas, and so this is still evolving, but some of the expertise
> that this new office has is in molecular and cell biology, viral and
> nonviral gene therapy vectors, nucleic acid chemistry, genomics,
> proteomics, tissue and organ regneeration, developmental and
> reproductive biology, stem cell biology and physiology, obviously, our
> clinical expertise and pharm/tox.
>
> We look at our ability to regulate in this area as one that\'s going
> to require a lot of outreach and get a lot of scientific input,
> because clearly all these areas will have an evolution, and the Agency
> cannot handle this all on our own. We\'re going to have to rely on the
> interaction with scientists outside the Agency.
>
> The Office of Cell, Tissue and Gene Therapies, the Acting Director is
> Dr. Phil Noguchi, who will be speaking to you shortly. Joyce Frye
> \[ph\] is the Acting Deputy. And the structure really deals with three
> primary divisions: the Division of Cellular and Gene Therapies, the
> Division of Human Tissues and the Division of Clinical Evaluation and
> Pharm/Tox.
>
> I would just say while Phil was\--at the time this slide was made the
> Director, Dr. Raj Puri, has been selected as the Acting Director. Raj
> is here. Where are you, Raj? Oh, there he is, right over there. And
> you\'ll see him. Dr. Ruth Solomon, who is the Division of Human
> Tissues, and Ruth\'s group will be continuing her work on the safety
> of banked human tissues, and certainly will continue as those areas
> expand, and a new Division of Clinical Evaluation, Pharmacology and
> Toxicology. Recently Phil has selected a new Acting Director for this,
> Dr. Cynthia Rask, who is\--is Cynthia here? I don\'t see Cynthia, but
> we\'ll make sure she gets\--she\'s doing the work. That\'s good.
> Somebody\'s got to be doing the work.
>
> So under the Division of Cell and Gene Therapy, there\'s a cell
> therapy branch, a gene therapy branch, a lab of molecular immunology
> and virology, a lab of tumor biology. Many of our cellular products
> are used as therapeutic vaccines. A lab or immunology and
> developmental biology and a lab or stem cell biology.
>
> All of these things, obviously have great importance in terms of not
> only looking at therapies, but certainly in coordination with novel
> vaccine protocols.
>
> The Division of Pharm/Tox, again, Dr. Cynthia Rask, who\'s now in the
> upper box. And we\'re going to be recruiting for a person for Clinical
> Evaluation Branch. And we are very close to selecting new leadership
> on an acting basis for the Pharm/Tox Branch.
>
> And then I just wanted to mention the Division of Human Tissues, and
> Dr. Ruth Solomon.
>
> I\'m going to stop my formal presentation at the moment, to just talk
> about the interrelationship of cellular therapies, and also the
> proposed reorganization of having the therapeutic products from CBER
> be considered moved to CDER. I have expressed to certainly Dr.
> Crawford and Dr. Lumpkin the concerns that I the Center Director, and
> certainly the staff at CBER have regarding this particular transition.
>
> We believe that the therapeutic products that we are talking about
> currently in this transfer, which include cytokines, growth factors,
> monoclonal antibodies, and a number of enzymes, as well as other
> related products, have important public health benefit. And I really
> think that the science behind these and the scientific issues with
> these products are not all solved. And the need for having a research
> reviewer base model to deal with these issues continues to be
> important.
>
> There is also a link in a relationship between these products and the
> ability of our new office to function. Many of the components in cell
> tissues and gene therapies require cytokines, growth factors, and
> monoclonal antibodies in order to propagate and use these new
> products. So in essence they are integrally linked.
>
> When we had designed our new office, our office was designed so that
> these two offices were going to coordinate very closely within the
> Center for Biologics. That is, the clinical review, the review teams
> from our scientists in Dr. Rosenberg\'s group, which is therapeutic
> proteins, Dr. Webber\'s group, which is monoclonal antibody, to really
> support this as a whole program. We feel that it is a problem.
>
> We also feel that many of our scientists under this scenario will
> leave the agency, and this is of grave concern to FDA beyond just the
> scope of the function of the new office.
>
> I will not go into all the reasons. I want to link the predominant
> reasons to the new office that I\'m here to discuss today. Dr.
> Crawford and I are in discussions on this, and will be further about
> the impact of this on the FDA as a whole. And I certainly wanted to
> make the Science Board aware of this. This is a very important issue,
> not only to the products we currently regulate in the Center for
> Biologics including the therapeutic proteins, but also the future of
> how we\'re going to deal with these new evolutions of new products.
>
> So I\'m going to stop here. I would like to introduce Dr. Phil
> Noguchi, who will come and discuss some of the specifics of the new
> office, and then I\'d be happy to come back and answer any questions
> you might have. Thank you.
>
> DR. NOGUCHI: Yes, thank you. I\'m used to using a touch pad, so I
> didn\'t notice there was a mouse here.
>
> Thank you very much. It is my distinct privilege to able to present to
> you today and give you both a personal view of what I see the office
> doing. But I can assure you that this personal view is just a slight
> variation of what you will find throughout the agency at every level.
> The reason I call it a simple complexity in an evolving world is
> literally my professional life has been at the Center for Biologics.
>
> I was actually started as a medical student when I was part of the
> NIH, and the next year I came back to continue some of my research,
> and was told that we were part of the FDA. And not knowing anything at
> that time, I hardly noticed the change. But my boss then was Dr. John
> Petrucianni, and from John is really the philosophy of how we do
> business at FDA, and especially at Biologics. And as my own personal,
> kind of, this is about all I know how to do.
>
> When I first started, John looked at me, and he said, \"Well, let\'s
> see, you\'re young medical student. What\'s the problem, what\'s the
> issue, and what are you going to do about it?\" And that basically is
> the same theory I\'ve taken throughout the years and that we will
> continue to do throughout this particularly complex, or simplicity, or
> thus complex.
>
> There will be three topics. I\'m going to touch briefly on our
> counter-terrorism activities and show you how actually that weaves
> together directly into the function of the new office. I\'ll describe
> that, when we talk leveraging, I call it \'federal stone soup.\' I
> mean we have enough to be able to create the regulatory framework, and
> create the regulations and the approval process, but we need
> everybody\'s help to contribute to this soup, so can finally have
> something that\'s useful at the end of the day.
>
> And then finally I want to talk about patient-centered therapies. This
> sounds almost like individual tailored therapies, but it really is a
> little bit different. As I get to that, it\'s really that this society
> should be able to meet the needs of just one person who have the
> rarest genetic disease or other type of disease on earth. We have the
> capacity, we have the wherewithal, we have the approval mechanisms.
> All we need is the will to do that.
>
> First of all, some of the efforts in counter-terrorism: Whether
> you\'re a victim of terrorism, whether it\'s physical, chemical, or
> biological, or you\'re a victim of disease or injury, you\'re going to
> need things that repair, replace, restore, and regenerate normal body
> functions, and that\'s partly what we do. For example, with the era of
> human tissues, we\'ve had some rules on the books since 1993. Last
> year, we believe that there are 600 to 800 thousand tissue
> transplants, musculoskeletal transplants, that have been done.
>
> With the increasing numbers of transplants being done, obviously there
> also comes the need to have a closer oversight over that, but in a way
> that does not impede the currently vastly usable supply that we have.
> We will be finalizing the rules for our tissue framework, which will
> in fact go beyond infectious disease control and will introduce some
> of the concepts Dr. Crawford has for the reinvention of good
> manufacturing practices. We call it good tissue practices. This will
> emphasize record keeping, tracking, and donors\' eligibility rules,
> all within the context of infectious disease control.
>
> Hematopoietic stem cell transplantation has gone on for quite a number
> of years and is certainly now being considered to be the standard of
> medicine in many places. Radiation so-called dirty bombs, as one
> example we know from Chernoble that were the technology better
> available to be able to delivery hematopoietic stem cells in a timely
> fashion, perhaps there would not be nearly as many tragedies at
> Chernoble as there was.
>
> So we\'re actually taking a slightly different modified approach to
> this, because we do want to mobilize this industry, both for its
> medical needs for standard transplantation as well as for the future.
> We\'re reviewing data that has been submitted by a number of our
> partners out there in the academic center. We believe we have at least
> enough to begin to start to do what we called \"deemed licensing,\"
> that is, in lieu of a formal premarket demonstration of safety and
> effectiveness and the attendant lengthy times for that, we do believe
> that some of this area can actually be done in a somewhat
> retrospective manner, but without sacrificing anything in terms of
> safety and effectiveness. We\'re not nearly done with this, but we
> will be bringing back our current efforts in this area, probably in
> the next several months, the beginning of next year.
>
> When we say \"deemed license\" we will to make sure, of course, that
> in fact, even though we deem it and we don\'t have a formal premarket
> approval mechanism for it, that it does, in fact, talk about a safe
> and effective product. We have heard about other stem cells now.
>
> Again for terrorism, counter-terrorism, some of the effects are really
> not known in the immediate sense. Anthrax has an immediate kind of a
> sequela, even though by the time you get the full-blown disease, the
> anthrax bacillus is simply nowhere to be found. There may be
> longer-term consequences from that, such as neurologic damage,
> pancreatic damage, or other tissue damage. We have been doing a lot in
> the area of embryonic stem cells and adult stem cells that are similar
> to these. We\'ve held an FDA public workshop on that.
>
> In your materials that I\'ve passed out today, we\'re very proud that
> in the original primer for embryonic stem cell research, there is a
> Chapter 10, called the safety net for how you develop these things.
> This was authored by actually Donald Fink of the FDA, one of our staff
> members. And in fact when the report first came out, the first part of
> it that was leaked was actually Chapter 10, that is, how are we
> actually going to use this in the clinic. These are all the steps that
> need to take place.
>
> We are going to continue to work on that and to work with the National
> Institutes of Health. We with the NIH have been meeting with the
> approval stem cell providers, both from a scientific basis as well as
> from a regulatory basis. It\'s been extraordinarily fruitful to make
> sure that the FDA and NIH are not only at the same table but we\'re
> asking the same questions, that in fact the NIH is realizing quite
> dramatically that they need to fund those types of studies that need
> to be done, so that we can have safe and effective products for
> something that we don\'t quite know how to do yet.
>
> Even tumor vaccines. Now, tumor vaccines as a theoretic entity have
> been around for 30, 40, 50 years. We have one sponsor, Dr. Don Morton,
> who\'s been in it personally for 40 years, and we see some progress in
> it. If we can get Don Morgan to finally admit that \"Well, of course
> you have to make these products under GMP quality\" and he built his
> own facility for that and has now transferred that to the Cancer
> \'Vax\' sponsorship, we think that this is coming to fruition.
>
> Well, what does this have to do with counter-terrorism? Well, one of
> the long-term sequelae of a dirty bomb, and what we saw in Nagasaki
> and Tokyo, is obviously development of all sorts of malignancies.
> Perhaps one area of use for this would be in the area of tumor
> vaccines, both for the need of the public at large and for the need of
> the victims of terrorism. We are having an international workshop in
> 2003 to follow on a workshop we had earlier and we\'re beginning to
> start a partnership with industry to now start to get down to the real
> nitty-gritty issues. What exactly are going to be the release
> criteria? What exactly do you mean by \'potency\' if in fact this is a
> tumor vaccine, but it\'s individualized, an autologous tumor vaccine?
>
> This is what i described as federal stone soup. When we started about
> ten years ago in the area of gene therapies, gene therapy was then
> really quite new, and as the INDs were being submitted, every single
> one we put on clinical hold because they didn\'t have such things as,
> oh, like their clinical plan was, how they manufactured the virus and
> the vectors, simple things that we decided that we could teach each
> one of the sponsors and go through on an individual basis: \"Well,
> here\'s your IND, these are all the questions you have to need.\"
>
> But we think it\'s a far better way to actually first teach our own
> reviewers what do they need to look for. We\'ll be starting to release
> a series of what we call \'reviewer templates,\' which are for our
> internal use, but will be for public dissemination and discussion.
> With these templates, these are all the things that we\'ve learned
> over the last 11 years about what to look for, being put down in a
> document. We have our reviewers look at this, look to see whether or
> not they\'re in the submission. There are links to all the
> regulations, to the ICH guidelines, to our current policies and
> practices. They\'re updated as we go along.
>
> And by the way, we feel that within three to six months we can take a
> naive reviewer, and that reviewer can then generate about a 15-20 page
> review that\'s comprehensive. It\'s not excessive. We can identify the
> immediate issues to be developed at the IND stage, and will obviously
> be a good template for how we create the pathway for these and other
> kinds of products.
>
> We are thinking, as a matter of fact, that these templates are so
> useful to use, we know that industry is going to be very interested in
> looking at these, so they know what kind of questions we\'re going to
> be asking. And these are not simple questions. This is not a fact of
> \"Oh follow this and you\'ll get an IND and an approval.\" Some of
> these you\'re to have to spend perhaps literally millions of dollars
> to build the technology to address the question, but if that\'s what
> it takes to get something on the market, we already know industry is
> not looking for the easy path. And academia is not looking for the
> easy path. You\'re looking for the path that will give you products
> that will be patient-centered and that will lasting and can be
> developed for the future.
>
> In terms of partnerships and federal stone soup, speaking of Jesse
> Gelsinger\'s death in late 1999, the NIH had a very large three-day
> meeting about it, and one of the recommendations is \"create a
> reference material standard for adenovirus, so we can compare our
> cross-trials.\" We have trials for cancer. We have trials for genetic
> diseases. We have trials that are just marking studies. A whole
> variety of things. But the infectivity one trial may use is different
> from another, is different from another, is different from another.
> This is an old concept of \"create the standards so people at least
> can include that in their development, and we can now complete does
> 10-to-the-7th infectious units in the cancer trial equal 10-to-the-7th
> infectious units in the gene therapy trials for ornithine
> transcarbamylase.
>
> With an interruption from 9-11, about two years ago, we put together a
> proposal. It was handled by the Williamsburg Bioprocessing Foundation.
> We set up a system which is quite remarkable. We actually called for
> bids for portions of what needed to be done, and the idea was you can
> bid for producing GMP quality material. You would bid for being one or
> more of the testing facilities to do the standardization for
> infectivity. You can bid for the testing for infectious disease and
> adventitious agent. Now the other part of it is \"and you will
> volunteer everything for that.\" This is all pro bono.
>
> We estimate that the material cost for this very large effort was
> something on the order of \$750,000. However, the man hours that were
> involved from at least 40 different institutions\--both large, small,
> academic centers, was clearly somewhere in the low to probably high
> millions of just man effort. An absolute prime example of what we
> should term federal stone soup: we provide the framework, we provide
> the ball park. You know, \"Build the park and I know you will come.\"
>
> We are also working with the NIH Stem Cell Task Force. This has just
> been initiated by Dr. Zirhoni, and that goal of that particular task
> force is \"Well, you know they have all cell lines available, but
> there really haven\'t been very many applications for that. So the
> task force is to identify what are the impediments and they want to
> make sure FDA is there so that they can make sure that the studies
> that are being done will contribute to their present and future needs
> for any future cell therapies that use stem cells.
>
> And finally to get to the concept of a patient-centered therapy. This
> is not individualized therapy. This is not taking pharmacogenomic
> measurements and trying to exclude patients based on a particular
> phenotype or genotype. This is really trying to say that \"What if you
> turn the whole pharmaceutical development process on its head? That
> is, when you do a large clinical trial at Amgen, as an example,
> although you are looking for a patient population, you identify that
> up front, by and large it\'s \"If you take this, it will work.\" Of
> course, it doesn\'t fit any one person exactly well, but for the
> average, for the bulk done during a clinical trial, it works not too
> badly.
>
> We think we\--everyone, you all\--can do better. This is where the
> patient defines the therapy. The patient walks in the door, may need a
> knee replacement, needs a new mechanical device, and at the same time
> has psoriasis with another treatment. And so forth and so on. This
> means that we\'re turning everything upside down. We\'re talking about
> market share, because everybody needs to play in this. The large
> pharmaceutical manufacturers absolutely must be a part of this. It is
> only they who have the large capacity to produce the reagents, to
> produce the cytokines, to produce the monoclonal antibodies, that are
> necessary for patient-centered therapies.
>
> So it\'s a share, it\'s a niche. It is not dominance for the market.
> The delivery is obviously evolving. If we\'re going to do a gene
> therapy, where do you go for that? Can you go anywhere in the country?
> The answer is \'no.\' Somewhat facetiously I give the example of \"We
> need thinking like, well, you can go anywhere in the world and get a
> McDonald\'s hamburger, and you may not like it very much, but you know
> it\'s going to be same. You know it\'s going to not cause you food
> poisoning.\" Whereas Jack-n-the-Box, they couldn\'t even do that very
> basic thing of quality control.
>
> So there are opportunities for delivery for the infrastructure that
> needs to be built. A part of it is we also need to get the first
> patient therapy approved. Obviously, financing product developments
> are evolving. But most of all, I\'d like to propose that for this
> process, the patients who are out there, who have missed the
> opportunities of biotechnology are the ones to drive this process. It
> doesn\'t matter how pure the insulin is, if you are a brittle
> diabetic, you still feel lousy, you still are not controlled. You may
> die from your diabetes, and not necessarily from the diabetes. Very
> often these patients just pass out right while they\'re driving a car.
> My stepfather almost did the same thing, as a brittle diabetic.
>
> Now, do we have any examples. We think we have at one prototype
> example of a patient-centered therapy. There is a syndrome called
> \"X-Link Severe Combined Immunodeficiency Syndrome.\" X-Link because
> it\'s on the X-chromosome. The popular term is \"bubble baby
> syndrome.\" This is a lack of a gamma C chain, which is a part of what
> makes up receptors for cytokines. This particular gamma C\--actually
> without having it you loose five different cytokine receptors, and so
> you have essentially no T-cell function. You have relatively normal
> relatively normal but not adequate B-cell function. There is a death
> within the first year of life if it\'s untreated, from severe
> recurrent infections.
>
> If you could get a full HLA identical transplant, usually from the
> sib, you can get greater than a 90 percent survival. Unfortunately
> only about 20 percent of the time do you have such a person available.
> Haplo-identical transplant becomes the second level of
> transplantation. It still carries between a 50 to 30 percent mortality
> rate. And in both of those cases, the reconstitution that you see is
> adequate; that is, you can survive, you can do pretty well. But we
> don\'t know about the long-term survival very much. The oldest is now
> 19. And usually the patients at the minimum need monthly or quarterly
> infusions of gammaglobulin because their B-cells, while somewhat
> normal, really are not adequate for typical antibody responses.
>
> Now, it\'s not without its own hazard. In France, nine of 11 children
> showed evidence of immune reconstitution following gene therapy. Just
> late this August, actually right at Labor Day, one successfully
> treated child out of the nine that were treated in France developed a
> leukemia-like syndrome.
>
> We had a quickly constitutive BRMAC meeting, or Biologics Response
> Modifier Advisory meeting, on October 10, 2002, and in a way it was
> really quite remarkable. Because as science put it, \"What do you do
> when you have when you have a successful treatment and the risk is
> really unknown but it\'s there?\" The significant findings was that in
> fact, the gene insertion by gene therapy that led to the therapeutic
> effect also caused the leukemia-like disease. As Stu Orkin put it,
> more succinctly, if you see an animal with four legs and it has
> stripes, you call it a zebra. If you see a child with leukemia and
> it\'s got a gene therapy and a retrovirus has inserted in an oncogene
> associated with leukemia, you tend to call it leukemia. So the clear
> risk at an unknown frequency is that the same therapeutic event can
> cause a disease. The child has been treated, however, not in complete
> remission, but is still surviving at this time. Obviously we are
> looking at it very closely.
>
> Because of this potential superior immune reconstitution, these kids
> actually do well for both their T-cells and their B-cells. And
> ironically this one young child actually developed chicken pox and was
> able to withstand that and actually to throw off the chicken pox
> somewhere probably after the malignant event occurred. But clearly
> immune function restoration is quite large in these individuals.
>
> We are going to make sure that the trials that will start in the
> United States\--we have two for X-SCID, will have all this information
> available. There will be new test requirements for looking for clonal
> expansion, and within any child that is treated, and a whole bunch of
> other things that are related to that.
>
> We will also be going back and making sure all the informed consent
> process for all retroviral gene therapies are done. And that is a
> process, in fact Dr. Cynthia Rask is right in the middle of heading
> that project up.
>
> Let me just illustrate to you what we\'re talking about here. It\'s
> very simple to say, \"Well, we had a gene therapy and we got a cure.\"
> Here we\'re talking about exactly what was done in France and what
> will be done in the United States in several trials, trying to
> replicate that experience. The end product is on the right-hand side
> the CD34 putative stem cells\--probably not the stem cell, but within
> that population are the primordial stem cells\--that is now expressing
> the normal gamma C receptor. That is the product, per se. You notice
> that the Office of Cellular Tissue and Gene Therapies does not have
> the word, \"product\" in it, because this product, we lose count. You
> start with cord blood, you pass it over an FDA-regulated column that
> has FDA-regulated antibodies into a dish that\'s FDA-regulated because
> it\'s a flask. You take a murine retroviral vector, which is an
> FDA-regulated product, into a fibronectin, oh that\'s another
> FDA-regulated product flask, to do your transduction, in which you add
> three or four growth factors that by themselves have yet to show
> clinical benefit to patients, but in combination are critically
> important for the ability of the retroviral vector to actually
> transduce those cells and lead to a therapeutic effect.
>
> With apologies to Dr. Davis, three out of the four are now at Amgen.
> Stem cell factor Flit 3 ligan \[ph\], and IL-3. The pegylated MDF is a
> different product. Just to divert just a little bit, there are issues
> in terms that are still available because Amgen owns the intellectual
> property for three out of these four. And clearly they do want to make
> sure that their products can be used and developed, but they don\'t
> want to lose the intellectual advantage, nor do they want to be in a
> position where if something goes wrong, they get blamed for that.
>
> Well, we\'re working with Amgen and with the National Cancer Institute
> to work out an arrangement whereby in fact we can start to address
> those kinds of things. The issue right where is that as an entity,
> this particular patient-centered therapy, it is unlikely that any
> pharmaceutical company wants to do the whole thing. On the other hand,
> clearly if we start thinking about market niche, if we have stem cell
> factor that is clinical GMP quality, from a licensed manufacturer, why
> would we prefer that over getting something repackaged by Sigma? And
> that\'s part of the issue of where we are going, part of the types of
> issues that we will be facing.
>
> I put this in a little bit of a tabular form, here, to just say there
> are about five different areas, each of which overlap because, for
> example, we have devices, but the devices have monoclonal antibodies.
> We\'re looking for surface markers. Some of those devices have
> extracellular matrix whose regulatory status, per se, may be a little
> bit confused, but in this context, are part of that whole cellular
> therapy.
>
> Specified products, or these recombinant products, stem cell factor
> Flit-3 ligan\--in no way does the fact that they\'re used in small
> quantities in an ex-vivo situation mitigate the fact that they need to
> be in their own right as safe and as pure as possible. We feel that
> the pharmaceutical biotech industry is a place where that can be done
> on a reasonable basis, and must be done. The quality of each part of
> the products that go into the final therapy here, we cannot compromise
> on the quality. And that quality simply comes from the coordinated
> review, the coordinated review of the science, the coordinated review
> of the research reviewers, that can make that happen.
>
> If you look at all this, and I am not going to spend a lot in terms of
> what the proposed transfer of products will do, but let me put it to
> you in a very practical way. It is a little bit daunting, and I was
> much more comfortable just a few weeks ago to launch a new office that
> actually is smaller than most divisions at FDA. Because I knew I had
> the support of OTRR. I had the support of the Center Director. We
> could do this, we could work it out.
>
> Transfer of the scientists, of the products, of the expertise, no
> matter how you cut it\--some will be lost, some will want to go, very
> likely not too many. Some will leave. Some will go to other centers.
> Some will enter private industry because we train the very best. Our
> folks can go out any time they want, and they know it, but they don\'t
> want to. They want to do the right thing, which is this.
>
> We need that expertise for the medical review. We need that expertise
> for the products. I need to know for sure that a CD34 monocloncal
> antibody actually has undergone the same type of review that we have
> for a therapeutic monoclonal antibody. And you know what? Sometimes
> that slips through the crack. And you know what? If it\'s not within
> our Center, it\'s going to be extraordinarily hard to necessarily
> figure out where it\'s going to be don. In our Center, we are a
> product-oriented center, so in one sense we try to package the whole
> review of the product, the clinical Pharm/Tox review, the compliance,
> and everything else. Although they are in different offices, we are
> one center that does it. If it goes instead to a medical indication,
> so Flit-3 Ligan may go to several different divisions because of the
> medical indication, it will be impossible to adequately address the
> issues for a therapy, a patient-centered therapy such as this.
>
> We think that the reasons for it\--we don\'t know what the reasons for
> it really are. But in fact I can tell you that for the new office to
> function, it\'s a bit of a bite. And I\'ll leave it at that.
>
> But no matter how hard this may be, at the end of the day the question
> is \"Is it all worth it?\" and we say \"yes.\" Learning the lessons of
> the past absolutely enables a future, and what can be imagined will be
> done. And as we move forward we always do this with hope, because we
> always hope next year it\'ll be a little bit better. We know for those
> X-SCID babies, even the parents who know that one of them may develop
> leukemia, they want to take that risk. We need to have appropriate
> humility. Far too often as we move forward, we kind of forget just
> basic things.
>
> Originally 1902 Law for Biologics was because people kind of forget.
> Horses get sick too. A horse named Jim came down with tetanus before
> it was discovered. That was to create a diphtheria antitoxin. The
> diphtheria antitoxin was a wonderful therapeutic agent, but its use
> was being discredited because of that.
>
> The 1938 Food, Drug, and Cosmetic Act. I don\'t know how many men,
> women, and children died because sulfonylmide was insoluble in water,
> so what did they use? They used antifreeze. They didn\'t even try it
> in animals first.
>
> We need to remember that nature\'s been everywhere, she\'s done
> everything. And if it doesn\'t exist, there\'s a good reason why. And
> when we perturb that system, we need to tread with due caution with
> humility and not hubris. This is progess. The race is not to the swift
> or the battle to the strong, but as everybody in a manufacturing
> facility knows, time and chance happens to us all. And most of all, as
> we move forward, we need to move forward with compassion.
>
> Thank you for your kind attention, and Dr. Zoon and I will be pleased
> to take any questions.
>
> DR. LANGER: Thanks. So, we\'ll open it up to questions. Harold, why
> don\'t you go first?
>
> DR. DAVIS: I actually have\--the CBER/CDER reorganization, but I\'m
> not sure if this is the time we want to do that in an open discussion,
> et cetera. I\'m not sure how you\--
>
> DR. LANGER: I think that probably the best time to go over anything is
> now, unless people want to break things up, but it seems to me now we
> should go over any of the topics that Kathy or Bill raised.
>
> DR. DAVIS: I guess I was a little confused about the fact
> that\--procedures for recruiting somebody and then
> calling\--recruiting. Are these internal recruits\--are you
> recruiting\--
>
> DR. ZOON: Most of the recruits\--when you establish a new office it
> takes time to write all the position descriptions and formally
> advertise them. So in order to implement a new office what we do is do
> an advertisement for a detail, which is an acting position. All those
> position descriptions can be written and then formally advertised.
> This is a method that helps the program get started and up and
> running, and clearly it\'s important to do that and get people\--in
> this, but sometimes that could take anywhere from six months to a year
> to get all those position descriptions written, classified, and
> advertised and ultimately filled. We need to do this in order to get
> the operation up and running.
>
> DR. DAVIS: \--the child who came down with leukemia, how long post
> treatment\--
>
> DR. NOGUCHI: We don\'t know the exact date of the actual\--there was a
> development of\--we don\'t know, but it was at least two and a half to
> three years after the initial treatment.
>
> DR. DAVIS: I guess my comment, and this comment ought to be taken from
> Harold as opposed from Amgen. In the time I\'ve been on the panel, I
> don\'t think anything we\'ve discussed as a science board,
> potentially\--like the proposed\--and I\'m not \--even good or bad,
> just the fact that it could potentially impact that. So I\'m very
> surprised that the Science Advisory Board\--considering being brought
> in to offer an opinion on that, or to view that, et cetera. If we are
> to review the issues around the science of the FDA, to me nothing
> we\'ve looked at since I\'ve been here potentially has an\--impact
> like that. I was actually very happy to hear Dr. Crawford\--say some
> members of the board or subcommittee or something would be set up. My
> concern around that is\--did that come from\--. Did BoB, did you and
> somebody else propose that? If that\'s an FDA thing\--
>
> DR. LANGER: Yes, I think I\'ll have to ask Lester about that. I don\'t
> know the answers to that. I think all of us probably want to do
> whatever we can to help in any way. So, probably what could happen on
> this is get a sense of how different members of the board feel and,
> you know, we could make some recommendations to Les. I\'m not sure
> what else we can do. I mean I\'m open to anything, myself. Yes?
>
> DR. ROSENBERG: I also would like to comment. I spent yesterday, I just
> spent the afternoon, very enjoyable afternoon, listening to the
> science programs at CBER, and perhaps that combined with the fact that
> I\'ve also had fifteen years of interaction with that organization
> from my prior experience in the pharmaceutical\--and when Kathy was
> talking about this research or review model, what came across
> yesterday loud and clear was how important that model is and how well
> it works for the type of review they do, in terms of novel biological
> materials, and how integrated that process is and how it requires this
> kind of interrelationship, to be able to have the cutting-edge science
> in place to be able to look at those kinds of novel products.
>
> And the case that was just explained, of course, is just one in terms
> of how therapeutic modalities intermix with cell tissue and gene
> therapy. I think it\'s even much more complex than that. I think
> there\'s interactions between adjuvants and vaccines, and the same
> cytokines that are being used therapeutically are being considered as
> adjuvants.
>
> The whole process of what they do is so integrated, and it\'s
> integrated right from the point of view of helping companies to
> develop these things, in providing feedback to those companies, that
> assistance. Also in approving them and getting the right approval
> capabilities. And then regulating them, particularly regulating them
> from the manufacturing standpoint, and all the again kind of unique
> properties of these kinds of molecules and the science base it takes
> to monitor that.
>
> So given that kind of background, I would like to certain support what
> Harold just said, and that we just heard about all this week. And
> given the importance of that science base to the ability to give
> feedback to the industry, to regulate this industry, to approve
> products in this industry, to monitor manufacturing processes across
> the divisions that were discussed\--I really am very concerned that we
> do not disrupt that science, that we make sure that whatever gets
> done\--and again, I don\'t enough about this to know the reasons for
> or against moving things, but I think before you move something,
> somebody\'s got to present a very logical and rational reason for
> doing that. And I certainly haven\'t heard that. As a member of the
> Science Board, nobody\'s presented that. It\'s never come up for
> discussion. And I\'d like to hear more about why this is going on and
> where it came from and what its purpose it, because I know that its
> potential effect sounds like it could be pretty traumatic. And
> therefore, we\'d like to know and help out if we can to do something.
>
> DR. LANGER: I don\'t know if there are any comments from the FDA, or
> whether we should just\--Les is not here\--or whether we should just
> continue with comments from members of the Science Board, or
> questions.
>
> Okay, Bob?
>
> DR. NEREM: Several comments. Number one, this is not something that
> just happened. It\'s been in the news for at least a month, if not
> longer. But it was my understanding that in fact Lumpkin was going to
> give some background on that, and then unfortunately had to go down to
> the White House, or whatever. But certainly it is something that
> probably deserves further discussion, but it\'s unfortunate in a way
> that this has come up the way it has, without hearing first what the
> rationale of upper management is, and it\'s difficult for me to know
> to be pro or con, as probably most of the Science Board members. But I
> do think it\'s important.
>
> Here, one of the things, which at least my understanding from Dr.
> Crawford was that this subcommittee talking was not to look at this
> specific issue, but to look in a broader way at the organization of
> the FDA, and certainly I would support the FDA thinking out of the
> box, in terms of how they should be organized with the products of the
> 21st Century. And I consider it a very positive thing. Because I would
> assume that a subcommittee would meet before the next board meeting
> and at least produce some homework. So I viewed that comment by Dr.
> Crawford as a very positive comment, but not something that was meant
> to address this particular issue, which doesn\'t mean that it
> shouldn\'t be addressed by some group.
>
> I don\'t if Kathy\--now, I like to come back to this office, and I
> would gather that you\'re probably not ready, you and David Feigal, to
> talk about some of your ideas, and you\'d rather wait on that. Is that
> fair?
>
> DR. ZOON: Yes, but I think in terms of conceptually, I think the
> discussions we have are going to very much reflect how we think. We
> can work together in a seamless fashion to deal with these products in
> a step-wise, risk-driven strategy, where the amount of oversight and
> regulation is coincident with the products and the issues surrounding
> the products, and that we do this in a way that is mindful of both the
> scientific underpinnings from both centers to make sure that we\'re
> coordinated timely and working in teams.
>
> And so I won\'t go into more details \'til we work out the specifics,
> but I think much of the philosophy and the needs of this particular
> tissue engineering field have been heard loud and clear, and we\'re
> trying very hard to incorporate those ideas into the concepts of
> furthering the science in this area and to make sure that the centers
> do it in a coordinated fashion.
>
> So right now we have our teams working very hard on this issue and
> coming up with a strategy. We will be presenting that to Dr. Crawford
> and others, and hopefully they will be pleased with what we come up
> with, or provide feedback that we can go back and work on. So my sense
> is there should a positive solution.
>
> DR. NEREM: Just a couple of comments. You know, one of your slides\--I
> think it was your slide\--was expertise, and that list of expertise
> was actually striking in terms of what you have and equally striking
> in terms of what you don\'t have in terms of what you don\'t have when
> it comes to tissue engineering products, and that\'s why it\'s so
> important that there be a cooperative effort. And I would hope that in
> thinking out of the box, you would even be considering the possibility
> of a joint office that is jointly staffed. Having gone through the
> CDRH review a year ago, the idea of calling in consultants doesn\'t
> seem to be the optimum situation. You need people who are working side
> by side on a day-by-day basis, and that are helping to educate each
> other as to the problems that come from the different sides.
>
> DR. ZOON: I totally agree with you, Bob. I think that we recognize
> that each of the centers has some very precious expertise. It does not
> serve either center well to duplicate expertise, but to coordinate and
> bring teams together that have responsibilities. And so that is what
> we are trying to achieve in our planning and our strategies to work
> together on these new products. And I think that teamwork and
> dedicated teamwork will be a reflection of the concepts that we are
> putting together.
>
> DR. NEREM: The other thing I would suggest is that one probably should
> not be talking about a device approval process versus a biologics
> approval process, but sort of starting from scratch, what is the right
> approval process for these complex products. And I don\'t know whether
> a different process would require legislation, but if it requires
> legislation, so be it, because we need the right process, not some
> shoe-horning products into an existing process.
>
> DR. ZOON: Yes, I think there\'s a way to approach this. And
> particularly because the centers have the opportunity to use all of
> our legislative authorities and regulatory schemes, we actually have a
> lot of flexibility on how to manage these products. And so my view is
> that we should give it a go, and use what the tools are we have to
> make it the very best we can. If after an evaluation, because I think
> it\'s important not only to act but to evaluate what you do and how
> effective it is. But to implement something, look at its
> effectiveness, talk to the people in the field, and then see is this
> effective.
>
> And then once we can do that, we can do an iterative process as to how
> this should be best moved forward. But we have to start somewhere
> within the given tools, and I would say this field needs to move
> forward and not get tied up in knots. And then we can work together
> with the patients, with the industry, with the academic institutions
> to move it forward.
>
> DR. DAVIS: Thanks, Bob, for clarifying that around the subcommittee.
> That\'s actually quite helpful.
>
> But two points. One, I still believe if we\'re going to attack an
> issue or deal with an issue with the subcommittee, what I\'ve seen to
> date with us is that the agency brings an issue to us they\'d like for
> us to consider or wrestle with, and then this committee has sort of
> decided how to deal with it\--to put a subcommittee together, et
> cetera, et cetera. So that doesn\'t allay all my concerns about the
> fact that there will be future subcommittees.
>
> And you also made a point which I agree with. In the last few years
> we\'ve actually reviewed issues around various individual centers, and
> I can\'t understand how we would deal with individual center issues
> around how they\'re structured. We\'ve looked at the retention issues,
> the seniority issues, hiring people, where do you find people, et
> cetera\--how those issues were any more scientific oriented for this
> Board than the potential issue around what\'s going to happen if we
> should merge CBER into CDER. And please understand, I\'m not speaking
> for it or against it at all. It\'s just the fact that if the agency is
> going to that, I would say that my friends who would hold up and see
> that FDA has a science board, advisory board, and that my name is on
> that science board, would probably have assumed from a public
> standpoint that that was discussed at this board.
>
> And we are very far along, there\'s a quick time to turn this whole
> thing around, et cetera, and I\'m not sure of what the board can say
> or do or what will be discussed and what impact we can have, et
> cetera, and that concerns me.
>
> DR. LANGER: Other comments or questions?
>
> Yes?
>
> DR. SCHWETZ: I can\'t speak for Dr. Crawford or Dr. Lumpkin, but in
> the absence of both of them\--I know you\'re going to leave
> today\--unless we have an opportunity to discuss this with Dr.
> Crawford yet today, which I don\'t have reason to believe is going to
> happen\--I would predict you\'re going to go home with a feeling of
> nonclosure on this. And while I can\'t close it for Dr. Crawford, let
> me just say that you\'ve made some very good points and I appreciate
> your effort to make this a generic issue as opposed to a very specific
> one, and I think your recommendations are good.
>
> I would suggest a couple of ways that we might help to bring some
> closure to this, even if it isn\'t today, to do it in the near future.
> And that is\--I think I can speak for Norris. Norris and I will relay
> the nature of the comments to Lester immediately, as soon as we can
> meet with him to share your concerns, because of the time lines of
> what is going on, that we don;t want to go in and talk to him after
> the fact.
>
> So we will talk to him and relay the thoughts that you have put
> forward.
>
> I would also volunteer that you might personally call him. There
> isn\'t reason by Science Board members can\'t call the acting
> commissioner and share off-line thoughts, raise questions, interact
> with the person to whom you are the advisor, outside of meetings. So I
> would encourage any one of you to ether speak on your own behalf or
> you and your fellow board members to the extent that you want to relay
> the discussion that went on here, and your concerns, and the
> discussion that went on yesterday over at CBER. I think it would be
> appropriate for you to share your feelings with him by telephone or by
> whatever means you would like.
>
> Thank you. Norris?
>
> DR. ALDERSON: I agree with what Bernard just said. Bob just gave me a
> draft of something that I think he\'s going to pose to the board to
> relay to Dr. Crawford. And I think that\'s very appropriate that you
> do that. I think he\'s captured here in a statement your concerns that
> I hear you saying. And I think the point that Bern made about this is
> not specific to this issue, but it\'s more of a generic issue which
> you are addressing, and I think that\'s the way you need to do it.
>
> DR. LANGER: I want to see if there are comments from the audience.
> Anybody want to make any comments from the FDA or elsewhere around the
> table? Okay, sure.
>
> MS. ROSENBERG: I\'m Amy Rosenberg, and I\'m the Director of the
> Division of Therapeutic Proteins in CEBR in the Office of
> Therapeutics. And I would like to make a comment that echos some of
> what I\'ve heard around this table. And basically that is that we feel
> that this consolidation plan was formulated in the complete absence of
> what is regarded by the scientific community as critical input. That
> is, input from authorities responsible for oversight of FDA scientific
> programs. The Science Board to the FDA, the Biologic Response
> Modifiers Advisory Committee, or other subcommittees appointed through
> these committees.
>
> The plan to move much of OTRR\'s research programs into CEDR
> contradicts recommendations previously made by a subcommittee of this
> Science Board that drafted a report finalized in October of 1998.
> It\'s now known as the Bennett Report. And in his report, the
> committee resoundingly reported the requirement of a high-quality
> intramural research program for regulation of biological products,
> including biological therapeutics, and the committee stated that \"It
> is the consensus of the committee that CEBR requires a strong
> laboratory research focus and not a virtual science review process.
> Otherwise we risk the potential to damage not only the health of the
> population of the United States, but also the health of our economy.\"
>
> They further stated in no uncertain terms that the culture of science,
> which is so strong at CEBR and necessary to the regulation of
> biological products, is specifically absent from other centers. In so
> stating, the committee stated that the review committee in expressing
> its strong support of the need of laboratory research in CEBR and
> other centers in FDA, recognizes that this position is contrary to the
> experience of the agency and the industry in the review and approval
> of drugs by the Center for Drug Evaluation and Research.
>
> So among the many critical reasons that the committee offered in
> support of CEBR\'s and OTRR\'s intramural laboratory research programs
> were the following: one, regulators and policy makers require expert
> knowledge and firsthand experience with the latest technology being
> applied to biological products. And I think a group of you yesterday
> saw a presentation that highlighted the cutting edge proteomics,
> genomics, and other programs that we have at CEBR, and the fact that
> our scientists stay there. We have very low turnover. They stay there
> because they love what they do. They love they love the integration of
> science and regulation. And they\'re dedicated to it. These people
> could make much more money if they went elsewhere. But they\'re
> dedicated to this. But they\'re dedicated to it because the science is
> incredibly satisfying, as you all well know, and they\'re not going to
> go to a center wherein research will not be supported.
>
> Secondly, the committee stated that an intramural research program is
> required to assess risks of new therapies, to develop assays and new
> approaches to increased efficacy, safety, and reduced risks.
>
> The third comment was that a strong well-maintained intramural
> research program provides the basis for a climate of science and
> scientific communication within CEBR that enhances the ability of the
> agency to recruit and retain high-quality scientific staff. And in
> that light I would ask you to consider the presentations yesterday and
> also the bibliography that we passed out this morning of publications
> from the Office of Therapeutics. I believe that this shows that we
> have an outstanding publication record, and it\'s remarkably done so
> while over 50 percent of the time of these research reviewers is spent
> in regulatory responsibilities.
>
> Furthermore I would highlight that the proposed consolidation poses a
> real threat to retention of the high quality scientific expertise.
> Recently we conducted an anonymous questionnaire of OTRR personnel,
> and found that about 90 percent of principal investigators and tenure
> track fellows, and staff fellows, will seek alternative employment if
> the consolidation plan goes forth as planned.
>
> Fourth, the research program facilitates the ability of CEBR to
> address existing regulatory issues and anticipate future problems, to
> keep pace with rapidly emerging and complex cutting edge technology.
> And I have already alluded to the cutting edge science that we have at
> CEBR, which may not stay, should it be placed in an office where
> science is not supported and there\'s not a critical mass of
> scientists.
>
> With regard to existing regulatory issues, we interact extensively
> with industry. We\'ve organized many, many meetings to address what
> for biological therapeutics are critical issues, that of
> immunogenecity, comparability, and the prospect of generic biologics.
>
> So in summarizing, because the conclusions of this report are so clear
> with regard to the requirement for research, we feel that the input of
> the Science Board to the FDA to this consolidation plan is of vital
> importance, and notably has been absent.
>
> And we welcome your comments, we welcome further input of the Science
> Board, and really very much encourage your participation. Thank you.
>
> DR. DAVIS: The questionnaire that you said was done? How many people
> are we talking about? How many people were sampled? You said 90
> percent of the people responded one way or the other? Are we talking
> about ten people, 100 people?
>
> MS. ROSENBERG: We\'re talking about, I believe it is 100, at least
> that we\'ve so far gotten questionnaires back from. But the majority
> of persons are within DTP and DMA.
>
> DR. DAVIS: That\'s 100 out of 140? 100 out of 300, or\...
>
> MS. ROSENBERG: Do we have the numbers? Dr. Max can speak to this.
>
> DR. MAX: I believe there are approximately 140 to 150 people within
> OTRR. We had a response from about 86, so it\'s not complete. We
> don\'t know if it\'s representative, but that\'s what we got. We tried
> to assemble this so we could give you some idea at this meeting. We
> carried this out earlier this week and it was primarily in response to
> comments that Dr. Crawford had made, suggesting that the attrition
> rate that we could expect and that he\'s seen so far since the
> consolidation was announced was no greater than the normal attrition
> rate at the FDA.
>
> Of course, it\'s only been announced for one month, and to allow
> people to seek alternate employment as professionals, we wouldn\'t
> expect to see any change in the attrition rate, even if they did have
> the intention of doing so.
>
> DR. DAVIS: So the 90 percent is 90 percent of the 86?
>
> MS. ROSENBERG: Yes.
>
> DR. LANGER: Other questions or comments by anybody?
>
> Thank you very much. Any other comments from anyone in the audience?
> Or the FDA?
>
> I think that a number of good suggestions were made about how we can
> all individually collectively follow up. But I think probably it\'s
> also important to have something on the record for sort of capturing
> briefly what has been said here today. So I\'ve made an attempt at
> that, based on Marty\'s and Harold\'s comments, and I wanted to just
> read that and then let people modify it, so that we could somehow
> capture the spirit of this briefly. So here\'s what I will say on the
> proposed move of therapeutic products from CBER to CDER. The board is
> concerned that the science not get disrupted and wants to better
> understand the reason for this move. I tried to just make it\--that\'s
> actually taking a number of things that you said, but I just want to
> try to put something down that captures this in some way, and I just
> want that we can put it in at the end of the day.
>
> Again, I want to open this up, so if anybody wants to modify that or
> just say it\'s fine. What do you think?
>
> \[No response.\]
>
> DR. LANGER: If there\'s nothing else at this point, we\'ll take a
> break for lunch, and we\'ll resume at 1 p.m. for the Open Public
> Comment.
>
> \[Whereupon, at 11:37 a.m., the proceedings were adjourned, to
> reconvene at 1:03 p.m., the same day.\]
>
> A F T E R N O O N S E S S I O N
>
> 1:03 p.m.
>
> DR. LANGER: We\'ll get started with the 1 o\'clock session, where
> there\'s Open Public Comment. So I just wanted to check to see if
> anyone from the public would like to make comments. Do we have any
> comments?
>
> \[No response.\]
>
> DR. LANGER: There is one written comment that\'s been submitted by a
> Dr. Kathryn Stein. Dr. Stein was unable to be here to present these
> comments, so I\'d like to give these to the transcriber to incorporate
> them into the official transcripts and dockets for the meeting. This
> letter covers the proposed CDER/CBER move that we discussed earlier
> this morning. So let me give that.
>
> \[The statement of Dr. Kathryn Stein follows.\]
>
> DR. LANGER: Just in case anyone did walk in, are there any other, any
> public comments that anyone wants to make before we close this
> particular session?
>
> \[No response.\]
>
> DR. LANGER: So I\'m checking with my colleagues about what we\'re
> going to do next. We\'re moving so quickly. Let me get the advice of
> my colleagues at the FDA, unless someone would like to tell some
> jokes.
>
> DR. SCHWETZ: I don\'t tell jokes well, so I don\'t attempt to, but I
> would like to raise something serious that we might talk about in the
> few minutes before they arrive, and it is to take advantage of the
> transition in chairs and to have some discussion, either some thoughts
> from yourself or discussion from the board, on how we might do a
> better job of Science Board meetings, of keeping the Science Board
> members informed, while identifying issues to bring to the Science
> Board, how we might operate, whatever details you might like to raise.
>
> And, Mike, as you look at filling this chair, there are things that
> aren\'t necessarily fixed in concrete in how this happens, and we
> would welcome some new thoughts. We\'d welcome recommendations from
> people who have been on this for a long time and have obviously seen
> how we work. Bob, any thoughts on how we could do this better?
>
> DR. LANGER: I think we can always do better, and really the only way
> is doing exactly what you said, just getting advice from people on the
> Board, at the FDA and from people here. I have no particular ideas. I
> do think, and we\'ll talk about this later in the day, you know,
> further defining the precise role of the Science Board is an important
> thing to all of us, and so I think that\'s something we discussed in
> the morning and at lunch a little bit more, and we\'ll go over that in
> one of the written statements at the end, but I think it\'s really
> just getting feedback from people to see how we can do it the best
> possible way.
>
> Whatever we\'ve tried to do the last few years has been based on, you
> know, what I\'ve heard from different people, both at the FDA and on
> the Board. So I think it\'s just continuing to get feedback from
> everybody here. I don\'t have any specifics. I know we\'re going to be
> in great hands.
>
> DR. DOYLE: Well, I think we have been in great hands for four years,
> so there\'s some big shoes to fill here.
>
> But I guess one major question I have is how do we go about
> identifying agenda items for the Board, and I know many or not all of
> the agenda items come from the FDA, and are you receptive to having
> more input from Board members in terms of identifying agenda items
> and, if so, how do we go about that?
>
> DR. SCHWETZ: Absolutely. We are interested in items that you would
> like to have on the agenda. We haven\'t had meetings between meetings,
> where you might have that as an agenda item to talk about what do you
> want to have in the next formal meeting, but, Norris, I think we
> should come up with some kind of a mechanism whereby we solicit
> comments, maybe halfway between meetings, a couple months after the
> meeting to get some ideas and then pass the agenda for the next
> meeting, maybe more than just in front of the Chair. We could pass it
> by in a draft form to the other members.
>
> DR. ALDERSON: I\'m personally open to anything you want to do relative
> to the agenda. The only thing I would tell you, it takes a while to
> put the program together, in terms of scheduling staff, so we need to
> start, you want to do this, tell me how you want to do it,
> Chairperson. So I\'m perfectly open to any input you want to have on
> this.
>
> DR. DOYLE: I think we\'ll have to talk about that as a group and get
> back to you.
>
> DR. ALDERSON: Okay. That\'s good. It could be in the form of a
> conference call, for instance, and we could set that up or you could
> come with a number of list of proposals. You could give us some things
> that you\'d like to see, and we can determine whether they\'re doable
> or not.
>
> DR. DOYLE: And another point that has been discussed among the group
> is the idea of what Dr. Crawford had brought up about a subcommittee
> of the Science Board to address how the FDA might be reorganized, and
> the sense that I have from my conversations with the group is that
> they\'d rather have everybody be invited, and some may be too busy,
> but they\'d rather have it an entire Board activity, instead of just a
> subcommittee, if that would be acceptable.
>
> DR. DAVIS: I guess my point, along that line, I think there might be
> times where a subcommittee is very appropriate to dig into something,
> get the ball rolling, bring it back to the Board, et cetera. I just
> think the Board ought to be, it ought to be up to the purview of the
> Board how to attack an issue on behalf of the Board, but I could see
> times when a subcommittee might be useful.
>
> DR. SCHWETZ: I would remind you that in the past we have also used
> members of the Board of Scientific Counselors to be part of a larger
> subcommittee, that we would bring together with specific expertise to
> deal with a question, whether it was review of a center or the Korn
> report kind of thing or if we wanted to have a group of people, when
> you think of the IOM reviewing the structure of NIH, I would hate to
> be in your shoes as a member of the Science Board and be assigned the
> task of reviewing the structure of the FDA. That could be a huge task.
>
> On the other hand, if there are parts of this that you would like to
> take on, it sure would be helpful, even if it meant just getting your
> opinions without doing a huge amount of homework on it would be
> valuable.
>
> DR. DOYLE: Another question that comes to mind is the issue of
> obesity, which is a big issue today as we read in the paper, and it
> would be interesting to know what FDA is doing in regard to this
> public health issue.
>
> DR. SCHWETZ: This is an issue that I have personally taken up as one
> that I want to, and being in this position of being the ex-acting
> Commissioner, I\'m fortunate to have time to be able to devote to this
> issue. So I have been working within the Agency to raise the level of
> attention to nutrition and overnutrition, and obesity, and what other
> things might be all a part of that package.
>
> So I agree, Mike, that that would be a great topic for discussion. I
> would like, I would suggest that if we do talk about that, we might
> expand it in the broader picture of the public health service, and
> maybe it would be appropriate to have somebody there from CDC, who is
> very actively engaged, I mean, they have people who are very heavily
> engaged in obesity as a problem.
>
> We could have somebody from the Surgeon General\'s Office, we could
> have somebody from various Institutes of NIH, and if we want to
> explore how the FDA could be doing more in the context of the
> Department structure on obesity, that might be a fruitful discussion,
> as opposed to the brief discussion of saying that, in reality, the FDA
> is doing some, but not a huge amount. That\'s the status today.
>
> DR. DOYLE: Does anyone else have any thoughts?
>
> \[No response.\]
>
> DR. LANGER: Thank you. Great. Okay. We\'ll get started then.
>
> So the next topic is Pregnancy Labeling/Research & Study Design on
> Medications Used by Pregnant Women, and Susan Wood is going to lead
> that, and we\'ll also have Margaret Miller and Kathleen Uhl speak as
> well.
>
> Susan?
>
> DR. WOOD: Thank you. Go ahead and have Peggy come up, and when
> Kathleen Uhl gets here, we\'ll\--
>
> \[Interruption to fix microphone.\]
>
> DR. WOOD: We\'ll slightly reorder the presentation today, but we want
> to talk to you about a number of the activities focused on pregnancy
> and medication use by pregnant women and what we do and don\'t know
> about it, and what we do and don\'t regulate about it.
>
> So we\'re going to talk about a couple of different areas throughout
> the presentation. First, I\'m going to briefly do an overview of the
> Office of Women\'s Health, and I think a number of you are familiar
> with this already, what we\'ve been doing around clinical trials in
> women, and what the problem really is, in a nutshell, around
> addressing issues of pregnancy and medication use during pregnancy.
>
> If Dr. Uhl is here, we will then move on to discuss revising the
> pregnancy labeling. If she\'s not, we\'ll save that part till the end
> and move into the research activities, which Dr. Miller will speak
> about, and then we\'ll talk to you about some of the issues that we
> have regarding pregnancy labeling, research, information about
> medication use and ask your input on where we, as an agency, we, as
> the Office of Women\'s Health, need to be going and what are some
> strategies that we can take on and adopt to try and tackle some of
> these complicated questions because we know these are both not
> trivial, and there are no simple answers as well.
>
> The Office of Women\'s Health is part of the Office of the
> Commissioner, and we focus no a wide variety of activities in women\'s
> health, serving as a champion for women\'s health, both inside and
> outside the Agency.
>
> Our activities range from funding a number of research products,
> including the specific area of pregnancy research, but others as well.
> We also have an outreach campaign this year focusing on diabetes in
> women and their families, and we also then get involved in regulatory
> and policy issues. Again, the pregnancy rule and regulatory activities
> is a prime example of that type of activity that we\'re involved in
> across the Agency involving multiple centers.
>
> As you all know, the clinical trials approval process, we\'re asking
> questions about products being safe and effective. We ask for data on
> proper doses, and we want to know about adverse effects. I think when
> you take these questions and apply them to pregnant women, we often
> find that the information is lacking and does lead to questions about
> are we dosing pregnant women properly to effectively treat whatever
> the condition is and are we really getting information on adverse
> effects, both for the mother and for the infant.
>
> In 1993, and continuing through to the present, we work under a
> guideline on studying gender differences in the clinical evaluation of
> drugs, and we encourage the participation of women in clinical trials,
> although it is not required, in terms of numbers per trial. We call
> for the collection and analysis of data looking for gender
> differences, and we recommend that there are methodologies that can be
> used to minimize risk of fetal exposure by eliminating pregnant women
> from studies through design of the studies at all phases.
>
> But, in fact, that eliminating of pregnant women, although done for
> very clear and understandable reasons, leaves us with a problem. When
> we come to looking at pregnant women as patients, pregnant women with
> health conditions that do require treatment and that how, as more and
> more effective treatments come on the market, how do really treat, and
> advise, and label products for use during pregnancy when we know women
> are taking them?
>
> The problem, as stated on the slide, is that pregnant women are
> healthy, and I think we know that chronic conditions, in particular,
> ranging from hypertension, asthma, epilepsy, diabetes, these all
> require treatment, and women who have these diseases get pregnant and
> pregnant women have these diseases. So we have to work on these
> conditions and recognize that medications are taken.
>
> There\'s also a belief that pregnant women should avoid taking
> prescription drugs at all, even if they do have conditions that
> require it, or only use older medications with good safety profiles.
> That may be sort of where we are, as a reality of where we are, but
> there is also a reality that some of those older medications may not
> be as effective, and they may have more adverse events than newer
> products on the market, not necessarily the ones that have just come
> on the market yesterday, but ones that are several years old and we
> have experience with, as opposed to 20-year-old products.
>
> But the fact is, as I mentioned earlier, many pregnant women do need
> prescription products to maintain their health and to maintain the
> pregnancy, but these products are not tested in pregnant women, and
> pregnant women are actively excluded from clinical trials.
>
> What we\'re going to talk about today is not only the labeling
> information and what is and is not available and how useful is the
> information on a label regarding use during pregnancy, but how to go
> about ethically, safely, and usefully do studies on pregnant women who
> are taking medications to begin to get the information on the
> appropriate dosing and efficacy of these products during the various
> stages of pregnancy and postpartum.
>
> That sort of is laying the groundwork of where we\'re going to talk
> about today to lay out this problem, and ultimately we want to ask you
> questions about how to prioritize our efforts, how do we encourage
> more research in industry and academia, because FDA is limited, and
> then what other strategies are out there to actually collect data and
> other information on drugs that are used by pregnant women.
>
> We\'ll circle back around to those questions at the end of the
> presentation, but because of, again, the range of topics and the
> complexity of some of the questions, we\'re going to try to go through
> both the labeling issues in some of the research that we\'re doing.
>
> And right on cue. So you didn\'t hear my introduction, Cook, but
> that\'s okay. She knows exactly what I said.
>
> So, again, these are the issues for the Board that we\'re going to be
> looking at, prioritization, how do we facilitate research and what are
> some other approaches and strategies.
>
> At this point, I will turn it over to Dr. Cook Uhl, who is a medical
> officer at CDER. What\'s the official title?
>
> DR. UHL: Pregnancy Labeling Task Force.
>
> DR. WOOD: Pregnancy Labeling Task Force.
>
> DR. UHL: Thanks, Susan.
>
> Good afternoon. Thank you for the opportunity to speak. What I\'m
> going to do is go through kind of where we are now with the Agency
> with respect to labeling for pregnancy and lactation, where we are,
> why we\'re there, and what we\'re trying to do. I have about five
> slides with which to tell you that.
>
> So, currently, in the CFR, the regulations addressed pregnancy
> labeling in 1979. Prior to that, there was nothing that was required
> in labeling about pregnancy. The intent of that legislation or that
> regulation was to assist health care providers when prescribing for
> women who are already pregnant.
>
> It does not address anything regarding inadvertent exposures. What do
> we mean by inadvertent exposures? We mean a woman who is pregnant,
> doesn\'t know that she\'s pregnant and is taking a medication and then
> finds out that she is pregnant.
>
> Why is that a concern? In the United States, 50 percent of the
> pregnancies are unexpected. That means they\'re either mistimed or
> unwanted. As far as numbers go, there are 6 million pregnancies in the
> U.S. per year and women of reproductive ages of 15 go 45, 10 percent
> of those women in the United States become pregnant annually. So it\'s
> a pretty significant problem about unexpected exposures or unintended
> exposures in pregnancy.
>
> The current category system focuses specifically on teratogenic risk,
> and it uses letter categories. I\'m briefly going to walk you through
> what the current pregnancy letter categories are.
>
> The categories are A, B, C, D, and X. A is when there are controlled
> clinical studies in humans, and A is used very rarely. There are about
> five products of which currently have a Category A.
>
> Pregnancy Category is B is when the human data are reassuring, but
> there have been positive findings in animals or the animal studies
> show that there\'s no risk.
>
> Pregnancy Category C is a conglomeration, basically, and the majority
> of our products are labeled as Category C. More than two-thirds of our
> products are Pregnancy Category C. A Pregnancy Category C can come
> about when there are no human data, there are no animal studies or the
> animal studies show some findings. Animal studies are positive.
>
> Pregnancy Category D is when human data show risk, and there\'s a
> concern here about benefit outweighing the risk. For example, some of
> the products that are used for seizure disorder, some of the
> anticonvulsant medications, where a woman has to be taking this
> medication for controls of her seizures. However, we know there\'s a
> teratogenic risk. Some of those compounds are labeled as D.
>
> Now X is when there are either positive animal or positive human.
> Another interpretation of X, though, is that these products are
> contraindicated for use in pregnancy or these are drugs that should
> not be used during pregnancy.
>
> Now let me give you an example of that. Oral contraceptive products.
> Oral contraceptive products are obviously not intended for use during
> pregnancy. They are intended to take to prevent pregnancy. Because
> they are not intended for use in pregnancy, they have been given a
> Pregnancy Category X designation.
>
> So, needless to say, there are limitations in our current system. The
> current pregnancy categories are overly simplistic. The A, B, C, D, X
> is oftentimes felt to represent a linear continuum of risk, meaning A
> is better than B, B is better than C, C is better than D, and so on.
>
> From a clinical standpoint, this type of labeling is not very helpful,
> and it\'s not very informative. The categories combine different
> levels of risk assessment. For example, that\'s the Category C. You
> could have a Category C because the animal data are positive or
> because there are no human data.
>
> The current system also combines risk information with benefit, and
> that\'s specifically seen in the D and the X. Currently, most of the
> products have only animal data, and by nature of the way that the
> studies in animals are done, the findings in animals are commonly
> positive, and with that a lot of the products then are Pregnancy
> Category C.
>
> At the current time, there is no requirement or incentive to update
> these labels with human experience. From the pharmaceuticals
> standpoint, as well as from the medical-legal standpoint, oftentimes,
> warnings in labeling are perceived as optimal. It\'s felt that it\'s
> better to just warn don\'t take these if you\'re pregnant.
> Unfortunately, because of that, it\'s very rare that these labels will
> be updated with human experience.
>
> Now, despite that or probably because of that, there are changes
> coming to the Agency. There are changes coming to the current
> pregnancy labeling, and that\'s predominantly what my job is. That\'s
> what I work on, but what we are working on, there we go, is to have a
> label that provides clinically useful information and information
> that\'s useful to the patient, as well as the physician or other
> health care provider when making a decision about prescribing drugs in
> pregnancy or prescribing decisions that had been made prior to
> pregnancy and pregnancy has occurred.
>
> So what we\'re in the process of doing is working on revising the
> regulations. Now the current physician labeling rule addresses
> pregnancy and lactation as a special population. However, that portion
> of the labeling rule does not provide the information that should go
> into that. So we view this as a regulation that just provides the
> content and format for pregnancy labeling.
>
> What this does, first and foremost, is to get rid of the pregnancy
> category designation. The intent is to separate out information about
> risk from information about benefit, and this will use a standardized
> descriptive text that characterizes risk, has built-in flexibility,
> but it is not a simple letter categorization.
>
> In addition, this will separate out animal data from human data and
> risk that\'s ascertained based on animal or human.
>
> Also, the labeling will distinguish what says here is clinical advice,
> but actually considerations that should be given in the clinical
> setting for prescribing in pregnancy or for discussions of inadvertent
> exposures, and it will separate out that type of information from
> fetal risk information.
>
> In addition, the label will address the inadvertent exposure, and it
> will address\--it will address it by providing information about dose,
> duration of exposure or the gestational timing of exposure for which
> you would be most concerned for fetal risk.
>
> Because there are numerous physiologic changes that occur in
> pregnancy, the point has been raised about whether the dose that\'s
> provided in labeling for an otherwise healthy male is an appropriate
> dose to give to pregnant women. So information about optimal dosing
> will be provided, and this will include whether there are any
> pharmacokinetic or pharmacodynamic changes that occur during
> pregnancy; in addition, any information about unique maternal adverse
> events.
>
> Lastly, because the risk information requires looking at all data that
> are available, there will be a requirement to update the label and to
> provide clinically relevant information in the label.
>
> With that said, Dr. Margaret Miller, from the Office of Women\'s
> Health, will now address some other issues.
>
> DR. MILLER: So as Kathleen said, as we were working through this
> reformatting exercise, it became clear that having good information to
> put in the label was going to be critical to improving the health of
> pregnant women and to helping prescribers make accurate prescribing
> decisions for the pregnant women.
>
> So what I\'d like to do now is talk about some of our efforts that
> we\'ve been engaged in over the last two years to try and improve the
> content of information that would go into a label, and in embarking on
> a discussion about research and pregnant women, I think it\'s
> important to mention the ethical concerns and the ethical rules that
> we have to comply with.
>
> The basic regulations for conducting research in human subjects for
> federally funded research are contained in 45 CFR Part 46. They are
> subpart (a), which are the regulations that cover protections for all
> human subjects. And when you\'re doing research on pregnant women, you
> also have to comply with what\'s known as subpart (b) of those
> regulations.
>
> Now, under the basic protections or subpart (a), if a product or a
> study represents minimal risk for the patients or the participants,
> you would be able to get an expedited review through the IRB. However,
> when you\'re doing studies in pregnant women, they are considered
> vulnerable subjects, and so all studies involving pregnant women have
> to comply with all of the full IRB approval requirements.
>
> In addition to complying with all of the requirements under subpart
> (a), when you\'re doing studies in pregnant women, you also have to
> comply with subpart (b). Now the regulations under subpart (b) changed
> about a year ago, December of last year. We have a new regulation
> under subpart (b). Let me just briefly talk about the new regulation.
> I\'m not going to go into the changes for this group.
>
> First of all, if you are a pregnant woman, you can give informed
> consent and engage in research if the research that is being conducted
> has already been conducted on animals or nonpregnant women. So that we
> have information about the safety of the product in animals or
> nonpregnant women.
>
> DR. DAVIS: Those are pregnant animals?
>
> DR. MILLER: It does not say pregnant animals. It says appropriate
> studies. So there\'s some flexibility about what is the appropriate
> study in animals, but it has to be appropriate studies in animals. One
> would assume they\'d be reproductive type of studies.
>
> If the research is designed to meet the health needs of the mother, so
> we\'re doing the study to meet the health needs of the mother, and the
> risk to the fetus is minimal or the minimum that can be achieved under
> the studies, then the woman\'s consent alone is sufficient.
>
> Also, if the research is designed to meet the health needs of the
> mother, the mother and the infant or provide general knowledge that
> would help us in treating other pregnant women in the future, then the
> consent of the mother is sufficient for her to participate in the
> study.
>
> If, however, the research is solely for the benefit of the fetus,
> you\'re enrolling pregnant women, but you\'re really not worried about
> the woman at all, you\'re looking at the benefit to the fetus, then to
> enroll those women in the study, you need to have informed consent by
> both the mother and the father before the woman can participate in the
> trial.
>
> Now, as we\'ve mentioned a couple of times, pregnancy, for those of us
> that did it kind of remember this, it\'s a time of dramatic changes.
> You end up having these changes I think for the next 25 years, but
> I\'m still recovering.
>
> \[Laughter.\]
>
> DR. MILLER: You have this huge fluid volume issue. Your heart rate
> goes way up. Your urine output just goes through the roof, and then
> there\'s all these metabolic changes in the liver that help you do
> this remarkable event.
>
> And all of these changes or some of these changes or maybe these
> changes, these dramatic physiological changes, have an effect on how a
> drug is distributed and metabolized in the woman during pregnancy, but
> as we\'ve mentioned already in this talk, really we have very little
> information on what the pharmacokinetic and pharmacodynamic changes
> are because for most drugs that has not been established. And so
> clinicians are relying on information from nonpregnant women, we hope,
> but in many cases it may be healthy male subjects that those studies
> were done in.
>
> So some of my partners in crime over in Drugs thought that perhaps we
> could make a dent in this problem if we were to conduct some studies
> on pregnant women and work through the protocols of how you would go
> about doing these studies if they were to be done, and so we put out a
> solicitation with the Department\'s Centers of Excellence on Women\'s
> Health. These are 14 academic institutions that are one-stop shopping
> in women\'s health. They have research, clinical services, education,
> both of professionals and outreach component.
>
> And we wrote for them a statement of work and asked them if they could
> do a PK/PD measurements on pregnant women that were currently
> receiving prescription medication to treat a chronic condition that
> they had during the pregnancy. The idea was that we would take these
> women that were currently undergoing therapy for some chronic
> condition, and at discrete periods during that gestation, collect PK
> and PD information from them.
>
> We thought that this would serve as a prototype for how we could
> collect needed dosing information in both an ethical and hopefully
> economical way. It is our intention, as Kathleen told you, we have a
> place in the label where you could put this type of information in the
> proposed new labeling. So this would be the type of information that
> could be incorporated into the pregnancy label.
>
> So, as a result of that solicitation, we funded, in fiscal year \'01,
> two studies. The first is kind of a traditional PK study, in which we
> have a cohort of about 20 women that have hypertension, and they\'re
> receiving Atenolol to treat their hypertension, and we have recruited
> them into the study during the second trimester.
>
> During a window during the second trimester, they undergo intense
> blood sampling, so that we can determine the PK characteristics during
> that period. They do a similar thing during the third trimester and
> then in the postpartum period.
>
> The second study is what\'s known as a population PK design, and what
> this does is this gathers up a lot of\--Cook is laughing because this
> is so different from you\'re used to. You take a whole population of
> pregnant women that are receiving Labetalol for control of
> hypertension and you do spar sampling. What you do is you use this
> large number of people to draw your population pharmacokinetic
> variables. So they don\'t have to be during a certain window, they
> don\'t have to be off of concomitant medications. They could be
> lactating/nonlactating, because you\'re drawing the kinetics over the
> whole population of pregnancy during the whole time.
>
> So we have one of each of these different designs that we\'re funding
> in the hopes that then we can see how these would, if we were to write
> guidance, how do you work through issues? Have we thought of all of
> the different issues that need to be thought of in designing these
> studies because now we\'ve lived through it.
>
> So this year what happened, and probably you\'ve already had a
> briefing on bioterrorism, but with the anthrax scare, it became very
> clear that we did not have dosing and safety information for many,
> many of the products that were going to be used to treat infections
> that could occur as a result of bioterrorism in special populations.
>
> Most of the studies that are done on those medications were done in
> the military, and the military does not intend to have a high
> percentage of pregnant and lactating women or elderly. So our database
> of information on those populations was severely lacking.
>
> And so to address this issue, we once again thought that we could do
> some studies in the pregnant and lactating women, and we set out two
> different solicitations. The first was to try and collect some safety
> information to assess both maternal effects and infant outcomes in
> pregnant women that were exposed to medication during pregnancy, and
> these were medications that we might want to use to treat women
> exposed to a bioterrorist agent.
>
> And it\'s our thinking, at the Office of Women\'s Health, that if
> there\'s a fetal safety concern, if you\'re worried that this drug
> might harm the fetus, the likelihood that you\'re going to give that
> medication to a pregnant woman is probably diminished. So it\'s not
> going to be a case where you\'re sure she\'s had an exposure to
> anthrax; it\'s going to be the case where we\'re not sure, and we\'re
> going to want to prophylax, and it\'s going to really influence your
> decision of whether or not to provide prophylactics to a woman during
> pregnancy.
>
> So we were interested to see if we could use these large automated
> databases and the diagnostic codes to try and get some information on
> infant outcomes.
>
> And the second solicitation was very much like what we had already
> done with the antihypertensives, where we would ask for PK/PD studies
> to be conducted in special populations.
>
> So the study that we funded under the safety studies, although we
> asked for both fetal safety and maternal effects, the databases that
> were available and the solicitations that came in only were available
> to address fetal safety. So we are only looking at infant outcomes.
>
> The study that we\'ve contracted to do is with Vanderbilt University.
> It\'s going to look at infant outcomes and Ciprofloxacin, Doxycycline,
> Amoxicillin and Azithromycin. And you can see the number of pregnant
> women that were exposed to those medications in their database there.
>
> In addition, we\'ve asked them to do a control group, and this is
> pregnant women that were exposed to an ACE inhibitor during their
> pregnancy, and we wanted to include this group because we wanted to
> make sure that if women were exposed to a product that we know causes
> birth defects or adverse infant outcomes, that the databases that we
> use will be able to pick that up. Because, remember, these were
> prescription databases and treatment databases. They weren\'t
> databases designed to look at safety. So we have included pregnant
> women exposed to ACE inhibitors as a validation group or a positive
> control group.
>
> We also have a group of women that were pregnant and exposed to no
> antibiotics, and the study includes a group of women that were exposed
> to Erythromycin. These investigators have already investigated
> Erythromycin in their database and shown that there is no increase in
> adverse infant outcomes. Women are exposed to that drug during
> pregnancy.
>
> We are looking at infant outcomes at birth, three months and a year to
> see whether you pick up more teratogenic effects if you go longer, and
> the patient population that\'s in this database, it\'s the Tennessee
> Medicaid database.
>
> The projects that we\'re doing with the Centers of Excellence, the
> dosing projects are very similar to the ones that we did in \'01. We
> asked for PK/PD studies in pregnant and lactating women, and we also
> asked that they collect information on infant outcomes if they\'re
> doing the study in pregnant women, and we asked for the elderly.
>
> Now we\'ve funded four projects under that, but I\'m just going to
> talk about the two that are having to do with pregnancy. The first is
> a PK study on Amoxicillin in pregnant women. This drug is excreted
> renally, and so we think that dosage adjustment may be needed in
> pregnancy.
>
> The second contract is actually quite interesting because the
> University of Wisconsin is going to conform a consortium of five
> different Centers of Excellence in Women\'s Health, and they needed to
> form this consortium because in order to get enough women exposed to
> these drugs while they\'re pregnant, we couldn\'t just go to one site.
> They\'re not being used because of fetal safety concerns.
>
> So we have a consortium of five different COEs that are going to try
> and address Ciprofloxacin, Azithromycin, and GENT.
>
> Just one last point, the CDER has recently put a guidance on how to
> conduct a pregnancy registry. That is on CDER\'s website, and one of
> the things that we learned, as we were talking to the women\'s health
> community is, while CDER has issued guidances, actually, required
> pregnancy registries for a number of products, that the women\'s
> health community was not aware of this activity.
>
> And just to let you know that a pregnancy registry is a very effective
> wy of collecting safety information on marketed products, and you
> enroll pregnant women after they\'ve been exposed to a drug, but
> before the birth outcome is known so that we can see what is the
> effect of the drug on fetal outcomes by enrolling women in the
> registry.
>
> So what our office did is we came up with a pregnancy registry
> website, and the point of this website is to tell women about
> registries, explain to them what they are in as simple terms as we
> could come up with, and then tell them how to participate in
> registries. And we have provided on the website a list of all of the
> registries that are currently enrolling women that comport with
> CDER\'s guidance. So, if someone is conducting a registry, but it\'s
> not conducted the way CDER would like a registry to conduct it, we\'re
> not including it on this website.
>
> So that is all I have, so I\'ll turn it back to Susan.
>
> DR. WOOD: To round all of this up, I think, in talking about the
> labeling issues, which all of these steps are sort of in process, the
> labeling changes are still very much in process and will require a lot
> further input from not only the rest of the Agency and the Department,
> but also then obviously, you know, input from the practice community
> and the women\'s health community about whether the proposed changes
> are what ultimately will become the rule from FDA.
>
> The research projects, again, are just taken on to sort of break, you
> know, break through the barriers, the beginning barriers on doing this
> kind of work. We are very aware that the Agency and the Office of
> Women\'s Health or any other parts of the agency are not going to be
> funding drug-by-drug, study-by-study to collect the information on
> products both currently on the market, but products coming onto the
> market, but rather we want to be able to develop a model system, work
> through what the issues are and what the problems are, and then
> develop a guidance on how to carry out this research by others, others
> who have a vested interest in this.
>
> I think there\'s a real question that if we have products that are out
> there on the market that we know are being used by pregnant women, and
> we know that we don\'t have the information on how to properly dose
> and treat women with either chronic or acute conditions with
> medications, there is sort of an ethical question, you know, is it
> ethical to not do the research.
>
> We have a number of issues that we have to make sure we handle doing
> studies on pregnant women very carefully, and with the highest
> scrutiny, and to make sure we\'re doing it in the safest way possible,
> but at the same time, we know there are women out there taking drugs
> every day, and they\'re pregnant, and they need to be taking them, but
> we don\'t have the data to support appropriate clinical care, and if a
> woman requires an antibiotic, but is underdosed and then needs to take
> a different product, another course, or a second course of the same
> product, we\'re not minimizing risk here, we\'re actually mistreating
> both the women and potentially the offspring. So that\'s sort of our
> motivation with trying to start this, but it leaves us with remaining
> questions.
>
> Peggy also talked about the outreach to women themselves, and I think
> using the web page and by talking about these activities, we\'re
> starting that process, but there\'s a long way to go with a lot of
> this information. I don\'t think we want to be telling women too
> loudly that we really don\'t have the information on how to treat
> them, but we do\--but I think it does behoove us to start collecting
> the information and making that information available in a label as
> soon as we can.
>
> So here are our discussion issues. Did we want to hand out?
>
> DR. MILLER: I did.
>
> DR. WOOD: Okay. Did you hand out the little flyer too? We also have
> just a summary sheet, which is not exactly up-to-date. The
> counterterrorism studies are still listed as future activities, but
> sort of summarizes as a take-home of some of the activities that both
> we and CDER are doing in the area of pregnancy.
>
> But these are our discussion issues for the Board, which is given the
> complexity of this problem, how should we prioritize this effort, in
> terms of either identifying products to study, focusing in different
> methodologies and so on.
>
> How should we encourage others to take up this research on pregnant
> women to help, again, break down those barriers and the very natural
> hesitancy to take on this work?
>
> And then are there any other strategies that would be effective, other
> than these direct intervention-type studies for obtaining information
> on drugs used by pregnant women?
>
> I\'ll ask my colleagues to come back. But these are our thoughts on
> sort of where, and you\'ve gotten this sort of very quickly all of the
> complexities, but if there are any other\--
>
> DR. LANGER: That\'s great. Do you want to ask questions or give her
> the answers?
>
> \[Laughter.\]
>
> DR. RIVIERE: \[Off microphone.\] \[Inaudible.\]
>
> \[All microphones are now off.\]
>
> DR. MILLER: There was no question. He has a comment. He\'s commenting
> on my question.
>
> DR. RIVIERE: \[Off microphone.\] I think the population
> pharmacokinetic strategy is probably the most effective way to
> leverage the research because some of this \[inaudible\], and it\'s
> just not excluded for various things. They\'re excluded for very good
> reasons, but as the whole database gets built up, collecting a little
> bit of information in the pregnant population knowing the disposition
> for the rest of the population, we can learn a lot.
>
> So, anyway, I encourage that. That\'s more effective than some of the
> most classic approaches.
>
> DR. WOOD: Peggy, did you or Cook want to comment on how well that
> design is working or how it was received by the statisticians and so
> on?
>
> DR. MILLER: \[Off microphone.\] I, too, liked, well, I didn\'t like
> it. I found it very difficult to figure out the population
> pharmacokinetics. I struggled with that for a very long time. We are
> not having as much success recruiting the large number of women that
> we need in that trial.
>
> The traditional design has full patient recruitment, and we\'re
> basically just following them through, and the other trial has lagged
> behind because we have so many more women that we\'re trying to
> recruit into that trial. So the challenge there is finding the larger
> numbers of women, and that\'s why, with the COEs, that\'s a completely
> population approach, the five consortiums is taking the population PK
> approach across the different centers.
>
> DR. RIVIERE: Because the advantage of the population approach is you
> will also pick up other co-variants and other concomitant variables,
> and you can leverage the nominal population into detecting that. So,
> again, I would just encourage that\'s the direction it\'s harder to
> get patients, but when you do have the full study developed, you\'ll
> get a lot more information out of it.
>
> DR. UHL: I appreciate your comments. One of the interesting things
> though that we had was the IRB. The fortunate thing for the population
> PK was that we had a statistician on the IRB who had a very good
> understanding about Bayesian theory and hence made that very simple.
>
> For people who don\'t have a kinetic background, first of all,
> clinicians don\'t have a kinetic background to begin with. So when you
> start talking kinetics, it\'s very difficult to simplify that to the
> clinician level to the bedside, and how we take population PK data
> then and do that will be very challenging because of the same thing.
>
> A lot of kineticists have a difficult time with population PK, but
> from an enrollment standpoint and also in pregnancy, where you may not
> use therapy continuously throughout pregnancy, but you might want to
> dose differently throughout pregnancy, the population design helps
> very much.
>
> DR. RIVIERE: I would think today most of your Phase 2 clinical trials
> and Phase 3 clinical trials use population in kinetics.
>
> DR. UHL: Right.
>
> DR. RIVIERE: Right. So there should be some expertise to leverage\--
>
> DR. UHL: Oh, yeah, I\'m not talking about in the drug industry or in
> the Agency.
>
> DR. RIVIERE: Right.
>
> DR. UHL: I think that that expertise is there, but who uses the drug?
> The patients and the health care community, and population PK doesn\'t
> mean anything to them. I mean, what you need to do is translate that
> then into a recommendation for dosing appropriately.
>
> DR. RIVIERE: To get that information, the best route is, seems to be,
> population kinetic\--
>
> DR. UHL: Well, we\'ll see. We\'re looking forward to what we get out
> of this.
>
> DR. LANGER: Do other people want to make comments or would you like to
> just kind of go down the list and\--yes?
>
> DR. DAVIS: I\'ve got a question, and I hesitate to ask it, it\'s out
> of naivete. I would assume where is the big problem, and you kept
> talking about prescription drugs, which I think I understand, but I
> had this picture of all of these pregnant women out there taking
> over-the-counter drugs that we have no idea about what\'s going on, et
> cetera, and I\'d just assume more pregnant women are taking OTCs than
> they are prescription drugs, even, and so we have no idea what it\'s
> doing or\--
>
> DR. WOOD: I think that\'s a very valid question, and someone may have
> an answer to in terms of actual prevalence, but I think our concern
> with prescription drugs is that we\'re talking about medications that
> women need to the level that they\'ve gone to their health care
> provider, and they\'re under care, and they need prescription drugs.
>
> I think the culture and the prevailing belief, even though it may not
> be acted upon in reality, is that women minimize, pregnant women
> minimize drug use of any kind, over-the-counter or otherwise,
> throughout pregnancy in order to avoid a bad fetal outcome.
>
> Whether that, in practice, I agree, I mean people are maybe taking
> their OTCs by the handful still and laying off their prescription
> meds, which actually we\'d probably prefer the reverse, that if
> they\'d lay off the OTCs and only take what they really need to be
> taking for a direct health condition.
>
> Did you have\--
>
> DR. UHL: I can maybe comment a little bit on the prevalence of use in
> pregnancy. There are several studies that have been reported in Europe
> about drug use. It\'s easier to get to that data in those type of
> health care systems, and what\'s been reported is approximately three
> to five prescription drug products are used per woman during her
> pregnancy, and that excludes prenatal vitamins and iron, as well as
> some over-the-counter.
>
> In our country, it\'s hard to get to that type of information about
> the prevalence of use. The most recent study published in the U.S. was
> almost 10 years ago, and it confirmed what\'s been seen in some of the
> European countries, but it\'s about three to five drugs per pregnancy,
> and the number of drugs increases with increasing complexity of the
> pregnancy and increasing maternal age.
>
> But your issue about OTCs is well-founded, as well as other things
> that we don\'t like to talk about, like dietary supplements and such,
> because people think that those are safe.
>
> DR. LANGER: Other questions at this point or would you like us to try
> to go down that list or what would be most useful?
>
> DR. WOOD: Sure. I mean, we can just start with the first question. I
> mean, in terms of priority, I mean, priority can be interpreted to be
> priority of how do we prioritize products that we should be
> evaluating, how do we prioritize whether going at some of these
> research questions versus some of the other approaches, that would be
> our first question.
>
> Any thoughts or comments?
>
> DR. DAVIS: If you look at\--if you believe the data there is three to
> five drugs on the average, they must fall out into perhaps some kind
> of category of drugs. So one of the things I was thinking, you could
> make a decision around the prevalence of drug types, and then use
> representatives of those categories.
>
> On the other hand, you could decide that certain categories of drugs
> are much more likely to have effect based on what you already know
> about them, and prioritize that way.
>
> DR. WOOD: Yes, I think that\--and, unfortunately, sort of the
> cross-hatch of that is probably then most drugs. You know, that most
> drugs fall into one of those two categories.
>
> There is an effort referred to as the Safe Motherhood Campaigns that
> have been going on reflecting a variety both of elements within the
> nation, you know, from the public sector to the private sector to
> advocacy and so on, focused on how to promote safe motherhood and
> healthy pregnancies.
>
> A piece of that is trying to get at this priority\--at women taking
> medications, because they\'re the ones who are at highest risk for not
> having a healthy pregnancy. And a piece of that is looking at trying
> to pass legislation calling on FDA to work with NIH to set up a
> prioritization of products along those lines in terms of prevalence or
> highest risk and developing a priority listing of drugs, highly
> dependent on, I think, NIH to then carry out some of the research
> that\'s necessary.
>
> But that is a pie-in-the-sky kind of thing right now and is not really
> moving forward in terms of a mandate for the agency to do that. So I
> think within the agency now there is interest in doing that kind of
> thing, but lacking of the resources or the ability to bring in our
> colleagues at NIH to carry out some of that activity.
>
> DR. ROSENBERG: Again, just a question mark. Obviously you\'ve chosen
> antibiotics, I assume, for the reason that there must be a prevalent
> use of antibiotics among pregnant women? Do you have enough
> epidemiology to know which things you should be looking at?
>
> DR. WOOD: Well, part of that\--I mean, I think the antibiotics idea
> came from the counterterrorism and sort of the list from, you know,
> what\'s going to be in the national stockpile and that sort of thing.
>
> DR. ROSENBERG: How do you know what to study without knowing what
> they\'re most\--
>
> DR. WOOD: Part of that came from the proposals in terms of what they
> think is in their patient population, but\--
>
> DR. UHL: I\'ll be happy to address that. the Office of
> Counterterrorism and Pediatrics\--am I saying that right? Something
> like that. Well, as CDER was undergoing a reorganization, we were
> located within that office, and the office director was given monies
> to study for the counterterrorism. And one of the aspects was special
> populations, and it was blatantly obvious this time last year when the
> whole anthrax scare happened that we did not have ample information to
> provide about dosing for the special populations, meaning pediatrics,
> geriatrics, and pregnancy. And it was very\--you know, the
> recommendation from the CDC as to what were the drugs to use for
> prophylaxis for anthrax, there was not good information for what we
> should be doing for pregnant women.
>
> So, given that, the monies were allocated for counterterrorism; in
> conjunction with that office we selected which would be the drugs that
> would be used in the event of some type of biological attack.
>
> DR. WOOD: I think he\'s asking how do we know that there\'s actually a
> patient population taking it on a normal basis for care. And I think
> part of that came in from the proposals. They were able to say we have
> access to a patient population X. Not all the products that we
> identified were selected for study, and they were selected for study
> in part by the fact that there were patients available who were taking
> it for other reasons during\--
>
> DR. UHL: Right. And these centers were able to provide information to
> us as to how many patients they have had at their institutions, any
> pregnant women at their institutions treated with those drugs of
> interest.
>
> DR. WOOD: In order to say they\'d be able to do it again in the next
> year.
>
> DR. SCHWETZ: As a result of anthrax, more than 30,000 people got some
> antimicrobial agent. Some of them must have been pregnant, and it\'s
> been more than nine months. Do we have the outcome of those
> pregnancies to do the study based on the data that we already have?
>
> DR. MILLER: Pregnant women were not prophylaxed. I mean, the
> recommendation\--I agree. Half of them got pregnant, and then CDC is
> collecting pregnancy outcomes if women were inadvertently exposed. But
> the decision was not to prophylax women that were pregnant.
>
> DR. WOOD: So it would have been very early-term pregnancy.
>
> DR. MILLER: Yes, so it would have been an inadvertent exposure, and we
> don\'t have the results of those yet. But it is being collected by
> CDC.
>
> DR. DAVIS: Having some experience with the NTP where, in terms of
> choosing chemicals to study, you know, where they do bioassays, and
> there\'s never enough resources to study all the compounds, but there
> is a mechanism in place where different agencies make recommendations
> and somebody picks based on some criteria which compounds to do, sort
> of shooting from the hip I could see where various centers, based on
> some criteria\--prescriptions written, toxic profiles,
> whatever\--might want to make recommendations to a central group like
> yours to study compound X, class effects, representation of class
> members, et cetera, so that you could\--because I don\'t think any way
> you do it you\'ll ever have enough resources to make a dent in terms
> of all of the compounds that are out there, obviously. There needs to
> be some rhyme or reason behind it.
>
> DR. WOOD: Yes, I guess that actually segues into the second question
> about how do we\--I mean, and after\--I mean, I think that\'s a really
> interesting model because the NTP program\--but it sits there with
> that mandate to do that, and with a pocket of money, although not the
> world, but it works on a prioritized set. And if we were to get in
> that kind of place, you know, perhaps we could move forward. But at
> this stage, if we were to try and say at this point industry, whose
> products are the ones we\'re talking about, as well as academic
> centers who are interested in developing this kind of database
> systems, but are very hesitant about doing studies on pregnant women,
> I mean, I sat in a meeting not too long ago surrounded by a few
> clinical trialists and explained\--and this is actually before we were
> about to award our first round. And they, you know, were shaking their
> heads and saying, well, I would never apply for that money. I mean, to
> the point where they say they wouldn\'t apply for money, that was sort
> of a shocker, you know. And that much less trying to spend their own
> money to do this in terms of industry.
>
> DR. LANGER: Jim?
>
> DR. RIVIERE: Following up on your earlier comment, everything seems to
> be looked on either on the infant outcome or the pregnancy outcome of
> the use of these antibiotics, which many of them are really relatively
> safe, generally. I guess the question would be: What about the
> treatment outcome, the efficacy? That\'s where I would see all the
> physiology totally\--
>
> DR. WOOD: That\'s what we were interested in, and we tried with the
> database method that Peggy described, but we couldn\'t link\--we knew
> we had the prescription use data for the mother and we had the infant
> outcome, but apparently the database had trouble getting long-term
> outcome health data on the mother as well as\--
>
> DR. RIVIERE: Well, even short-term outcome\--
>
> DR. WOOD: Even short\--I don\'t think\--they couldn\'t\--they didn\'t
> have any good markers. I was really pushing for that as well. And
> there weren\'t any good maternal outcome markers that they could get
> out of this particular database, which is one of the better ones
> around.
>
> In terms of the direct studies, I think the PK/PD studies that we\'re
> doing, I mean, I think that is our goal, is the PK/PD to some degree,
> you know, outcome\--short-term outcome data for the mothers, how well
> are these antihypertensives working, how well is the antibiotics
> working. And we\'re getting some of that.
>
> DR. RIVIERE: If you go back to the bioterrorism situation, what
> happens if pregnant women were exposed to anthrax? The important
> question, I mean, looking at these drugs, I wouldn\'t be concerned
> about ampicillin being a teratogen. The key is when you effectively
> get a dose of drug to prevent anything happening to the mother\--
>
> DR. WOOD: Well, I mean, I think that\'s our interest, and Peggy
> pointed out, though, even if there\'s a\--if there\'s a hesitancy,
> even if there\'s some good outcome data on some of the products, or if
> there\'s some known risk to the product for an infant outcome, there
> may well be a hesitancy to dose the mother, particularly
> prophylactically, if you weren\'t sure. So that\'s our concern because
> if we don\'t have the data on how to dose her correctly, there\'s
> still the issue of will she get the dose at all.
>
> DR. RIVIERE: I would think there\'s got to be some databases out there
> that link through\--there\'s different databases on
> controlled\--again, there\'s got to be databases that a pregnant woman
> is put on this drug and taken off that drug, there\'s a reason
> relative to response. That might get at this a lot faster.
>
> DR. UHL: There are lots of problems, though, with the longitudinal
> databases, and the purpose of those databases are for billing. And to
> be able to extract information for epidemiologic purposes, although
> they\'re used, there are limitations to their use. And you would have
> to know what code you would be looking for for failed efficacy, and
> that\'s not usually coded. If a woman\'s being treated, say, for
> pneumonia and has failure to improve in 72 hours on this antibiotic
> and is switched to another one, the code would probably still say
> pneumonia, and you\'d have to capture the switch in therapies so that
> the clinical record has to be linked to pharmacy record as well. And
> there\'s a lot of problems with that.
>
> Hence, our reason for using the PK/PD approach where we\'re not
> looking at efficacy in the pregnant woman, we\'re looking at
> similar\--how can you get a similar kinetic profile at different
> stages of gestation because, from a PK/PD standpoint, that should
> translate into efficacy. As long as you know what PD parameter for the
> antimicrobial interest is the important one. Is it time above MIC? Is
> it an AUC to MIC? That type of thing. So we don\'t have to do an
> efficacy study to get to that. We can assume that if you have the
> appropriate dose that you\'ll have the same efficacy.
>
> DR. ROSENBERG: Again, just a question. Is there anything you can do in
> the hospital setting that, again, because of risk/benefit and because
> of the controlled environment you could learn about certain things
> that might be relevant more generally by using a hospital setting
> where maybe more serious infection or pregnant women are now in a
> controlled situation where you\'re getting\--you\'re constantly tapped
> into the bloodstream, draw as often as you want? Is there anything
> that could be done there that would help\--
>
> DR. WOOD: I think that\'s similar to some of\--the antihypertensive
> studies, the women are in a very high-risk pregnancy situation.
>
> DR. ROSENBERG: They\'re in the hospital setting\--
>
> DR. WOOD: Well, they\'re not in the hospital setting, but they\'re in
> a very\--an outpatient clinic that specializes in high-risk pregnancy.
>
> Do you want to comment?
>
> DR. UHL: They\'re done like any other kinetic study is done. They\'re
> done in a clinical research unit. But if what you\'re saying is you
> think it would be easier to study, I mean, maybe\--that\'s what I\'m
> interpreting. It would be easier, potentially, to study pregnant women
> in the hospital setting.
>
> The flip side to that would be you still have to get IRB approval, and
> that seems to be the biggest stumbling block. And would these women be
> potentially at higher risk than women with the same condition that
> didn\'t warrant that they were hospitalized? It\'s a huge can of
> worms. Could you more easily get the data that you want? Could you
> more easily get blood draws? Possibly. But you\'d still have to go
> through the same administrative issues.
>
> DR. WOOD: I think the point about the risk, if the woman is
> hospitalized for her health or for, you know, potential miscarriage
> going on, you know, the likelihood of interest of participating in a
> clinical trial versus a PK/PD study is probably less than one who is
> at a high-risk pregnancy but not to the point where she\'s in the
> hospital and worrying about a crisis.
>
> DR. ROSENBERG: No, I didn\'t mean that. I meant more in a hospital
> because she has pneumonia; therefore, you\'ve got to treat her with
> antibiotic, irrespective of her pregnancy; therefore, you\'re going to
> get the data you want, not because she\'s in for another reason.
> She\'s in for the reason where the high risk makes you want to have to
> treat and, therefore, she\'s going to be treated anyway because it\'s
> her risk that\'s now forcing the treatment. Now the question is: Can
> you use that population to get the data?
>
> DR. MILLER: Just to interject here, we are doing IV gent, and I
> believe all of those women, even in this day and age, will be
> hospitalized. Maybe with HMOs I guess I should\--but they are going to
> be ill and they are going to be in the hospital, and they\'re going to
> be receiving IV gentamicin, and the consortium of COEs are going to be
> addressing that by getting five or ten women from each of the
> different sites in order to drive our population PK approach for that
> drug.
>
> DR. DAVIS: I guess you have to be careful if you so focus the group to
> those who happen to be available, because in the end, the question is:
> Is it gentamicin that you really want to know about, or does
> it\--because it is a highly used one, or is it just because those
> patients who get on it are so sick and clearly use it anyway, so\--but
> I think you have to define where you\'re trying to go with the data,
> or does it represent a group of drugs and so you\'re going to look at
> this as a class, because you\'re not going to be able to test every
> drug. So if you only test ten, do you test the ten you can get, or do
> those ten represent something or how you\'re going to interpret the
> results of those ten in light of all the other drugs? But if they\'re
> the top ten, you don\'t have to interpret in light of other drugs
> because they are the ones most commonly used and will stand on their
> own? And I\'m not sure what the premise is.
>
> DR. WOOD: I think we\'ve taken it from a couple of\--I mean, I think
> we\'ve combined those. We\'re taking it from a couple of different
> strategies. The first time around we said we can find a few studies
> and we want to look at products that are commonly used in chronic
> conditions because we think those are a high-priority set of
> conditions. And based on the proposals we got, we ended up with the
> two antihypertensives that we\'re looking at.
>
> With the counterterrorism thing, again, it was, you know, we have now
> a group and, you know, based on a priority setting of both the
> stockpile and what we think vulnerable populations might be exposed to
> or might need to be exposed to in a terrorist attack, and then, again,
> waited to see what was available, what\'s convenient within that group
> and what\'s doable\--rather than what\'s convenient, maybe the word
> doable, and we sort of went that strategy. But there probably are
> other strategies. You know, we\--and we could continue on and sort of
> dig down in those areas, or we could move on to other classes or
> priorities.
>
> DR. LANGER: I had a question that relates more to the second than the
> first, but is there\--and just my naivete. Has there been good
> research or significant research done on sort of trying to model, like
> say you understand the physical, chemical properties of a drug and you
> understand it\'s half-life, you know, so there\'s\--say you know
> pharmacokinetics and biodistribution in a non-pregnant individual,
> could you\--has there been any good modeling studies to say if you
> have that kind of information that you could then make even a
> reasonable prediction on a pregnant one?
>
> DR. WOOD: I haven\'t heard of any. Have you?
>
> DR. UHL: I don\'t believe so. To stretch that a little further, there
> has been a lot of discussion about, for example, drugs into breast
> milk based on physical/chemical properties and such. And in that case,
> there\'s enough discussion about the differences of across animal
> species and animal milk that we\'re not sure how well they correlate.
>
> As far as pregnancy is concerned, the changes are not static. They\'re
> very dynamic changes throughout the nine months of gestation that to
> model that would be very problematic.
>
> DR. LANGER: I\'m sure it would be very difficult, but, I mean, the
> question is\--but I wonder if that\'s\--I guess what I\'m trying to
> get at, is that a direction of research that\'s worth pursuing? In
> other words, let\'s say you could encourage NIH to put out a request
> for proposal. I\'m sort of thinking in answer to the second question,
> you get NIH to put out a request for proposals to try to do those
> kinds of models. It seems to me that that\'s something that
> pharmacokineticists or chemical engineers might be interested in doing
> if they were encouraged to do it. I guess the question would be
> whether it would be of any value to you.
>
> DR. UHL: I\'m not familiar with anything in the literature about doing
> modeling like that on the pregnancy side. There\'s a lot of
> information in the literature about physical/chemical modeling and
> PK/PD as far as lactation is concerned, but this would\--to do some
> pregnancies sounds to me like it would be creating a new field
> or\--which is good, but with limited resources, where do you want to
> go with that?
>
> DR. WOOD: I think your point about NIH\--
>
> DR. LANGER: But that\'s number two, not number one. I\'m not
> suggesting that the FDA fund it, but what I\'m thinking about is
> actually, you know,\--
>
> DR. WOOD: That might be less scary to people.
>
> \[Laughter.\]
>
> DR. LANGER: Yes, exactly. But it seems to me NIH has initiatives where
> they want to encourage research in the general area of women\'s
> health, seems to me\--you know, they just established like a new sort
> of bioengineering and radiology. It just seems to me that that\'s the
> kind of research that could get done, you know, and maybe there\'s
> models that would be of some value. That\'s really what I wanted. So
> then the question is: Could you initiate discussions with NIH to try
> to\--you know, they often put out these requests for proposals to see
> if people can come up with some good ideas.
>
> DR. WOOD: Yes, they\'re putting something out. Has it gone out? Not
> out. Coming out soon. The NICHD is very interested in the concept of
> sort of pregnancy as sort of\--pregnant women as therapeutic orphans,
> and they\--but their interest is clearly much broader than FDA\'s in
> terms of understanding the pharmacology of pregnancy, our interest
> being, you know, as evidenced by the research that we fund, being
> fairly targeted at how we\'re going to get useful information that can
> ultimately go on a label that can help with dosing and clinical
> practice, their interest being much broader in terms of the whole
> physiology, pharmacology of pregnancy and how that interacts with
> medications. And they are planning to put out an RFA with a very broad
> mission and a very general RFA in this arena. And I think your point
> is well taken, that that idea of modeling may not be in there, and it
> would be something worth to go back and look and encourage them to do
> because that\'s an interesting question.
>
> DR. LANGER: Yes, because I would think myself, just speaking for the
> bioengineering community, and I also think that there\'s a whole group
> of people in schools of pharmacy, pharmacokineticists, you know, that
> that would be a real good challenge, that there might be some
> contributions that could be made there. So if they were encouraged to
> do it, you know, that might give you\--because it just seemed to me
> when you were talking earlier, you know, you realize you\'re talking
> about changes in fluid and things like that, but maybe there\'s ways
> to get some\--I don\'t know\--
>
> DR. WOOD: Yes, and depending on where we are, we always need to go a
> step further.
>
> DR. RIVIERE: There\'s been studies done on\--toxicology studies and
> teratogens and placental transfer, and I don\'t remember when, but
> I\'ve seen PD/PK models of modeling pregnancy, that that kind of work,
> you know, physiological-based model\--
>
> DR. WOOD: And then moving it beyond, because I think the\--
>
> DR. RIVIERE: But I don\'t\--that\'s the problem. Animals and humans is
> a huge jump.
>
> DR. LANGER: Right, that\'s one jump. But, see, the other way of
> thinking about it is\--I\'m not just thinking about one drug. In other
> words, I think what you\'d like to think about is if you understood
> certain fundamental parameters, like if you understood the
> physical/chemical properties of it, like, say, you know, that it will
> lead to diffusion coefficients, partitioning. You know, so then\--and,
> you know, the half-life then maybe there\'s some predictions that you
> might\--you know, what I\'m thinking about is sort of a simple
> model\--I mean, it wouldn\'t be that simple, obviously, but could you
> plug something into the computer some day\--
>
> DR. RIVIERE: Some people have done some of that. The problem, again,
> is it\'s done in rodents, and then\--
>
> DR. LANGER: No, but I\'m\--yeah.
>
> DR. RIVIERE: \--the physiology is so\--and you can do that. I agree.
> But there has been some work done on that.
>
> DR. WOOD: But, again, that\'s not asking the question about how the
> physiology of the mother changes in terms of her PK/PD\--
>
> DR. LANGER: That\'s right.
>
> DR. WOOD: It\'s more placental transfer, which is, again, more akin to
> the lactation\--
>
> DR. LANGER: It\'s just one question. I\'m trying to think about a
> broader context, I guess.
>
> DR. WOOD: That\'s an excellent idea.
>
> DR. LANGER: Maybe we can see if there\'s more answers or suggestions
> to one, two, or any of the questions. Do people have any other
> comments on the first or second question, or the third? Do we want\--
>
> DR. WOOD: I guess I would also have a question. Does this\--you know,
> we\'ve had the experience both in terms of the labeling regulation and
> doing this research, that there is a very understandable hesitancy for
> people to take on this challenge. I guess in terms of how\--you know,
> does explanation relieve that anxiety or is it\--you know, or is it
> something we\'re never going to be able to overcome?
>
> DR. FEIGAL: Could I just ask a question on the third one? One
> informational question. Has there been a prospective registry larger
> than the acyclovir registry, or is that the largest?
>
> DR. WOOD: That\'s the largest.
>
> DR. FEIGAL: That one sort of illustrates kind of the problems with the
> registry strategy because it took them about ten years to get 1,000
> exposed women, and then only about a third of those were exposed in
> the first trimester. And so they ended up with really only the power
> to exclude a doubling of all birth defects if the hypothesis was that
> it would cause all those defects to evenly go up, and it only had a
> power to pick up a ten-fold increase in any specific common birth
> defect.
>
> And so I think the setting in which exposure cohorts are useful is
> something to take a close look at, because when we then looked at
> whether or not that registry should continue to get more power and you
> realize that power is the function of the squaring the sample size, to
> double the power we would have had to have gone, you know, to another
> 4,000 women. Obviously it\'s a very small fraction of the people who
> were exposed.
>
> My other question is if you don\'t start with an exposure cohort, you
> can start with an outcome cohort, and there are birth defect
> registries. And if you actually said for a second that, well, most of
> the exposures identified in the birth defect registry aren\'t going to
> be the cause of the birth defects, because we\'re not making much
> progress there. But it is an interesting source of information about
> what drugs those people took, because they very systematically
> interviewed, and there, when you\'re interested in the outcome, the
> dilemma is that they better remember the drugs they took, and so
> you\'ve got recall bias and you have problems doing causality for the
> outcome. But if you say I\'m not interested in the outcome, I\'m
> interested in finding out what drugs pregnant women are exposed to,
> and you realize a third of all women\--not a third, 3 percent of women
> have a birth defect, and you\'ve got states where reporting is
> mandatory, like California, you may be able to get quite a bit of your
> exposure targets to select the drugs that are feasible to study as a
> byproduct of some other kind of research. So that\'s another
> suggestion.
>
> DR. WOOD: Does OTIS or Mother Risk have that sort of data based on\...
>
> DR. MILLER: What pregnant women are taking, the prescription databases
> do a very good job of telling us that. So we know what prescriptions
> are being filled. We don\'t know that the women are actually taking\--
>
> DR. WOOD: But in terms of other drugs as well, the OTC or\--
>
> DR. MILLER: And certainly OTIS provides us lists with what questions
> women have about drugs, what drugs they\'re concerned about during
> pregnancy, so we could approach it that way. Usually what happens
> whenever we try to do a prioritized list is we have one less than
> every drug that\'s approved.
>
> DR. FEIGAL: The other comment is that if, in fact, as pregnancy
> probably is, it\'s so dynamic that, in fact, it\'s difficult to lump
> all pregnancies together to predict PK, it sort of implies that these
> general strategies of just studying pregnancy as a category may just
> blur everything together and miss the opportunity to identify certain
> times in pregnancy where the volume shifts or the metabolic conduction
> of liver is particularly active and you\'re not in a steady state, you
> may misleadingly conclude that everything is just about the same as
> the general population except the person might be bigger than they
> look because they\'ve got more volume.
>
> So I think that, you know, your real dilemma is whether to take some
> of these broad strategies or whether to go back and encourage the NIH
> and others to study the physiology in some detail, develop the
> hypotheses about which of those physiologic states would have the
> biggest impact on drug metabolism, and then see if you could show
> that. Then you\'ve got to find something for the clinician to actually
> figure out when they identify those states and what are the clues that
> are commonly clinically available. Is it anything as simple as recent
> weight gain or creatinine or whatever? You know, whatever. But if, in
> fact, it is such a dynamic state, then the question is how do you get
> the research for the additional clues so you don\'t just label
> everyone for all pregnancy, or as we sort of do sometimes, trimesters.
> But that\'s often picked that way because of exposure considerations,
> not physiology of pregnancy considerations.
>
> DR. WOOD: I think the studies we\'re doing now are based on trimester.
> It\'s not going to go much more in-depth than that.
>
> DR. UHL: Except the population PK study allowed you to work around
> that.
>
> DR. WOOD: Continuous.
>
> DR. UHL: Right, the time in pregnancy is a continuous variable and you
> can analyze it that way. That\'s one of, I think, the reasons why had
> said that it\'s probably a better approach.
>
> Additionally, as we\'re working with these studies, you know, it\'s
> very obvious that people need to think what time are they talking
> about so we don\'t just lump pregnancy as one time period, because the
> changes are so significant and so dynamic throughout the whole
> pregnancy. And Peggy didn\'t really get into the design issues, but we
> have addressed trying to really narrow windows if you\'re going to do
> a traditional PK approach, to really narrow the windows so you somehow
> decrease your variability. But, you know, that remains to be seen
> how\--when we finally get the results of that.
>
> In answer to your question about the pregnancy registries, the Swedish
> Birth Registry has huge numbers of patients and there are publications
> in the literature from that database where they capture, I believe
> it\'s like 97 percent of every pregnancy that occurs in their country.
> And they have links of the mothers\--the mother\'s file is liked to
> the baby\'s file, and they have published several thousand patients
> with omeprazole, with fudesanide (ph), things of that sort. But as far
> as American registries, they\'re not the size.
>
> The registry guidance document is published now in final form, and one
> of the things that it talks about is when you design your registry, to
> decide what sample size you will be able to enroll or anticipate
> enrolling, and also what sample size will give you what power to rule
> out, let\'s say, a two-fold or a ten-fold increase in
> whatever\--either specific birth defect you\'re interested in or the
> overall incidence of birth defects, which is the 3 to 5 percent. So to
> think about the power of a registry at the design phase, not at the
> end when you\'ve only enrolled 1,000 patients and then say, well, how
> useful has that been.
>
> DR. MILLER: I think if Diane Kennedy were here, she would insist that
> we mention we\'re going to be talking about margins of safety. So we
> may be just providing women with reassurance, you know, we\'re sure
> it\'s not a two-fold increase in a birth defect. And for me, that
> would buy a lot, I think. You know, we\'re sure it\'s not a
> thalidomide. We\'re sure it\'s not a really bad actor, and you really
> need this drug. So that\'s probably what we\'re going to be able to
> get for most drugs.
>
> DR. LANGER: Are there any comments from the audience, or questions?
>
> \[No response.\]
>
> DR. LANGER: Is there any way that would be useful to continue in
> future meetings any, you know, agenda items you\'d want to put on for
> the future that\--you don\'t need to answer necessarily now, but\--
>
> DR. WOOD: There potentially could be; particularly our work with NIH
> and their RFA might be something that we could come back to. And then,
> of course, if we get a proposed labeling rule.
>
> DR. LANGER: Okay. So you might want to consider that for future
> meetings, but any other things that we should do in this session?
>
> \[No response.\]
>
> DR. LANGER: Thank you very much. Excellent presentation.
>
> I want to just get a sense from both Janet and the members of the
> Science Board, would you like to take a five-minute break or just
> continue? I think people want to continue.
>
> The next topic will be the Pharmaceutical cGMPs Initiative, and Janet
> Woodcook, who\'s the Director of CDER, is going to go over that.
> Janet?

X DR. WOODCOCK: Why don\'t we get the slides up, Bob? I\'ll give you
some update.

> This is a large initiative that FDA announced a couple months ago, and
> I want to say that this really was an outgrowth of the PAT
> presentations that we had before the Science Board over the last year.
> We\'ve had two presentations, and the PAT meeting, Process Analytical
> Technology, and basically the introduction of new technology into
> pharmaceutical manufacturing.
>
> That initiative has really taken off. We have had several public
> meetings on this subject. We have put together a team between the FDA
> field organization and CDER that will inspect PAT. We have done
> training. We have a guidance document that is in development that
> hopefully should be out soon in draft. And we have a conceptual
> submission from the first manufacturer, sort of a proof of concept
> type of submission, and we expect five submissions of actual
> applications of PAT probably within the next year or so. And we have
> met with manufacturers about this.
>
> So this is really taking on a life of its own, and what it did really
> was stimulate us to look more broadly at the pharmaceutical quality
> regulation in general, using this as kind of an example, the PAT.
>
> So I\'d like to go through\--I\'ll try to be quick\--what we have
> announced and what this initiative is about.
>
> So what is it about? And I\'ll go through the background, some of the
> themes, some of the things we\'re going to do, and what we hope to
> accomplish out of this initiative. And I think you\'ll be able to
> relate\--those of you who were here at the previous discussions of PAT
> will be able to relate those two together.
>
> The initiative that we announced is not just about good manufacturing
> practices, which is the standard for conduct of a quality system in
> pharmaceutical manufacturing. It\'s about regulation of product
> quality, and this initiative goes across FDA\'s field organization.
> And I can see John Taylor is here, the science rep, as well as the
> Center for Veterinary Medicine, the Center for Biologics, and the
> Center for Drugs, all of which are involved in regulation of the
> quality of different pharmaceuticals.
>
> So this is a collaboration, and our system that these units are
> involved in involves a standard-setting component, a submission review
> components, an inspectional component. In the standard setting, we set
> standards for quality of pharmaceuticals, which some of you are
> familiar with, many of which are in ICH, in the International
> Conference on Harmonization for pharmaceuticals. They have to do with
> like stability, impurities and so forth. That\'s one set of standards.
>
> And, generally speaking, manufacturers have to submit information to
> the FDA, and those submissions are reviewed against the standards to
> make sure that they meet standards.
>
> Then we have the standards for quality systems approach to
> manufacturing, and that is the cGMPs, or current good manufacturing
> practices standards. And the field organization and to some extent
> some of the folks within the Centers go out and inspect the facilities
> against these standards, against the GMP standards. And that\'s the
> system, and this system is supposed to work together\--the whole point
> of it is supposed to be to make sure that the quality of drugs, animal
> drugs and human drugs, in the United States is high and those drugs
> are all fit for use.
>
> Now, what this initiative is doing, we\'re stepping back and we\'re
> looking at this, and we\'re asking how effective is this system in
> achieving its objectives today. Are we achieving its objectives and
> are we achieving them efficiently? And we have to step a little bit
> further back and ask what are the objectives in terms of specifics.
> What does quality mean in terms of a pharmaceutical? And how do the
> component parts of the system operate and cooperate, and do they
> cooperate, and how effectively? So that\'s what this is about, to step
> back and look at both the submission part and the inspection part of
> the quality system and see how it\'s functioning.
>
> Now, why are we doing this? This system was devised many decades ago.
> The last rewrite of the good manufacturing practice regulations that
> was significant for pharmaceuticals was about 25 years ago. So a lot
> has happened since then. And I would say the submission review part
> and the ICH part has kind of grown up over the years, the way we do
> that.
>
> There have been incremental adjustments over the 25 years. We had the
> major revision in 1978 of GMPs. The Center for Drugs and the field had
> an agreement on kind of who would do what in the 1990s, and that was
> more like a peace treaty. And we had a SUPAC, which is scale-up and
> post-approval changes. That was a series of guidances the Center for
> Drugs issued in the \'90s, and those had to do with what types of
> changes you could make in your manufacturing without doing a
> submission and which ones required a submission. And the FDA
> Modernization Act in \'97 brought some changes, required changes as
> well to our regulation, and then there\'s a concept of team biologics,
> which involved the biologics staff had done their own inspections and
> the field\--in the drug area, and the field personnel worked with the
> biologics folks, and that was a team biologics concept.
>
> So all these changes had occurred, but we hadn\'t really stepped back
> and looked at the entire system. But the environment, while the system
> has sort of incrementally changed and grown, the environment has
> really changed significantly. Not only are there a lot more approved
> medicines, hundreds and hundreds, of course, more approved medicines
> than before, but their role in health care has become central over
> these last few decades rather than an adjunct to hospitalization and
> surgery.
>
> There have been\--and we\'ve discussed this in PAT. There have been a
> lot of advances in both pharmaceutical sciences and our understanding
> of these substances and their properties, as well as manufacturing
> technologies, and particularly in other sectors. There have been
> advances in the science and management of quality. The GMPs are a
> quality system, but, in fact, there\'s been a quality revolution in
> the past 30 years in other manufacturing sectors, and so there\'s a
> new understanding of how you bring about quality compared to the
> understanding in the \'70s and how does that apply to our
> understanding of the GMPs.
>
> Biotechnology is being used much more broadly in a very wide range of
> applications, and the industry\--back in the \'70s, we were regulating
> a domestic industry, primarily, and that\'s how it was conceived.
> That\'s how the inspectional\--that\'s how the programs were set up.
> This is totally out the window now. We\'re regulating a global
> industry, and that really changes or needs to change the approach for
> a variety of reasons. It stretches us very thin in our inspectional
> role.
>
> For example, this is domestic inspections. I don\'t know whether you
> can see this. These are the non-medical gas type of inspections,
> inspections of regular pharmaceutical manufacturing, not pre-approval
> inspections but regular post-approval, good manufacturing practice
> inspections from 1980 through current. And you don\'t need to look at
> all the numbers. You can see the trend. The trend is down.
>
> We cannot stretch our resources across the number of plants and so
> forth. The inspections are more complex, and actually we probably have
> fewer resources to bring against this. So the bottom line is we can be
> in plants less often and in fewer plants than we were in 1980, and
> this trend has continued over the decades, in more or less an
> unremitting fashion, although it may have flattened out a little bit
> recently.
>
> And so this is another environmental change that we must recognize as
> we go about looking at our system. We can\'t be there. But, in fact,
> with all the changes in technology and scientific understanding, maybe
> being there isn\'t\--maybe we can devise a system where being there
> isn\'t quite as important as some other thing as it used to be.
>
> Now, in devising this initiative, we have some major themes and
> principles. First of all\--and this is something that there\'s\--more
> understanding has grown up, I think, over the last 20 years about a
> risk-based orientation, and this means a number of things. We really
> need to make sure we put our resources\--not all of our resources, but
> we put the bulk of our resources against the riskiest areas, and that
> would seem intuitive. But, in fact, back in the \'80s when we could
> sort of cover everything uniformly, that was not the approach. So we
> really need to make sure that the amount of resource put against any
> given area is proportionate to the risk to the public, the public
> health.
>
> But the same thing goes to the requirements that we have, and this is
> the public standards. It used to be that our requirements might be
> limited, say, by analytical methodology, and the limit of an
> analytical test might be something, 1 percent or something, one part
> per million or whatever. Well, it may be with excruciatingly sensitive
> instrumentation we have nowadays you could detect many, many, many
> orders of magnitude less. But that doesn\'t necessarily mean that that
> should be the limit, and when you\'re not limited so much by your
> analytical techniques, then you have to think about risk, and that
> needs to be your criterion.
>
> In general, the more scientific understanding we have about
> manufacturing and what the critical variables, critical control
> points, whatever, within manufacturing, the more we can tailor our
> requirements to the vulnerabilities and make sure the vulnerable
> sectors are controlled and not simply have blanket requirements about
> everything, because we don\'t know where the risk is. So that\'s one
> big piece.
>
> Another piece is that to the extent we can, we base our regulatory
> requirements on the best available science. And, again, in the 30
> years that have elapsed or the 25 years, we have gained quite a bit
> more scientific understanding in a lot of the areas that we\'re
> talking about here, formulations, a lot of things. And we need to not
> only recognize but, in general, we think we need to facilitate
> introduction of scientific and technological advances, and those of
> you on the Science Board who listened to all the discussions on
> process analytical technology, I won\'t belabor this point because
> that\'s the exemplar of this. But I want to say it\'s not limited to
> PAT. PAT is simply the example of why we should facilitate
> introduction of this science and technology because it does have the
> opportunity to achieve better quality at no increased cost or maybe
> cheaper.
>
> Another theme, of course, is that in doing this initiative we plan to
> maintain our traditional stance of strong public health protection. We
> don\'t think doing this initiative will interfere with current
> enforcement activities in the manufacturing realm, and we think
> achieving our objectives under this initiative will actually result in
> better public health protection.
>
> Another principle, we have talked to our international colleagues in
> other regulatory authorities and we\'ve talked to the folks in ICH,
> and we plan to cooperate internationally because this is now a global
> industry that we\'re talking about.
>
> Now, another principle that we plan to follow as we look at this is
> the integrated quality systems orientation to our approach, and that
> sounds a little jargon-y. What do I mean by that? Well, first of all,
> as I already said, we\'re going to look at innovations in quality
> systems outside the drug sector. And we\'ll be doing some benchmarking
> in some very different sectors and areas where at least people claim
> that certain quality systems approaches have given them quantum
> improvements in quality. And we\'re going to bring those folks in and
> talk to them and see about the application of quality systems from the
> quality revolution. And I personally can testify, in cars, I\'m old
> enough to remember when you bought a car and, you know, first the
> handles fell off, and then it stopped on the highway, and then all
> these different things happened. Yes, and then some people came along
> from other countries and they made better cars that didn\'t break all
> the time, and they claimed that was from their quality systems, that
> they made a good product every time or most of the time. So we want to
> look at that thinking and what kind of thinking is that and is that
> inherent in our approach to quality systems.
>
> Second of all, though\--and this is, you know, courageous of us, I
> think\--we\'re going to look at our system of regulating drug quality.
> Is our system a quality system? Does it have the attributes? Are we
> delivering a good quality product as we do during regulation in the
> quality area? And is it an integrated system? In other words, do we
> work with the field, do we work with the other centers?
>
> One of the issues that has been raised by various parties is of
> inconsistencies. A good quality system will surface and address
> inconsistencies. So we\'re going to see, and we\'re starting this
> effort. It\'s very interesting.
>
> Now, we\'re going to have some immediate steps as we do this. We plan
> to hold a series of scientific workshops with key stakeholders.
> That\'s on the science area. We\'ve already had a first Advisory
> Committee meeting of Pharmaceutical Sciences, but we had all the
> different centers involved in everything on aseptic processing. This
> is one of the areas, making sterile drug products and what are the
> parameters and how do you do environmental monitoring and what do we
> know about all these things. And we will be hopefully issuing guidance
> on that and having more scientific input on that.
>
> We plan to hold a major workshop in the spring, and that will have
> many different\--it will be partitioned into many different areas, and
> have discussions on different science issues, and we will invite
> academia and industry to come in and tell us what scientific areas we
> think we should focus on, what are the issues. So we will be holding a
> lot of scientific discussion and input over the next year or so.
>
> We plan to enhance scientific and technical expertise, and we have
> been doing that. In the Center for Drugs, we have hired\--we feel we
> need our chemical engineering and we need more engineering input, and
> some other kind of specific technical expertise, and we are working on
> acquiring that expertise. And we\'ll probably be involved in training
> people who are here and bringing up their level of understanding of
> some of these things.
>
> Encourage greater use of comparability protocols. Comparability
> protocol is a way a manufacturer can, if they modify their product
> somewhat or their process somewhat, they can demonstrate maintenance
> of quality and not have to submit something for FDA to review, because
> FDA has vetted this protocol.
>
> Increased use of product specialists and inspections. As I said, the
> product specialists, the scientists in the Biologics Center, often go
> out and are involved in inspections. We have always wanted, I think,
> in the other Centers to have the scientific reviewers also participate
> inspections. So we\'ll be doing more of that. And these are things we
> plan to\--all plan to initiate these within six months of the
> announcement, which was in August.
>
> We are centralizing the technical review of warning letters. Warning
> letters are letters we send to firms that have specific technical
> cites of violations, and this is a way of trying to understand do we
> have inconsistencies or not because of the issue of inconsistency. If
> we see areas in these warning letters where we have disagreement, then
> these are things that we need to bring some scientific expertise to
> bear on, perhaps issue guidance on.
>
> The next one is probably not of great interest to this group. The Part
> 11, the third bullet here is the regulation on electronic records and
> signatures. This is also somewhat a science issue in the science of
> validation and computer science, and we are\--the field has been the
> lead on this for a while. CDER is going to take the lead, kind of take
> up the baton for a while, and we\'re all working very hard on this to
> try to get this settled because we feel this is another area where the
> incorporation of new technology may be inhibited because of
> uncertainty about where FDA is going on Part 11. So we have made this
> a very high priority for us to get some guidance out there, to get
> some resolution of some of the issues around Part 11.
>
> This directly relates to process analytical technology because
> acquisition of data online or at-line sensors, you know, this is a
> computerized, an automated function, and we need to have guidance on
> how much data need to be archived and the technical requirements
> around that data.
>
> And develop a technical dispute resolution process. This means when
> there\'s a citation by the field inspector or the other people who go
> out in the field, an inspector in the firm feels there is a
> scientific\--has a scientific disagreement with that conclusion, there
> would be an appeals process so that we could get a board or whatever
> involved in this appeal, and we could discuss the underlying
> principles. And, again, this may help us in many ways. It helped me,
> helped us signal which scientific areas require some attention and
> perhaps issuing guidance.
>
> Again, you know, work planning process, we\'re currently altering
> that, and that\'s not as much interest to the Science Board, but we
> will be trying to use at least our crude approximation of risk, and
> we\'re trying to develop better data, surveillance and other data, so
> we can develop better models of risk, so then we can\--the work plan
> actually tells the inspectors what to inspect this year, where should
> they go, what should they look at. And we need much better data
> acquisition and data analysis to help us target according to risk.
>
> Then the Biologics Center is doing with the field an evaluation of the
> team biologics concept and how that has played out.
>
> Now, the approaches we\'re taking\--I don\'t want to take too much of
> your time, but we\'re going to do a contract that will be external to
> us and both to evaluate our process and perhaps assist us in
> evaluating some of the science aspects of our regulation. And we also
> hope to collaborate with academic groups because we can\'t directly
> evaluate industry. But in other industries, there are academic groups
> that actually study the industry environment and the business
> conditions and so forth and the relation to quality systems and so
> forth, and we would like to collaborate and encourage the development
> of that type of evaluation. And, of course, we would collaborate with
> the industrial sector in getting this done. But we wouldn\'t carry out
> that type of study ourselves. I don\'t think anybody would be willing
> to talk to us.
>
> Also, you know, we are going to do benchmarking, as I said, within the
> contracts. We\'re going to look at quality systems. We\'re going to
> benchmark other areas, other sectors as far as how they do standard
> setting. And we also want to benchmark audit and surveillance
> functions, of which there are a number of other government agencies,
> as well as other large purchasers and so forth that need to maintain
> quality amongst their supply chains or, you know, other\--we\'re going
> to cast a broad net and look at these things.
>
> The science review, we\'re going to look at all these types of
> science, not just the science behind the product itself, but the
> science of quality, what is known there, and the science of risk
> management, which the Drug Center has already spent a lot of time on
> risk management in the realm of the safety of medicines. So we have a
> lot of that expertise that we\'ve acquired that we can transfer to
> this.
>
> We\'re also going to work with the field and think about can we have a
> more dedicated crew to some degree of pharmaceutical inspectors. The
> field now\--John, you have 4,000 people in the field? Yes, there are
> 4,000 people, and that\'s very daunting to us to think\--you know, to
> train so many people, or get to know them and have a one-to-one
> relationship with them. So it\'s really trying to identify a group of
> people who really consider themselves pharmaceutical inspectors and
> that we can co-train with and center in the field, and I know the
> Veterinary Center is also quite interested in this.
>
> As we go along with this, one of the real focuses, as you probably
> gathered, is to issue guidance in this area. There\'s a lot of
> guidance, as I said, in the product quality area under ICH, such as
> stability and impurities and things like that. But there isn\'t as
> much guidance in the quality system area and the GMP area, and we
> think we need to get a lot more things written down and laid out. So
> we\'ll be doing that, and our compliance programs, which are actually
> the directions to the field inspectors about what they go out and
> inspect, will be revised, and we expect to do a lot of education and
> training with industry and the FDA as well as across the FDA Centers
> and groups that are collaborating, and then we probably will be
> issuing new policies and procedures. And we might have to work on
> regulations. That\'s up in the air. We have a lot of scope within the
> existing regulations, but we may at the end of the day find that we
> need to revise regulations, and if so, we will assess whether we
> should do that.
>
> We\'re setting up an Evaluation Group to evaluate this effort, and
> first of all, we have to identify what the problems are and what we
> expect to accomplish, and then we\'ll evaluate ourselves against
> whether we accomplish it.
>
> Broadly, we would like to demonstrate a move to risk-based approaches
> in our operations, that we have an overt culture of assessing risk and
> devising our programs based on as objective risk as possible. We want
> to demonstrate that we have actually enhanced the science base under
> which we operate in this area. We\'d want to demonstrate better
> integration between submission review and inspection programs. We\'d
> like to show that these are tightly linked and operate as a system.
> And we\'d like to be able to demonstrate that the industrial sector
> has actually gone ahead and adopted new technologies, and we are at
> least seeing the beginnings of that within PAT that that\'s actually
> happening.
>
> Immediate steps that I listed, we hope to accomplish by February 3rd.
> That doesn\'t mean we\'re going to solve Part 11 by February 3rd. It
> means we\'re going to transfer\--accomplish a transfer to the Center
> for Drugs for the lead and probably have some of the initial work done
> on Part 11 and so forth. So those steps that are laid out, those
> initial steps will be accomplished, we hope.
>
> We would run this project for two years\' duration from August when it
> was announced, and August two years from now we\'re going to stop and
> we\'re going to evaluate it, and we\'re going to have the report of
> the Evaluation Group. And we can report back to the Science Board if
> the Science Board is interested. But at that point, we\'ll see whether
> it\'s worth continuing, what have we accomplished and do we have more
> to accomplish.
>
> The Evaluation Group has been convened and is asking a lot of hard
> questions. We have many working groups that are working, and we\'re
> going to be seeking a lot of input from industry, which we\'ve gotten
> some already, and academia along the way as we move along in this.
>
> So that is a general outline of what we\'re going to do. We aren\'t
> ready really for specifics yet. We\'re getting into that right now.
> But I think we all feel good this was kicked off by the discussions of
> process analytical technology that we had over the last year before
> the Science Board.
>
> Thanks, and I\'m ready for questions.
>
> DR. LANGER: Thanks, Janet.
>
> Questions or comments? Harold.
>
> DR. DAVIS: Having been on the Board at that time, you\'ve come a long
> ways, pretty good.
>
> Two questions. You\'ve mentioned that industry has been involved and
> commented. What\'s been the nature of the comments so far, positive,
> negative, wait and see, whatever?
>
> And my second question, I\'m very much interested in your Part 11, and
> I\'m not sure I appreciated what you thought the mood would do. I
> heard you say it, but I\'m not sure it was clear to me. Would you
> restate what you\'re trying to accomplish there for me?
>
> DR. WOODCOCK: Right. Well, in the first part what does
> industry\--well, basically we\'ve heard from various groups. We\'re
> received some documents from people with suggestions on what we should
> work on. That\'s what we\'ve heard from industry, along with what has
> been discussed in the open public meetings we\'ve had both on PAT and
> aseptic processing. We will open a docket on this, a public docket, so
> that we can put all the comments within the docket, and people can see
> what everybody has said about it and what people\'s issues are. But
> mainly right now, from industry, we\'ve received suggestions on what
> the highest priorities might be, Part 11 being one of them.
>
> On Part 11, I think what we all bring to this\--and John is here from
> ORA\--and all of us, is that we have a will to get this resolved. And
> CDER, because of the PAT initiative and because of our electronic
> submission, our paperless review process, we recognize we must resolve
> the Part 11 issues and move on. And so we are committed to getting
> closure, to getting to a point where we understand the requirements,
> and we can promulgate them, and everybody can be on the same page
> about what the Part 11 requirements are and how to comply. That\'s
> really what we need.
>
> John, do you have any comments?
>
> MR. TAYLOR: No. I think Janet articulated quite well the rules that
> existed since 1997. In light of the fact that the Agency at one time
> was issuing its guidance verbally, there was recognized a need to
> formalize the guidance process, and more importantly, a need to
> resolve the outstanding issues that have prevented companies from
> adopting this type of approach, because both for reasons of economics,
> efficiency, for product quality and for other reasons, it\'s important
> to integrate these e-commerce principles, and we feel a need to
> resolve those issues so that we can not only facilitate those goals
> externally, but also internally in regards to our use of electronic
> submissions.
>
> DR. DAVIS: Does that mean by any chance that because of your
> recognition or concern, that there is this cloudedness about it so
> far, that until you come out with some clarity, that CFR Part 11
> inspections or 483s won\'t be issued, there\'s some hiatus until that
> time or what?
>
> MR. TAYLOR: Yes. There has been what\'s called a Compliance Policy
> Guide in place since 1999, where the Agency has basically stated that
> we\'re exercising enforcement discretion until these outstanding
> issues have been resolved. So to the extent that 483s have been issued
> with Part 11 issues on them, those are just educational. They\'re not
> for the purposes of furthering an enforcement action. In a few rare
> cases there have been warning letters where the underlying problems
> were so pervasive that no matter what interpretation you took
> regarding Part 11, that basically these are situations where there was
> almost no system in place at all, but for the most part, the only
> thing that we do is we issue 483 items for the purposes of education.
> We\'re exercising an enforcement discretion, and the reason for that
> was because the Agency recognized that there were outstanding issues
> that needed to be addressed. And in all fairness, it was unfair to
> hold people to a standard that we couldn\'t articulate ourselves, and
> that\'s what we\'re trying to resolve.
>
> DR. DOYLE: Very well done, Janet. I\'m curious to know a little bit
> more about the risk assessments that you\'re doing. Is the purpose of
> these risk assessments to identify what products are of greatest risk
> or what points in the process are riskiest, or where are you going
> with that?
>
> DR. WOODCOCK: There are three kind of meanings to this, okay? And,
> yes, the first would be for our inspectional program, where are the
> greatest vulnerabilities to public health? Because as you saw, we\'re
> not the Department of Agriculture and we don\'t have an inspector in
> every plant. And the number of inspectors and the number of
> inspections that have been able to be done over the years have
> dwindled. So we need to figure out what are the most serious
> vulnerabilities with respect to public health, and make sure the
> resources are concentrated there. I want to make sure people
> understand that doesn\'t mean they would be exclusively focused on the
> highest risk. We would continue to have a presence throughout any risk
> categories, but the emphasis ought to be on the highest risk products.
>
> Now, that doesn\'t mean we could say today, well, intravenous products
> for life-threatening diseases are highest risk. We think we probably
> need to construct a model that has to do with the firm\'s compliance
> history\--I\'m just making stuff up because I don\'t know the
> answer\--the inherent difficulty in manufacturing the product. You
> know, sterile products obviously are of more concern than toothpaste
> or dandruff shampoo. There are other factors that go into this, but we
> need to construct such models and then test them and so forth. So
> that\'s what we\'re talking about for inspections.
>
> For manufacturing, it\'s quite different, although it\'s conceptually
> the same issue. And Ajaz taught me a lot about this. So back when much
> of this was conceived, perhaps back in the \'70s, we didn\'t have as
> much basically engineering and material science understanding,
> especially for solid oral dosage forms, about what the factor were
> that create vulnerabilities that make things go wrong. For example, a
> blender. Why is there an inhomogeneous blend? And we didn\'t have the
> ways of monitoring blend that we may be able to introduce today. So
> the approach was we need to check everything and control everything
> carefully and control the process extremely carefully, because we
> couldn\'t predict which factors mattered.
>
> Now, as more knowledge has been generated, scientific knowledge, and
> you can predict, based on all sorts of things that I won\'t go into,
> certain failures because of certain parameters, those are the
> parameters that should be controlled the tightest and we may be able
> really to move to a system that really focuses on the risk or critical
> control points of vulnerability in the manufacture of many products.
> This would help everybody. It would help FDA because we wouldn\'t have
> so many records to inspect. There\'s a record burden for everyone here
> in all this testing and controlling and record keeping and everything,
> and it would help the manufacture because it would be more efficient,
> and it would help the consumer because you would have at least a high
> of assurance of fitness for use, maybe higher. So that\'s another
> meaning of risk. And we are exploring all of those parameters and
> thinking how do you apply this in a regulatory system.
>
> DR. LANGER: Other questions or comments?
>
> \[No response.\]
>
> DR. LANGER: I just had a minor one. First, again, it\'s great
> progress. You had mentioned about\--and this is really just to see if
> we can help in any way\--getting chemical engineers involved and stuff
> like that. Is that going fine or is there any help you would like?
>
> DR. WOODCOCK: This is H.S. Hussain from the Center for drugs.
>
> MR. HUSSAIN: This is Friday, casual day, so.
>
> \[Laughter.\]
>
> MR. HUSSAIN: I think we have been able to recruit chemical engineers
> and enlisted pharmacists, and we actually have set up a position
> description for that, and we will have some challenges with respect to
> people trained in pharmaceutical engineering, and support for
> education I think is needed, so I think the Science Board has a voice
> in that regard with respect to making arrangements of this with NSF
> and so forth.
>
> DR. WOODCOCK: Yes. We can come back to the Science Board at some point
> as we get to specific science issues. I think what H.S. was right now
> we\'re able to recruit, but there may be like more fundamental science
> issues that we really need to bring back to the Board and get some
> help, perhaps research support for certain kinds of research that
> really needs to be done.
>
> DR. LANGER: That sounds great.
>
> Any other questions from anybody in the audience or Board?
>
> \[No response.\]
>
> DR. LANGER: Janet, I think everybody thinks that\'s great progress.
> Thank you.
>
> DR. WOODCOCK: Thank you.
>
> DR. LANGER: So now, basically, this is the final session where we just
> make closing remarks and talk about future directions, so let me try
> to make some summary comments on each section. If I\'m missing
> something or state something in any way someone would like me to
> change, correct me.
>
> So the first topic was counterterrorism. The issues that came up there
> were to explore the issue of research priorities and counterterrorism
> and how the Agency\'s priorities\--prioritizes those with limited
> resources, also to explore how the Board can help, for example, with
> respect to capturing expertise from academia, for example. Any changes
> on that?
>
> \[No response.\]
>
> DR. LANGER: The second area was in the Office of Cellular, Tissue and
> Gene Therapies. Let me go over what we talked about there. There was a
> lot of discussion with the following comments came up. First, that the
> Board believes that as part of its function, that if administrative
> changes are being considered which could potentially impact the
> science basis of the FDA, the Science Board should be asked for input,
> and that specifically on the proposed move of the therapeutic products
> from CBER to CDER, the Board\'s concerned that the science not get
> disrupted and wants to better understand the reason for the move.
>
> Any comments, changes on that?
>
> \[No response.\]
>
> DR. LANGER: The next point was there was a\--and that also came up in
> the open public comment.
>
> The next topic was on pregnancy and labeling issues, here that the FDA
> will explore opportunities for further research with NIH and will
> consider how the Board can help and continue to discuss this issue at
> future meetings.
>
> Any changes, modifications?
>
> \[No response.\]
>
> DR. LANGER: The next section was pharmaceutical cGMPs Initiatives that
> Janet just went over, and I think here everybody is really delighted
> with the progress and look forward to any way we can help at future
> meetings.
>
> And finally, came up, just for the future, other proposed items that
> might be discussed at future meetings would include combination
> products. These are not to be meant exclusive in any means, but
> combination products, counterterrorism follow-up issues as
> aforementioned, antibiotic developments from the April meeting earlier
> this year, obesity issues, further exploration of the pregnancy
> labeling issues.
>
> And Mike Doyle, as the new Chair in 2003 will work with Susan and
> Norris to prepare agenda items in consultation with other members of
> the Board.
>
> Any other comments or addition to that?
>
> DR. DOYLE: Did we want to include the topic about the Committee
> regarding reorganization at that meeting?
>
> DR. LANGER: Yes. What would be the best thing to say about that? I
> guess that was kind of left\--I don\'t think that was clear from what
> was said this morning, what was going to happen, but maybe that could
> be part of what\'s going to be\--when you work with Susan and Norris
> on that agenda, that could certainly be a part of it. Whether we need
> to say it more explicitly, I don\'t know. What do you think?
>
> DR. DOYLE: I just didn\'t want to lose the thought.
>
> DR. LANGER: Do you want us to do that?
>
> DR. ALDERSON: I would counsel you to go ahead and say that\--what I
> hear from the Board members this is something we would really like to
> engage in if this is something the Agency wants to do, and offer your
> services for that.
>
> DR. LANGER: So I\'ll put another item there. Basically discuss\--what
> should I say? What would be the best way to say it?
>
> DR. DOYLE: Restructuring of FDA.
>
> DR. LANGER: Discuss restructuring of FDA from a science standpoint.
>
> DR. DOYLE: Exactly.
>
> DR. LANGER: From a science based standpoint. We\'ll put that down as a
> future item as well. Any others? Yes, Harold.
>
> DR. DAVIS: I would like for Janet to consider\--I really applaud the
> CFR part 11. I\'m not sure the whole Board appreciates what that\'s
> all about. For those of us in the industry I mean it\'s just critical.
> And so I would like to consider in the future, especially as you get
> past February the 11th and about to make some comments, decisions or
> whatever, so I\'d like to have you share those with us just because I
> do recognize how critical those are. And I\'m very happy you\'re doing
> it, that\'s for sure.
>
> DR. WOODCOCK: Yes. I would be glad to do that if the Board is
> interested. We are crashing on that part of the project because it is
> so critical, but we don\'t have anything to share right now. It\'s
> going to be a little while.
>
> DR. DAVIS: whenever.
>
> DR. WOODCOCK: When we have something, we can share it. Again, it\'s
> very technical, not that you guys can\'t understand it.
>
> \[Laughter.\]
>
> DR. LANGER: You have to tone it down for us.
>
> \[Laughter.\]
>
> DR. LANGER: So what I wrote, I basically just amended what I had said
> earlier. I just wrote, \"Excellent progress on the pharmaceutical
> cGMPs, and we look forward to following this more appropriate at
> future meetings.\" I didn\'t add the fact that we want it to be very
> simple. Is that all right?
>
> Anything else that anyone would like to add before we adjourn? Yes?
>
> DR. SCHWETZ: I would for sure want to thank you, Bob, for not only a
> good meeting today but many of them, and the help that you have been
> to us, and we look forward to a similar performance by Mike.
>
> DR. LANGER: Well, it\'s really the work of you all and the FDA, so
> it\'s been a pleasure.
>
> DR. DOYLE: I want to second what Bern said, and the representative
> Board has really appreciated your leadership, Bob.
>
> DR. LANGER: Well, thanks. It\'s been a pleasure to work with all of
> you.
>
> \[Applause.\]
>
> DR. LANGER: With that, any other topics?
>
> \[No response.\].
>
> DR. LANGER: I guess we\'ll move to adjourn. We\'ll adjourn. Thank you
> all.
>
> \[Whereupon, at 3:18 p.m., the meeting was adjourned.\]