UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

Friday,
April 6, 2001

The Committee met in the Second Floor Ballroom at 8120 Wisconsin Avenue, Bethesda, Maryland, at 8:30 a.m., Daniel R. Salomon, M.D. Chairman, presiding.

PRESENT:

DANIEL R. SALOMON	Chairman
RICHARD E. CHAMPLIN	Member
RICHARD C. MULLIGAN	Member
EDWARD A. SAUSVILLE	Member
ALISON F. LAWTON	Guest Industry Representative
GAIL DAPOLITO	Executive Secretary
ROSANNA L. HARVEY	Committee Management Specialist

ALSO PRESENT:

ABBEY MEYERS
W. MICHAEL O'FALLON
MARY D. ELLISON
BERKELEY M. KECK
AMY PATTERSON
PHILIPPE BISHOP
SUZANNE EPSTEIN
PATRICIA KEEGAN
PHILIP D. NOGUCHI
JAY P. SIEGEL
KAREN D. WEISS
CAROLYN A. WILSON
KATHRYN C. ZOON
SALLY SEAVER
MICHAEL WERNER
MALCOM McKAY
ELLIOTT GROSSBARD
JANET CHRISTENSEN

	AGENDA

Presentation of Certificate of Appreciation
for Committee Service	4

SESSION III
FDA Introduction
Long-Term Follow-Up of Gene Therapy Patients	8
Philippe Bishop, M.D.
Division of Clinical Trial Design 
and Analysis, CBER
UNOS Presentation
Mary Ellison, Ph.D	11
Berkeley Keck	14
FDA Presentation
Philippe Bishop	42

Open Public Hearing	137
Dr. Sally Seaver, Seaver Associates	138
Michael Werner, BIO	144
Malcolm McKay, Vice President of Quality and 
Regulatory Affairs for Cell Genesis	147

Introduction - FDA Proposed Rule
Dr. Philip Noguchi	149

	P-R-O-C-E-E-D-I-N-G-S
	8:30 a.m.
CHAIRMAN SALOMON:  Welcome, everyone, to the second day of the BRMAC meeting.  And what we'd like to do to start off with is introduce Kathy Zoon, the Director of CBER and Jay Siegel, the Director of OTRR in CBER to present a certificate of appreciation for Committee service.
MS. ZOON:  Good morning.  And it's a great pleasure always to attend our advisory committee meetings and take the time to recognize the service that our advisory members give us, and to recognize how important the advice that these members provide to the Agency on many difficult and important issues.  And today I have the pleasure of giving Dr. O'Fallon official recognition for his service on the BRMAC.  He has been one of our outstanding members, and I want to thank you from the Center's perspective, not only for your contributions on the BRMAC, but your participation as a consultant on some of our other advisory committees.  And we look forward to working with you in the future.
I always say this in gist, because it seems once you're on an FDA advisory committee you're asked to call back to service for important issues that the Agency faces.  And I'm sure, Dr. O'Fallon, we will be asking for your help along the way.
But as a special recognition, we have a plague and a certificate we would like to give you and to then say thank you very, very much.
DR. O'FALLON:  Thank you very much.
DR. SIEGEL:  		You know, we never rehearse this and it always seems awkward. And I think the reason is because it really only takes one person to do an introduction, but I always feel like, you know, after years of working together and receiving the donations of time -- well, they're not donations.  I guess we pay you well with the Government per diem
DR. O'FALLON:  That's called a donation.
DR. SIEGEL:  But I do feel like I have to express my gratitude.  Dr. O'Fallon, your contributions I guess in the first two or three years you were on our committee as we dealt with many clinical trials and drug approvals were extraordinarily insightful and valuable.  And we had a talk, you know, a couple of talks over the last couple of years as we moved to other equally critical but very different sorts of issues in product development for cell and gene therapies as to just viewing together and assessing what your role would be.  And I have been endlessly impressed with the value of your approach to data in general and insightful comments about how to look at data and how to assess what we're looking at, and how to collect data and how to evaluate the data that we've collected.  They've been extremely helpful and we're most appreciative and I think most fortunate to have such a distinguished scholar, scientist and statistician in our group.  And so thank you very much.
DR. O'FALLON:  Thank you.
CHAIRMAN SALOMON:  Well, given the 45 second rule that we had, Kathy gets the television.  My wife made we watch that.
I also just would like to say that transplanters like myself are a dime a dozen, and aren't missed when we roll of the committees.  But Michael really represents and has continued to represent for me a really unique perspective.  And I'm always looking forward to his contributions.  There's no way we're going to replace you, Michael.
So in the beginning of this Session III of this meeting we're going to pick up the theme of long-term follow-up in gene therapy.  And this is an issue that came up in the last meeting in November and generated quite a lot of concern by many of us that transcended issues regarding sponsors and their responsibilities and issues regarding investigators and their responsibilities.  Because the issues here, in my opinion, are extremely high.  
On one hand these therapies, and hand-in-hand the other area that I'm interested in xenotransplantation, I mean in both these areas the public is appropriately aware of issues that we're manipulating genes and other tissues in such a way that you can't look at two and three year follow-ups with any sort of surety that you're covering all that might happen later.  And everyone in the room here is well aware of that.
However, we're also well aware of the fact that this transition in our thinking is easy to talk about, but when one deals with the practical reality of taking four or five year grants, for example, and talking about 20 year follow-up, that these have just profound implications on institutions, responsibilities of individual investigators as well as small biotech companies and large PHrMA.  So this is really a really serious set of discussions.
It's easy to talk, but we really need to make sure that whatever decisions we make, make sense, can be pragmatically administered in all these different institutions and not cause such a situation that it would be a damper on investigation, particularly in academic institutions.
So, with that background, these were issues that we grappled with already and certainly have much more to talk about.  And so I'd like to introduce Philippe Bishop.  Dr. Bishop's in the Division of Clinical Trial Design and Analysis at CBER.  And he's going to introduce the whole issue.  Then we're going to have a presentation from UNOS, which Philippe will introduce.  And then we'll go on to an FDA presentation.  And then at that point we'll end our discussion.
DR. BISHOP:  Well, thank you very much, Dr. Salomon.  Good morning, members of the Committee.
Last November Carolyn Wilson and I presented issues pertaining to the long-term follow-up of subjects involved in gene transfer studies.  And what I would like to do today is to resume this discussion.
Dr. Wilson presented issues pertaining to vector classes with potentials for long-term risks.  And in our discussion last November she outlined a number of factors that can influence long-term risk, including two vector characteristics; namely integration and replication, but as well as other factors such as the route of administration for these vectors.  And then yesterday in addition to Carolyn's talk, we heard from Dr. Chanock that the immune status of recipients is also very important in considering potential risk.
My discussion last November focused on barriers to long-term follow-up as expressed by some of the current sponsors of gene therapy trials.  And what we heard from our sponsors is that essentially long-term or life long monitoring is very burdensome.  It requires an awful lot of resources to implement.  The clinical follow-up is not always practical, especially for participants in these trials whose life expectancy is measures in decades rather than months.
In addition, we heard that it is very difficult to obtain autopsies for a number of reasons.  Something else that we heard is that unless there is a clear reason that is obvious to all of the investigators and the individuals who are collecting these data, that it is very difficult to collect complete data sets or to get people motivated to collect these complete data sets.  And, therefore, the clinical relevance currently is not always obvious to those individuals who are charged with collecting this data.
And then we heard from our sponsors that it is also an unusual commitment.
Your Committee, Dr. Salomon, considered all of these points and made some recommendations to CBER to consider in formulating new policies and maybe new guidance with long-term monitoring of individuals in gene therapy trials.  And let me try to summarize in just one slide.  Certainly there was a lot more discussion that ensued around each one of these points.
But I think there was overwhelming consensus from your Committee that long-term clinical follow-up is indeed needed in order to determine the true risk to participants.  There is public concern in addition to scientific need to really document what those risks might be.
In addition, your Committee pointed out to us that rather than focusing on vector classes, we should really consider principles that would be governed by the biological properties of gene transfer vectors when considering changes in long-term follow-up.
In addition, the practical barriers that we had enumerated were very important consideration for future guidance.
Your Committee pointed out to us that there are existing models and successful organizations that have been able to collect valuable information.  And you pointed out to us that the United Network Organ Sharing organization, as well as the International Bone Marrow Transplant Registries would be examples that maybe we could learn from them when formulating new guidance.
What I would like to do today is to turn over the podium to two distinguished representatives from UNOS, Dr. Mary Ellison, who is Director of Research and Mr. Berkeley Keck, who is Director of Information Technology to actually come up and share with us some of their experience at UNOS.
After their presentation, I will come back and resume my discussion about long-term monitoring.
Dr. Ellison, Mr. Keck.
DR. ELLISON:  Thank you very much.
Berkeley and I were asked to come today to share with the Committee how it is that UNOS came to collect follow-up data on transplant recipients and what our experience has been with the collection of these data.
The story of transplant follow-up data collection began with the National Organ Transplant Act in 1984 which provided for the Secretary of Health and Human Services to establish and maintain a scientific registry by grant or contract.  The registry would include such information regarding patients and procedures as the Secretary deemed necessary in order to evaluate the ongoing success of organ transplantation.
Further, the Act provided for the Secretary by contract to establish an organ procedure and transplantation network, which a lot of people know as the OPTN.  And in 1986 the first OPTN contract was awarded to UNOS.  And in '87 that was followed up by a contract to establish the scientific registry through which data, the follow-up -- more than follow-up data were to be collected.  We collect data not only on recipients after transplant, but also on donors, demographic and clinical characteristics, candidates on the waiting list, information about the transplant procedure itself, and then follow-up data thereafter.
In 1986 Section 1138 of the Social Security Act stated that in order to be a Medicare or Medicaid provider transplant hospitals and organ procurement organizations must be members of and abide by the rules and requirements of the OPTN.  However, the authority for establishing conditions of participation in Medicare and Medicaid reside only with the Secretary and cannot be exercised by another party, including UNOS, without Secretarial oversight.
Therefore, in 1989 a Notice of Proposed Rulemaking was published stating that No OPTN policies could be legally binding without a mechanism for Secretarial oversight.  And subsequentially the UNOS contract with HRSA was amended to indicate that OPTN policies, including those governing data submission, were voluntary.  And UNOS adopted its own private corporate policies requiring data submission, policy compliance as a condition of UNOS the company membership, but no strings could be attached to OPTN membership if hospitals did not submit data according to UNOS policy.
The OPTN final rule was finally implemented in March of 2000, having been originally published in '98 and subsequently amended.  And this rule does lay out the structure for Secretarial oversight mentioned in the NPRM of '89.  And it stipulates that the OPTN Board of Directors with at least 60 days notice shall provide proposed policies that it recommends become enforceable, and that the policies will not be enforceable until approved by the Secretary.
Therefore, until and unless data submission policies become enforceable, as approved by the Secretary, UNOS can only do what it has always done in order to get follow-up, which is to hound, cajole, threaten, entice and use peer pressure and a corporate "member not in good standing" status as determined by the UNOS Membership and Policy Committee.
To date, as a peer, consensus-based organization, we think that UNOS has been relatively effective in achieving data submission compliance through its voluntary system.  And to give you more information about the factors related to compliance and about the success that we have had in this, I'm going to turn this over to Berkeley Keck, our Director of Information Technology.
MR. KECK:  The current iteration of the UNOS data collection system was implemented in October of 1999.  It is completely Internet based through a secure private site that we administer in Richmond at UNOS.  We currently have over 6,000 users for that system that are imputing data into a rather large database of 16,000 data elements.
We collect information from the time of wait listing throughout the listing period, the transplant event and then follow-up for the lifetime of the transplant patients.
For the follow-up system, it is basically event driven in that the event being organs have been procured from a cadaveric or living donor, and the OPO or transplant center comes into our system and lets us know that those organs have been procured.
We collect data about those organs which then triggers us to get transplant centers to remove patients from the list.  And we collect standardized data on all of those.  That allows us to classify the event being, more or less, the organ type.  We follow the organs from that point on, which determines our future data needs.  And the computer automatically will generate records based on those needs that we determine.
We are currently generating between 500 and 600,000 records a year of various types.  We have -- I lose count sometimes, but I think right now somewhere between 25 and 30 different data collection systems or form types.
We collect data specific to the event at the time of the event; clinical information, demographic information and use that to kickoff our follow-up for the rest of the lifetime of the patient.  The computer will automatically generate those records on the transplant anniversary date.  They are inserted into the database and those centers that are responsible for the follow-up are notified of the fact that those records have been generated and to come in and please fill them out.
Achieving compliances, Dr. Ellison mentioned that is a challenge and there have been several barriers to compliance and some solutions that we've implemented that I think have been fairly successful over the years to help us achieve compliance rates that we do have.
Obviously, barriers are a burden of reporting and, you know, there are human resource factors time and financial implementations to supplying the level of data that we require.  The centers are not paid to provide this data to us.  It is voluntary, as Dr. Ellison said.  And as health care has changed and there has been less and less money for this kind of thing in the transplant centers, the people that have been available to provide and fill out the forms have decreased.  And so that creates time constraints on the people that are there, as well as cost factors for the transplant centers.
The volume of data that we collect has grown tremendously over the years.  I first became involved with the UNOS database nearly 10 years ago.  At that time there were 3,000 data elements total that we collected.  Now there are over 16,000 and it grows every time we have a Board meeting.  So, it's constantly changing.
And that, I think, is one of the barriers that committees need to look at and begin to control.  As technology advances there is a push to collect more and more, and more data.  But as more data needs to be collected, compliance tends to drop because of the burden of reporting factors that we've already discussed.
One of the issues that we've seen is mobility of the patients.  We are a much more mobile society than we've ever been and loss to follow-up does become a problem over time.
Along with that is managed care, and that has become an increasingly big issue with follow-up of patients in that managed care corporations, insurance corporations are not allowing patients to be followed at the transplant centers following the initial transplant surgery.  They will go back to their nephrologist or their cardiologist who, you know, can be anywhere and centers tend to lose track of them because of that.  And I think that is probably the most significant issue that we face today.
Some solutions that we have implemented are allowing -- we have developed import schemes for people that have large databases in their own centers to create files and import them directly over the Internet into our system as long as they meet the standards that we have developed for all of the data that enter.
We do have computer generated reminders that we email out to those people responsible for providing the information.  And that has helped. We send compliance reports to program directors, to the transplant administrators and that provides them with a method of evaluating those people that are responsible for imputing the data.  
And electronic submission, we now are getting 98 to 99 percent of all of our data through the Internet system.  Very, very, very few paper forms are coming in at this point in time.  And we've had the system up, you know, for about a year and a half now.
While electronic submission may seem to help compliance, I will say that that alone does not.  What it does help is improvement in the quality and completeness of information that you get in terms of online editing, rejection of information that does meet the standards at the time of entry.  You know, those people entering the data know it doesn't meet the standard and need to, you know, provide complete, concise information based on the standards and edits you've built into your system.
The other thing it does is increase the timeliness a little bit because you are not getting pieces of paper that get shuffled around your organization, potentially get lost and then have to be hand entered.  Once it's in, it's in and it's there available for research immediately.  So the timeliness factor, I think, is helpful.  But, we have found that centers that were noncompliant on paper or slow to comply on paper are still slow on comply on electronic submission.
I thought you might be interested in some of our experience with achieving compliance over the years.  For follow-ups that we have generated in 1998 and 1999 these indicate percentages of that data that were received within 3 months all the way through 12 months.  And to date, for both of those, we have received 96 and 91 percent.
Loss to follow-up, also as I indicated, is a problem for many patients and many centers.  And to give you an idea of the longer term, I have '90 and '91 follow-ups that were generated.  Of those transplants that occurred in '90 and '91, these are the percent that are lost in our system.
As you can see, the largest area is kidney, and that is because those patients tend to go out and be followed locally as time goes by.
And then for short term loss to follow-up, I think from '98 and '99 transplants those figures are fairly low.
So that gives you an idea of the effectiveness of what we're doing.
And that's all I have.  Thank you.
MS. MEYERS:  Before you go, could you just say what do you do with the data?  Who studies it?  What kind of reports do you get?
MR. KECK:  What do we do with the data, how do we use it, what research is done?
DR. ELLISON:  The data are used in a variety of ways.  One of the primary uses is for transplant policy development,the OPTN committee and Board use the data in their deliberations over how to rank patients on the waiting list, and various other policies.  
We have a public data request system.  Anyone; transplant, profession, scientist, patients, Boy Scouts, anybody can call a request data and analysis.  We provide data sets for researchers.  
A primary use are deliverable reports required under contract, our HRSA contract: hospital specific outcomes reporting; the annual data reports that UNOS publishes; specific studies that the government is interested in having done or that the transplant community is interested in having done or specific individuals doing research.
CHAIRMAN SALOMON:  I would give you an example.  Actually, let me do one thing.  
Dr. Ellison, if you could join us here, I'd like you to join us at the table for the discussion that follows, just because we really value the kind of input.  And I think that some of the members have some more questions for you.
DR. CHAMPLIN:  Yes.  Can you continue to get organs through the network if you don't report?
MR. KECK:  Yes.
DR. CHAMPLIN:  The National Marrow Donor Program for bone marrow transplants has a policy where you need to submit data, and if you're delinquent or deficient in your data submission, both in quality as well as timeliness, they will stop you from receiving further bone marrow transplants through the system, which is a powerful incentive.
DR. ELLISON:  Well, the OPTN does not operate that way, because the data submission policies are voluntary.  And if you don't submit your data, you can't be excluded from participation in the OPTN.
CHAIRMAN SALOMON:  I mean, just to show you kind of how it works, I was writing a review for the FASEB Federation, Federation of American Society for Experimental Biology, and I had a question about needy and waiting times because I was trying to make a dramatic point about the waiting list.  And I went to the UNOS website and there was able to review a number of different online reports, but I still had a question.  And given the quality of what I was trying to write, I wanted the perfect data.  And I actually emailed them, within 3 days had gotten a spreadsheet with the specific answers to my question.  And I thought that was really a remarkable testimony to the quality of the way that the system works.
DR. SAUSVILLE:  		Could you give some general rough idea of the magnitude of the cost associated with running the contract and how many sort of dollars per deliverables from your point of view?
MR. KECK:  I can tell you what my budget is from an IT perspective in terms of collection and implementation of the data system.  And it's I would say around $6 million a year for the personnel, the equipment, the maintenance of the databases.  But it is a very large database and it is dynamic.
CHAIRMAN SALOMON:  So I should add just so that everybody has an idea of what the size here.  We're talking about there are 75,000, and that'll change, patients on the waiting list right now.  There are about 20,000 transplants of 13,000 kidneys, about 5,000 hearts and a distribution of the rest of lung and pancreas.  
MR. KECK:  Right now we're following around a quarter of a million patients that are alive at their last follow-up.
DR. CHAMPLIN:  Now, this is going to -- the National Marrow Donor Program probably is analogous organization for bone marrow transplantation and they have a system for reimbursement, which is important.  And that there is a fee that they will pay per form that is submitted.  And this is one of the big issues in follow-up, of course, if you're going to have people dedicated to doing this work, they have to be paid somehow and that reimbursement from the organization is a logical process.
In gene therapy it's going to be more complex, because you don't have the opportunity, at least, to simply limit their access to genes or DNA because that can be obtained through a number of ways.  But I would think that you really need to deal with the center of the academic center in some fashion and require assurance from them that they would be reporting over some length of time, because they're probably going to be the only stable player in this whole ball game.
And the investigators and the junior faculty move frequently.  Their half life in any one institution is often short.  Companies come and go.  But the academic centers, by in large, are more stable than any of the other components of the system, and they're the ones that you can probably count on for some long term follow-up.  But they need to have some budget for this, and so somehow that has to be built into what ultimate system is provided.
CHAIRMAN SALOMON:  If we're going to continue discussion, at this point it should only be just some questions toward UNOS in terms of their practical stuff.  Then what I'd like is Philippe to complete the process by kind of focusing on what he wants to, and then pick up these sort of discussion points again.
Yes?
DR. SIEGEL:  So you showed data on lost to follow-up from 10 or 12 years ago -- from patients over a 10 or 12 period that was in the neighborhood of 80 percent, I guess, in pancreas and maybe 90 percent or better for other organs.  My question is could you summarize what is the extent of follow-up information that you attempt to get on those patients and how often?  How much data are you collecting on patients that were transplanted 10 years ago?
MR. KECK:  We collect, I would say, the follow-up forms in general on each organ is around 35 data elements.  And they are collected annual at the time of the transplant anniversary.  And we have follow-ups.  We're now generating our 13th year of follow-ups.  The UNOS follow-up system originally began in 1988.  But we inherited around 20,000 kidney transplant patients in 1994 from the ESRD Networks, and they have follow-ups that are over 20 years now.
DR. SIEGEL:  That's the same elements then annually for the remainder of the life of the patient?
MR. KECK:  Yes.
DR. CHAMPLIN:  I think one of the other points you illustrated that's going to apply here as well is that the patients come back if they feel they need to come back.  Now, if the center has some special expertise that they really require, and then over time there's more and more fall off as people go elsewhere for their care, they move around the country and they feel no obligation to stay in touch with you.  And if one is particularly treating diseases where perhaps the gene therapy didn't do anything or that no ongoing care is necessary, it's going to be very difficult to keep tabs on those people beyond the first several years.  And when you talk about 20 years, I would suspect it's going to be very difficult to keep track of those individuals.
CHAIRMAN SALOMON:  Michael, Karen and then Amy.
DR. O'FALLON:  16,000 was the number that I heard up there, 16,000 data elements per patient -- per organ, I mean.
MR. KECK:  That's in the entire database there's 16,000 different data elements.  And we have 6 organ types that we follow.  Some of the data are common amongst them, but on any given patient I would say that we collect 500 or 600 different data elements throughout their span of collection.  And that changes because the information we collect at the time of listing through the time of transplant changes frequently.
DR. O'FALLON:  So how do you define compliance?  You had 90 plus percent compliance in one year.  It's certainly not with respect to everyone of those data elements?
MR. KECK:  It is compliance with the follow-up forms only, those 35 that we collect on an ongoing basis.
DR. WEISS:  Are there any procedures that you put in place additionally when you get a report back of lost follow-up?  And much sort of control and ability do you have to dig deeper to try to really retrieve information when you get a lost to follow-up type of report?
MR. KECK:  Not a lot.  You know, that would require a fair amount of staff to do that, and traditionally we have not done much of that.  However, I will say that that is one thing that the electronic system has changed, because for the first time centers were able to see, view, manipulate and modify all the information they have ever sent to UNOS.  So every patient they ever had, they could then all of a sudden follow-up, you know pull  up on the screen and see what we had in our database about that patient.
And some of those patients that we had lost have now been resurrected, so to speak.  And that's actually an issue that we have on our plate to discuss back home next week is how are we going to handle those situations.
DR. PATTERSON:  I was wondering if you could address three issues?  One is access to the data in the registry both to the public in general and the scientific community.
Secondly, if you could discuss the type of clinical outcome information that you collect on patients.
And thirdly, and this reflects on the second point, outcomes.  How do you handle information from transplant studies that are conducted when there's an investigation on new drug application underway and an investigational agent that's being studied, and therefore there may be commercial interests involved and some of the outcome data may be viewed as commercial confidential information?  And answer that question with a mind to who has access to the data and what type of outcome data you collect.
So, three points:  access, outcome and when you have a commercial sponsor or an investigational study underway.
DR. ELLISON:  Virtually no one has access to patient identified information.
DR. PATTERSON:  I should just interject, I don't even want to go down patients' identifiable information.  I just want to talk about clinical outcomes of the transplant work, what were the adverse events or complications not traceable to an individual patient.
DR. ELLISON:  We produce data sets upon request by anyone wishing to look at data.  Hospitals, of course, have access to everything that they have provided.  But researchers wanting more detailed information can get data sets that have identifiers encrypted.  And they can see the specific data elements so that they can associate any of the variables that we collect with regional characteristics, status, organ type, procedure type, that kind of thing.
CHAIRMAN SALOMON:  Mary, I think that is not clear to Amy is if I'm at a center, like University of X, and I'm doing a study, there's no way to get that kind of data -- I'm not talking about patient identifiers -- out of that system.  You can find out like how many kidney transplants and what their survival was in region 5, which is the region we're in.  But not a subset of patients within University X.
DR. PATTERSON:  If I may just try to clarify.  What I'm trying to get at because this whole discussion is aimed at shedding light on how this system is applicable and may provide insights into data collection for gene transfer research and clinical trials.  And one of the concerns and questions among investigators and commercial sponsors in gene transfer for the types of data that both FDA and NIH are proposing to collect, is who has access to this information.  And is information about outcomes, adverse events, things working, things not working; similar to the types of data you collected.  How long were survivals?  Did the organ function properly?  What rates of rejection did you have?
Are those types of information that in the transplant community, and especially when a commercial sponsor is involved, are viewed as commercial confidential information?  And I'm not talking about things that are traceable to an individual patient, per se, but I'm talking about data that may be traceable to a particular drug regiment, a particular investigational agent, a particular organ that drugs are administered through a particular route.  Because I think this is a very critical question for the development of the database in gene transfer and what types of data are collected long-term and certainly types of data that are shared with the scientific community in gene transfer.
DR. ELLISON:  I don't think that historically we've been involved in much of that.  The hospital specific data have been considered confidential commercial information, and there is on the horizon a discussion of broadening the data release policy such that hospital identifiers are available.
We don't do much analysis for pharmaceutical companies for FDA approval.  We have done some of it for them. We provide them the analysis and the data sets.
CHAIRMAN SALOMON:  So the first question is you can't even now breakout hospital specific data.  So if you know that at this hospital we're doing a trial with such-and-such a drug, you can't get that data.  The hospital can, but then that's the investigator.
But the question, Mary, if we do a kidney transplant and we use an investigational drug; it's listed on the data entry form for that kidney transplant patient or that heart transplant patient that they got cyclosporin, prednisone, celsept investigational drug, right?
DR. ELLISON:  Right.
CHAIRMAN SALOMON:  Okay. So that's what Amy's concerned about.  Can anybody get at --
DR. ELLISON:  The participants in the study --
CHAIRMAN SALOMON:  Can anybody get to your system and say the 10 kidney transplantations done with investigational X, what was their one year outcome, instance of rehopsitalization and rejection rate?
DR. ELLISON:  Not now, and the new regulations stipulate that such data be made available to bona fide researchers.  And the next step is for the data release policies to be reviewed in light of that.
MS. LAWTON:  So currently as a member of the public if I came to you and said "I want to know that data," you couldn't give me that information, is that correct?
DR. ELLISON:  Not with hospital identifiers.
MS. LAWTON:  No, I'm not interested in hospital identifiers.  I'm interested in generally if I come to you and say "I would like to see for all kidney transplant patients that were given cyclosporin, what was the outcome in those patients.
DR. ELLISON:  Yes.  Yes.
MS. LAWTON:  You can give me that information?
DR. ELLISON:  Yes, we can do the analysis an we can provide the data.
CHAIRMAN SALOMON:  But she's asking not for cyclosporin, which is an FDA approved drug.  She's talking about for let's say rapamyacin when it was being studied.  Could you have gone in during the rapa studies before it was FDA approved and track all the kidney transplantations on rapa?
DR. ELLISON:  No. 
CHAIRMAN SALOMON: And the answer is no, I don't believe so.
MR. KECK:  Well, it's yes and no.  We collect information on all of the FDA approved immunosuppressants.  We start putting them on the form when they're in phrase three trials or we start seeing a lot of centers wanting to write them in in a report that they're giving this drug.
We do not release to anyone other than the manufacturer of the phase three drug the data or information about that phase three drug.
Now, we do analysis on the FDA approved drugs, and that information is readily available to anyone that wants it.  But other than that, we do not release it and I would think that the Committee would say that if it's not approved, we're not going to release that information.  Although they may, I don't know.
MS. MEYERS:  Can I just clarify?  In other words, if I wanted to find out what the long term survival of somebody on cyclosporin is compared to  SK506, you would be able to tell me?
MR. KECK:  Yes.
DR. SAUSVILLE:  Actually then I'm confused.  I mean, SK506 when it was investigational, I mean, you could break that out at that point in time in comparison but you couldn't -- 
CHAIRMAN SALOMON:  Only when it's FDA approved.
DR. CHAMPLIN:  The data, presumably, is there it's your policy presumably not to release data on investigational projects that are ongoing?
MR. KECK:  Yes.
DR. O'FALLON:  You've been saying you do the analysis and then send the reports. Is that what happens?
MR. KECK:  Yes.
DR. O'FALLON:  So you don't send the data if Abbey requested it, you'd send some sort of a summary.  Is that a standardized -- do you have a standardized sort of way that you do that or does she get to tell you how she wants to receive this comparison?
DR. ELLISON:  We do it both ways.  I mean, we can do it either way.
DR. O'FALLON:  I'm amazed your budget isn't higher than you said it was.
DR. ELLISON:  Well, his budget is separate from my budget.  I mean, I have the analytical staff, so the programmers and the statisticians.  
DR. SAUSVILLE:  So he said $6 million.  What approximately is your budget?
DR. ELLISON:  About 1.8.
DR. SAUSVILLE:  That's pretty good.
DR. CHAMPLIN:  The International Bone Marrow Transplant Registry does a lot of the same things and depending on the nature of the request, if it's a simple thing, how many transplants have been done for this diagnoses and what's their crude survival; they can spit that out instantly.  There are other questions, of course, that are a research project to try to ascertain is cyclosporin better than techrolimus.  You know, that you need to do a risk adjusted analysis, which is complex, and there is a several month project.  So, those kind of things have to be done accurately and scientifically and so depending on the nature of their request, you may or may not be able to get a straightforward answer.
DR. SAUSVILLE:  So, Dr. Champlin, an organizational question.  The Bone Marrow Transplant Registry is different than the organ transplant registry.  Why isn't the bone marrow considered an organ?
DR. CHAMPLIN:  It's a tissue.  But it's fundamentally, you know, there's different problems involved with bone marrow transplants than with solid organ transplants, and the field just naturally evolved to have a sort of separate system for analysis of the data.
The IBMTR is a voluntary registry, about half of the bone marrow transplants and blood stem cell transports are reported to that organization.  And they do pay a reimbursement fee, which is sort of minimal for the data being collected.  When they didn't pay the fee, there was a lot less data submitted.  So that was actually an important component to actually getting participation.
And they serve much of the same role as has been described for UNOS in terms of providing information to the public regarding bone marrow transplants.
DR. SAUSVILLE:  Presumably this contract has been running for about 12 years or so, is that the -- right.
CHAIRMAN SALOMON:  Actually islet transplantation is also not at UNOS, unless it was transferred there recently, wasn't it?  Yes.  Okay.  So for a long time, though, you know UNOS had took a position that it was organs which had a lot of historical reasons for it, not cell transplant.
DR. ELLISON:  I felt we sort of got bogged done in the investigational studies question, and I didn't address Dr. Patterson's questions about what exactly we collect in the way of clinical information post transplant.  It's basically graft survival, patient survival, what immunosuppression they're taking, whether there have been any rejection episodes since the last follow-up, whether they've been hospitalized since the last follow-up, whether they're working.  And we've recently added questions about development of cancer.
DR. PATTERSON:  May I just ask one follow-up question?  How do you handle the instance when someone is on a combination regiment.  They may be on an investigational agent as well as an FDA approved drug and Abbey calls you and asks for the information of how many people with kidney transplants are in shape or form taking cyclosporin, what is the survival rate on them?  How do you give that data, particularly since there's a significant subset of those patients may in fact be on investigational agents as well?  How do you provide data that's comprehensible to those who ask for it?
DR. ELLISON:  Well, we provide a checklist of immunosuppressant agents and they put cyclosporin, yes, steroids, yes.  And it's a little tricky. There's not much of -- the granularity of the immunosuppression data is not -- we don't collect dosages, we don't collect information about regiments.  We know what they've been taking since the last follow-up, but we don't know exactly in what combination.  The immunosuppression data have limitations.
DR. KEEGAN:  Could you possibly expand on your cajoling process in terms of those people who are compliant; how many people comply on the first attempt, how many attempts will you make, is it only electronic at this point or do you send additional types of requests like letters and things like that?
MR. KECK:  It's every month we send a paper report to the  person at each program that we call the data coordinator, and sometimes data coordinators will service multiple programs,  of all the forms that are what we call outstanding.  And it's broken out by groups of days outstanding in H, analyzed, and that kind of thing.
Every other month we send that very same list to transplant administrators who are more or less like hospital administrators for the transplant programs.  And often times they are tasked with ensuring that all the requirements for the transplant program were met, data being one of them.
And once a quarter we send this compliance report of percent compliant to their program director of the program to let them know what their compliance is with submission of data to UNOS with the incentive being that most programs are going to want their information up to date because it is used for center specific survival rate reporting.
In the past we would send printouts and say "Here's all your data we're going to use for this report, please verify it."  And that gave them a chance to sort of get things cleaned up. That did not prove cost or time effective in terms of getting the information out.
We don't do that anymore, so now we are beginning to see people keep up with their data a little better.
We do call centers that are extremely noncompliant and ask them is there a problem.  What's going on?  Is there something we can help you with?  And often we find that the person that did the forms, you know, quit and they haven't replaced them or the person that does the forms is on maturity leave and she'll get them caught up when she comes back, and that kind of thing.
But people that don't meet the standard of what we consider 99 percent of your forms within 12 months of their due date, get referred to the Membership Committee and go through a deprocess there.
DR. CHAMPLIN:  Yes, there's some parallel and nonparallel things, as I would see it, with gene therapy.  Part of the compliance is related to the fact that they need to collect this same information for their own institution.  Often they need to provide that for insurance contracts. And they also want to remain a good member in standing in the transplant community and the colleagues that they're working with.
It's not totally clear that this will apply to gene therapy where there could be a sort of startup group that succeeds or doesn't.  And the big issue is going to be the ones that don't succeed.  Now the ones that fail and breakup and go away, they have no incentive because they're not continuing to participate in any program to maintain their long-term follow-up.  So the successful ones, of course, will be part of the team and the community and be leaders, even, but the failures are the ones that are going to be hard to keep track of.
CHAIRMAN SALOMON:  I think that's an excellent segue into Philippe's presentation.
MS. ZOON:  Just a brief question.  Can you talk a little bit about the security of the data and do you have any problems with people inadvertently getting into your database?
MR. KECK:  No.  Yes, it is an Internet based system, it is a private site.  It's password and user name protected, behind firewall -- behind two firewalls, actually.  All the sending through, back and forth on the Internet, it's 128 encrypted.  And we have been certified by HIRSA to be safe.
CHAIRMAN SALOMON:  Philippe?
DR. BISHOP:  Thank you Dr. Ellison and Mr. Keck for your valuable input.
Now to resume the simple task ahead of us, which is the problem of long-term follow-up of subject and gene transfer protocols.
Before I go on to resuming the comments from the Committee back in November and then uplining a sketch of what may be a system for discussion for long-term follow-up, I would like to revisit the guidance for retroviral gene vector studies.  And the purpose for doing this is twofold.
Number one is to refresh everybody's mind in terms of what it is that is currently recommended, but also to clarify one point.  Since the last BRMAC meeting a number of our sponsors were under the impression that maybe they didn't need to meet and spirit the current recommendations.  And I think it's important to stress that reviewers at CBER are currently when they look at retroviral gene vector studies are applying the current guidance document.  And it is the expectation of those reviewers that there is some attempt at meeting those recommendations.
So very quickly, the guidance document, the current guidance document was finalized on October 18, 2000.  It is available on our website.
The document talks about methods for testing for RCR and also defines some time points that should be obtained for blood sampling of patients or individual participants in gene vector studies.  And namely being at baseline are 3 months, 6 months, at one year.  If followed those results are negative for RCR, then yearly thereafter archival of those specimens is sufficient.
In addition to the laboratory monitoring there is also provisions for clinical follow-up, and it recommended that an individual be seen at least on a yearly basis for clinical evaluation.  And as part of this clinical evaluation there should be an attempt at least eliciting some clinical history pertaining to denovo cancers, to neurologic disorders, hematologic disorders.  In addition, the document recommends that autopsies be obtained on individuals who may have expired and that tissue sampling be performed and RCR testing done on those tissues.
Currently there are two mechanisms for reporting those results.  The laboratory and clinical results that would be positive, either for RCR or there was a significant clinical finding, it is currently the expectation of CBER that these be reported as expedited reports.  And then all of the data should be provided to us in an annual summary.
Now to go back to our discussion, last November the Committee felt that life long monitoring might be a pretty big task for sponsors of gene therapy trials and rather than life long monitoring, it was suggested that we consider long-term follow-up monitoring.  So let me try to summarize what your recommendations were.  And essentially when we talked about long-term monitoring we implied that this would be monitoring that would take place approximately a year following the registration of a participant recognizing that monitoring that takes place during that first year would be probably specific to protocols and well described in each individual protocol.
So, for the purpose of this discussion we will try to focus on long-term monitoring from one year and beyond.
The Committee had envisioned in an attempt to alleviate some of the burdens of the sponsors of gene therapy a bi-phasic long-term monitoring plan, one that might be intensive for up to 5 years.  This, by intensive, we mean both a laboratory component as well as a clinical component in terms of the information that would be derived.  And then subsequent to this the recommendations that your Committee put forth would be that we would focus on clinical information looking for rare events above the general population.  And in order to do this, that this information needed to be collected and somehow be put into a centralized place in order to be visited periodically and analyzed for trends.
Once again, your Committee outlined to us general principles that revolved around the properties of gene transfer vectors.  It was your recommendation that these properties govern our future recommendations for long-term monitoring; these including replication or the potential to generate replicating virus, integration and then also with looking at vectors with altered tropisms or vectors with long latencies.
What we have done at CBER, we've taken the summary of your recommendation and try devise an outline, a sketch for discussion of a proposal that could maybe be the basis for formulating future guidance with long-term monitoring.  And what we have done is envision a three tier system.  And what I would like to do now is take you through each one of those tiers; tier 1 being the least demanding category and tier 3 being the most demanding category.
So let's consider tier 1.  It was the recommendation of your Committee that we have some provisions for studies that would involve vectors or studies that would involve essentially ex vivo gene transfer in non-replicating vectors that was put into cells with limited survival, probably less than 2 weeks demonstrated in vivo.  And that the recommendation was that these types of studies probably could be exempted from long-term follow-up as they did not represent a comparative significant risk compared to the other types of studies that may be going.  
So tier 1 would essentially encompass the types of studies that could be exempted from long-term follow-up.
For the purpose of discussion let me take you now to the other extreme, which is the most demanding tier, tier 3.
And essentially tier 3 would be all the types of studies that would employ the types of vectors that had the characteristics that we outlined:  replication; potential to generate replicating virus; integration; altered tropism of factors with latencies.   And you had envisioned that this is the type of studies that would fall into this bi-phasic long-term monitoring plan that would encompass both an intensive laboratory and clinical follow-up for up to 5 years and then move on to a focus that is primarily tried to derive meaningful clinical information maybe through a clinical questionnaire.
As part of this kind of program also it was recognized that an essential component should be patient education in order to ensure participation.
The intermediate tier, or tier 2, is essentially a category that would encompass all other gene transfer products that were not in tier 1 or tier 3.  And essentially for this category the laboratory component, which can be very costly to obtain and also the archival can be quite costly to sponsors, would be essentially eliminated and the focus would be primarily on trying to derive clinical information for up to 20 years via a clinical questionnaire.
Within CBER currently we have essentially six vector types or vector classes that are commonly used in INDs of gene transfer studies; retrovirual vectors, adenovirual vectors, plasmid, poxvirus, AAVs and the herpesvirus.
What I would like to do in the next series of slides is consider each one of these vector classes and see how they would be effected under the proposed system for discussion.
So retrovirual vectors have a high potential for integration.  They also have a potential for latency.  Currently it is required that lifeline monitoring be implemented for subjects involved in these trials.  Under the proposed system under discussion they would fall under tier 3, the intensive bi-phasic monitoring plan.
Herpesvirus by virtue of their high latency and the clinical implication there, and then also because they have the potential to replicate would also fall under tier 3.  Currently there are no recommendations for long-term follow-up.
I will refer everybody to the March 7th FDA/NIH Gene Transfer Safety Symposium for details on the AAVs.  There was much discussion there in terms of the potential risk of this vector class, but for the purpose of this discussion I will focus just on the principles that we were asked to consider in trying to group those studies under a long-term follow-up system.
AAVs has variable integration potential.  It has also the potential for latency.  Currently because of the safety concerns that were outlined at the March 7 Symposium there is long-term follow-up that is required of some of the studies that are currently under consideration at the FDA.  Under the proposed system they would fall under tier 3.
Plasmid vectors have a low potential for integration.  They do not replicate, they do not have latency.  Currently there are no long-term follow-up requirements.  Under the proposed system they would fall under tier 2 where clinical information would be obtained through a questionnaire.
Poxvirus is one of those vector classes that we are going to ask you to consider in a discussion that will ensure following my presentation, but poxvirus by virtue of being capable of replicating would fall under the second tier.  Currently there are no recommendations for long-term follow-up.
Adenovirus have the potential for integration.  Also have the potential for replication and currently long-term follow-up is not required.  Under the proposed system they would fall under the category 2 or where clinical information would be obtained.
I would like to point out, actually just in passing, some information that is thought provocative that just appeared in Journal of Virology where essentially the traditional concept where you need to have sustained oncoproteins expression for adenovirus in order to have transformation is being -- at least there is a system that is being reported where present expression with subsequent clearance of adenovirus vector was sufficient in order to eventually lead to oncogenesis.  And the authors of that article proposed a "hit-and-run" mechanism leading one to believe that it might be theoretically possible to see malignancies appearing at a later date.
The proposal for discussion, we envision that data collection should be the responsibility of the sponsors.  This was articulated at the last meeting and there are good reasons for thinking this.
Number one, it's consistent with current FDA regulations that the sponsor be responsible for collecting this data, but also it provides an element of patient confidentiality.  
And normally selected data would be submitted into a centralized database that could be queried periodically for trends.
The type of data that a sponsor might want to collect in order to allow an effective process would be, of course, keeping track of patient identifiers, addresses, demographics.  Also keeping track to the study site so at least being able to link that patient to a study site.  And then also trying to understand or having some concept of when was the last time that the patient was seen at the study site.  
And because long-term follow-up would require clinical information that might not be necessarily derived from the study site, it might be in the interests of sponsors to consider maybe trying to keep track of who the current primary health care provider is in order to try to facilitate some of this information at a later date.
The type of data that we would envision or would at least might be useful in the database, as was suggested by your Committee last November, would be: Whether or not a participant is alive or dead, lost to follow-up; whether or not an autopsy had been performed and if an autopsy was performed, maybe having the results of the report.
The type of clinical information that could be included in this clinical survey would be the appearance of denovo malignancies, hematologic disorders, neurologic disorders, autoimmune diseases and vector reactivation being important with those vectors with latency.  And then, of course, for all vector classes the potential for chronic infection.
So, in summary I have revisited the current guidance that are specific for retroviral vectors.  We did not address other vector types or potentially new vectors that may be developed by industry.  The current guidance is for long-term monitoring for both laboratory and clinical information, and a component of this is a requirement for specimen archival.
The new proposal that is outlined for you for discussion is essentially a three tier system that is based on principles that were outlined last November, namely relying on vector characteristics rather than vector classes, and therefore would allow some flexibility to encompass maybe new vectors that may be introduced at a later date into clinical trials.
We have tried to limit the laboratory monitoring and archival to up to five years in an attempt to address the cost that may be related to lifelong archival specimens.  And we recognize the need to have some clinical information over an extended period of time for up to 20 years in order to try to detect rare events over background for the population being studied.  And we envision that this information could be sent to a central database for periodic analyses.
This is my last slide.  I will be happy to entertain any questions.  
CHAIRMAN SALOMON:  Philippe, why don't you join us and we'll sort of address questions to you and start the discussion as well.
Michael, do you have a --
DR. O'FALLON:  I think several times you used the term "study."  Certainly if the FDA gives approval these drugs or these cells would be implanted, not on study but we would still want the follow-up, right?
DR. BISHOP:  That is correct.  There could be some post-marketing commitments in order to continue providing this long-term follow-up.
DR. SAUSVILLE:  So, Philippe, could you give your vision of how this would work logistically?  I mean, in other words you mentioned at one point sponsors' responsibilities and then you talk about a centralized database.  So what do you see as the interface there?
DR. BISHOP:  Because these studies are done under INDs for the most part, and it is the sponsor's responsibility to collect the information that pertains to this IND, we would envision that the information very much like UNOS currently collects information from their transplant centers.  This process equivalent here would be that the sponsors would be charged with collecting that information.
And then we would envision logistically that some of that information could be forwarded to the Agency for inclusion into a database that could be queried periodically for analysis.
DR. CHAMPLIN:  But the precedent to this is just what we heard, you know, similar to the National Marrow Donor program where the government has enacted either legislation or the FDA, or NIH have had an RFP to develop a registry.  And in this case the registry's goal is to collect toxicity data and adverse events information.  And if you're looking to pick up increases in the rate of secondary malignancies or autoimmune diseases, these are going to be rare events.  So in one small study you're never going to be able to see these things; you need to be collecting all of the adenovirus trials and see among thousands of patients is there an increase among the expected rate of any of these major adverse complications, will that occur in that population.  
And I would think that the logical thing is you would require that people who file an IND pledge to enter their data into that system and then require that the institutions that are supporting, not the pharmaceutical sponsor but the academic centers that are doing the clinical trial, commit to having providing long-term follow-up the clinical information for this registry as part of their agreement to participate in the IND.
DR. SIEGEL:  Right.  There are a lot of discussions.  The Committee is aware that you've participated in some regarding the FDA -- with the FDA and the NIH and further database development.  And I think that's exactly what we plan to do.  Indeed, these data are currently databased, if you will, at the FDA.  As safety data come in, long-term or short-term, on gene therapy it goes into our database.  We're working in conjunction with the FDA to develop a more targeted database with enhance functionality specifically focusing on gene therapy.
In terms of sponsor responsibility, we're really talking about two different responsibilities.  One is the responsibility for collecting the data from the patient, something the FDA is not involved in in any areas that I'm aware of.  And the other is maintaining, storing and analyzing those data cross studies.  And that later responsibility definitely FDA and NIH will be very much involved in. 
On the data collection we have  been quite cognizant of the comment you made now and earlier, and probably at our past meeting as well.  And as you'll recall from our last meeting, Philippe talked about a survey, an informal survey of sponsors which raised some of those issues, too, about the role of the sponsor, the institution and the investigator.
Our current thinking along those lines is that we would, I think, pretty much along the lines of what you're saying.  We do not have a direct regulatory relationship with an institution where we can go to an institution and require a commitment for long-term follow-up.  But we have a legal opinion that says that it's well within our authorities when a sponsor proposes an IND gene therapy study to us to require that sponsor to have plans for long-term follow-up that might well include plans for how they will obtain long-term follow-up should the investigator leave or should the sponsor go out of business.  And such plans we would envision would, in many cases, involve arrangements and commitments from the institution where the patients are being treated.
And, hopefully, as we can outline what the follow-up entails and put that in the protocol, then those things could be costed out in such a way that the sponsor proposing the study would be able to determine whether they can adequately fund the real cost of their study including follow-up.
CHAIRMAN SALOMON:  Richard.
DR. MULLIGAN:  You know, the premise of this is that it's definitely a safety concept.  Is there any interest in collecting good news as opposed to bad news on these patients?  Because if there is any interest in having success of a therapy or something, which there ought to be a mechanism for, then obviously the guidelines that we set up are not really appropriate because things that may be safe or less risky may be just as likely to be good things as bad things.
So, I'm just curious.  I assume what we're talking is strictly a safety monitoring, but will there be anything in the database of interest to people that has to do with efficacy, anything like that?
DR. SIEGEL:  Well, FDA collects those data.  We're not sure at this point the time in the field that -- of a role, if any, of collecting that sort of data integrated across many different investigations which have different dosing routes, vectors, entry criteria one can logically say that there are safety concerns.  Does a particular vector class cause cancer or latent neurologic syndromes.  But when you get to the question of treating particular diseases, it's often very difficult to try to pool data from studies.  At least at the current point in time the design of studies of gene therapy at these early stages is so diverse that that's not a current focus.
DR. CHAMPLIN:  I would agree that as much as UNOS and the IBMTR and the National Marrow Donor program are looking at adverse events, they're also trying to look at efficacy issues.  And right now the field is in its infancy.  It would be difficult to do that in a major way.  But as things develop, hopefully in a positive direction, that would be a natural evolution of the database as well.  And so the logical process is to work with the Gene Therapy Society and community to put together the leaders to define the fields in the database that could be used ultimately for efficacy analyses as well as the public need for toxicity monitoring.
DR. SAUSVILLE:  There isn't a live column that they have.
DR. SIEGEL:  I guess what you're suggesting is it's just that at this point in time you could say, okay, for kidney transplants there's many different variable ways of doing it and you can, in a large database, study and look at those.  If we had one particular disease, let's say cystic fibrosis and many different investigations looking at fine tuning how to treat it, then you might want to be collecting outcome data for multi-study analysis of outcomes.  		But, yes, as I said, I think we're not there but I think as we envision our systems, and I know the NIH has expressed interest in this in terms of the nature of data collection systems, you want to build systems that will be able to address those sorts of questions as they arise.
CHAIRMAN SALOMON:  Richard, and then Amy.
DR. MULLIGAN:  The other premise of the difference between the classifications for the vectors is that essentially persistence of the genetic material is guiding us in terms of the way we do the long-term follow-up.  And I just wonder whether everyone's comfortable with that; that is a short term procedure can have a long-term sequel even though the genetic information isn't persistent.  And so you'll miss the kinds of toxic events that has to do with a accumulative effect of the treatment that may have a longer term effect. So if you have a CNS gene transfer that's even short term, like for brain tumor or something, you may well do some damage that doesn't manifest itself for a very long time.  
And it just seems like the total way we've looked at this is from the point of view of just what's the likelihood that the vector DNA persists?
DR. SIEGEL:  You want to specify the type of damage in that case that you're speaking of?
DR. MULLIGAN:  Well, there could be -- let's say there could be neurological damage due to an acute lytic infection that goes away.  And, you know, I don't think that's particularly unlikely relative to other adverse events you might have.  So it just makes the point that it's really the disease, first of all, and then the vector.  But I'm not so sure that it's so key to be fixated  on how long the DNA persists.  That line of reasoning is a very specific line of reasoning that pretty much, I think, has to do with integration causing cancer or something.  And there's many other kinds of things that could happen.
DR. SIEGEL:  Well, let me, and I'll cede to Philippe to address this further, but what we're talking about here are kind of generalized long-term safety data collection systems.  For every protocol in gene therapy or elsewhere we look specifically every experimental protocol at the risks of that protocol and what the data collection based on what the disease and the intervention are, what the specific data collection needs of that protocol are to be.
So one should not take this system to mean, even if you took a vector that might be type 1 but you gave it in a way that raised or gave a treatment or a gene, or whatever, that raised a risk of a long-term outcome that you wouldn't have to study that long-term outcome. 
Beyond that, it's my understanding of the system as discussed and based on earlier discussions with this Committee and others that it's not fully based on genetic, indeed on persistence of genetics and that there are other factors looked at.   
DR. BISHOP:  A couple of comments.  Number one, immediate adverse events that would occur under a protocol would probably be covered under the specific requirements of the study.  The purpose for long-term follow-up was to detect rare events in the total population and, hence, the need to have that data collected in a centralized fashion and analyzed periodically.
The focus, if I could say, is on clinical information.  And that is information that would be obtained through these clinical questionnaires for up to a period of 20 years, as was discussed last November.  The laboratory information that would be derived would be limited for up to 5 years.
So the emphasis is on clinical data that would be imputed into the centralized database for the majority of these patients with long term survival.
DR. MULLIGAN:  I think a good example might be autoimmune disease.  You list that as one of the things you'd look at.  And that's a very clear case where a short term gene transfer could well -- and let's say it's a lytic kind and it goes away, and there's no trace of it, could well have long term effects.  And that's not going to be dependent upon, really, very many characteristics of the vector.
DR. WILSON:  If I might just clarify.  Tier 2 is really designed with your points exactly in mind, and that captures all the other vectors that don't have those characteristics of integration and persistence. So, I think if you take into account tier 2, we've taken into consideration your point.
DR. MULLIGAN:  So really the only issue is the 5 years of actual specimen collection, was that right?
CHAIRMAN SALOMON:  This is really where I want to go next, and then sort of letting everybody just kind of follow their natural thing here, which is good, but what I wanted to do in a minute after Amy and Dr. Lawton have given their point, to go back and like just look at tier 1, and look at tier 2 and then look at tier 3 and get into this in a little more detail.  Because I think a couple of us have some questions about the specifics here, and I think that's what they need to hear.
Amy.
DR. PATTERSON:  Well first, I just wanted to offer NIH's commendations to FDA and the Committee for taking this issue up.  But I wanted to underscore a couple of points and then address a question that I think was raised by Dr. Champlin about scientific user community input into the design of these studies.
First of all, I think it's an obvious thing that deserves being stated that this must be an evolving strategy and the level of follow-up that's required over time will have to be titrated according to the data received.
And I think at your last meeting you very amply covered the points that this is a tremendous investment.  It's a tremendous investment by scientists, by the sponsors, by the patients who volunteer to be research participants that once the study's over, they still give time and part of their life to be followed. Therefore, I think there needs to be a tremendous amount of that and much broader expert analysis into the types of clinical follow-up, how those studies are designed.  Because to follow-up on Philippe's point that the detection of denovo cancer, neurologic or hematologic disorders that may be very rare events, that the design of those studies is going to be so critical.  And my concern is that we don't end up 10/15 years down the road with very heterogenous studies that really the results are comparable and a tremendous amount of resources have been invested by all and we have no data for medical or scientific utility.
And, therefore, I think that I would urge that the process here be that these recommendations move forward, and NIH is very willing.  I've talked to Dr. Siegel about this, we would like to hold a policy conference and a series of intensive workshops on this topic to get input from the scientific community, from the epidemiology community on how to appropriate structure studies that will give valid results.
CHAIRMAN SALOMON:  Alison.
MS. LAWTON:  Some of my comments kind of go along the lines.
I guess one of the things that I have a question on is around the database establishment.  We've just heard from UNOS that basically we heard it's about $8 million worth to keep this database maintained.  And so I do have a question around if we're going to ask the sponsors to make the commitment to this long-term collection of this data, do you have the funding, do you have that ready to be able to do this database?  And what kind of commitment are we going to have on how that database is going to be  put together so that the data that's collected can be analyzed and reviewed, and is useful?  And as part of that I would also emphasize I think it's very important we always talk about risk benefit, and the one thing we don't want to be just collecting safety information without understanding the different patient populations and some of the other aspects to put that into context for these gene therapies as far as the risk benefit.
I think that's it what I wanted to say.
CHAIRMAN SALOMON:  I mean there's two directions that I think we need to go in in the next short period of time.  One is to, of course, address a series of specific questions that Philippe and the FDA staff have put forward.  And I thought a good way to begin to get at that, that at least I find easy to do, would be to sort of breakdown this tier system and look at tier 1, 2 and 3.
The other thing to do is to talk a little bit more about some of the practical implementation of a database system, which I understand that our UNOS colleagues have to leave at 10:30.  So maybe just in interest to spend 10 or 15 minutes just sort of talking a little bit more about a specific implementation, and then if you will, I'll sort of take the Chairman's prerogative at some point to kind of cut that off and move toward a specific discussion of the questions and the tiers.
Is that reasonable for everybody?
So, just to focus a little bit on implementation of a database system, though I might have chosen to this in the adverse direction.  How large do we think a database system for gene therapy would be now and in the relatively foreseeable future relative to the size of this UNOS system, which has been around for 12 years.  We're throwing money around, like $8 million, as if that number is relevant to the cost of a gene therapy system.  So I think we ought to start with considering how big do you think a gene therapy system would be?  Would it be that big?  Would it be bigger?  Would it be smaller?
DR. NOGUCHI:  Well, I think one of the considerations of that that would be good to hear is what about scaleability?  Is there a concept that a smaller number of patients cost proportionately less?  My guess is probably not depending on what you want to collect.  I think for talking about 16,000 data elements, no matter how small or how big, part of the cost is going to be relatively constant.  So that might be a good place to start.
MR. KECK:  I think that the cost is directly related to, at least in the first year or so, the number of data elements you want to collect.  We're currently actually building a system for a private organization right now that is sort of similar to what you're talking about.  It is for ventricular assist devices.  And it has tiers of information.  They are probably looking at anywhere from 1500 to 2000 individual cases worldwide per year.  This would be a worldwide data collection system.
And they have a basic set of information that they get on all their patients that are participating in the system.  They have tier 2 which relates to adverse events that are driven off of follow-ups that are pregenerated all along, which kicks off another form that is specific to that particular complication and get more information on that.
There's also adverse event reporting and prompting people to remember to report their adverse events.
Over long-term there is integration of this system with other databases.  This particular entity has another database that we manage that they want integrated with this system, as well as integrated with the UNOS system for follow-up of those patients that get transplanted.
And so all of that is, I would say, over the next year going to cost probably half a million dollars.  And they're collecting right now 200 data elements throughout the whole system.  The follow-up as time goes by is yet to be determined on how much that will cost because of the unsurety of the volume of patients.  But to give you an idea of scaleability, that's the best example I can think of.
DR. CHAMPLIN:  The toxicity collection is pretty straightforward.  There is an NCI common toxicity criteria used for cancer treatment trials that's very detailed and could easily sort of be adopted to this purpose.
The efficacy fields they're a lot more controversial and complex and depend on the treatment and the objectives of a therapy.  But the way the NMDP worked was to create the organization, get the relative investigators together to discuss just what fields do you want to collect both from an efficacy and toxicity perspective, and gradually build that database.  And it was a big investment to get the computer system off the ground and work out the data entry system at the same time.  But that's sort of the beginning of the program.
Since at this moment gene therapy is sort of a small field with relative small number of patients, UNOS is obviously dealing with a large ongoing activity that won't be there immediately with gene therapy, although you will anticipate that over time and with the continued survival of patients that the number of individuals being followed and data collected will mushroom, but at the beginning the numbers will be relatively small.  But you need to basically go through that process of getting the relevant investigators together to identify the critical fields that need to be followed for both efficacy and toxicity.  But the toxicity part of it is pretty much standardized.
CHAIRMAN SALOMON:  Michael and then Amy.
DR. O'FALLON:  We've been talking about your cost, but there's an awful lot of hidden costs out there that are not part of your budgets.  You got any sense of the proportions?
MR. KECK:  Are you speaking to cost at the center?
DR. O'FALLON:  Of course.
MR. KECK:  I would hesitate to guess.  We have such a range of sizes of centers and the number of forms that they get.  We have centers that get thousands of forms that have been in existence for a long time and have a staff of 4 or 5 people that do nothing but fill out UNOS forms.  And then we have centers that might get a 100 a year and the clinical nurse fills them out.  It ranges very dramatically.
I will say that --
CHAIRMAN SALOMON:  We have a relatively small program and we have one data coordinator whose full-time job is filling out UNOS stuff.
MR. KECK:  Although I do think that in terms of development of data systems, and I have come to strongly believe that electronic is the only sensible way to go.  Paperback systems are just too costly and people have come to want to give information electronically.  We ran a dual based on two parallel system of paper and electronic for a number of years.  And I can tell you, it was extremely costly to have both.  And the ongoing magnets of the electronic system, I think, is going to be cheaper and easier to change as time goes by.
DR. PATTERSON:  I just wanted to follow-up with Dr. Champlin's point and give you a little update on some of the progress on the FDA and NIH collaboration on a gene transfer database.
Over the past several months the agencies have been in an intensive dialogue and have developed and almost finalized the system's requirements, the data structure from the feds' point of view in terms of the federal review staff at FDA and in terms of NIH's needs in terms of being stewardship over public funds in this area in the RAC review.
The next step, and we're in the process right now of setting up a series of user groups where we will be meeting sequentially with members, representatives of patient communities, the ASGT, other scientific groups and industry to discern what their information needs are and also to discern burdens of reporting an what from a scientific and practical perspective they think are important considerations.
So, just wanted to give you that insight into what the current process is.
CHAIRMAN SALOMON:  Can I ask of Philippe or Carolyn, and maybe Amy you can comment as well, we still haven't gotten the answer to my question, and that is what is the size of this program?  I mean, how many patients do you have per year on gene therapy INDs?
DR. NOGUCHI:  I don't think we necessarily have an ongoing accurate count of that date, because studies are in various stages and the reporting numbers of patients is also quite variable.  The best estimate overall I think does come from OBA, perhaps.
CHAIRMAN SALOMON:  Well, let me make a guess here.  I mean, from the data we saw yesterday, maybe being generous, 150 INDs were in that review?
DR. NOGUCHI:  Well, it's about 200 active ones.
CHAIRMAN SALOMON:  Okay.  200 active.  Okay.  And that's good.  I mean, that's close.
So 200 INDs.  But in a gene therapy trial, these days at least, is relatively small.  I mean 30/40 patients in a gene therapy trial is gigantic, right?  I mean, most of these gene therapy trials are 5/10 patients.  Again, I'm just testing.  If I'm wrong, tell me.  I'm just trying to come up with a number here in a second.
DR. KEEGAN:  Well, it's true that the majority actually -- unfortunately I don't think we can give you a specific number.  It's true the majority of the INDs are phase 1 and 2 trials; however, there are several phase 3 ongoing trials.  There are probably at least 10 INDs that have as many as 4 in it and 5 active protocols in them.
So there are some very active programs.  It's hard to generalize without going back and looking at the specific numbers.
DR. SIEGEL:  And you don't want to exclude those that are inactive or withdrawn.  They have patients that require long-term follow-up.  And there are certain types of things that we'd want to have in this database that were not within the scope of March 6th.  
So, it's going to be hard to come up with an exact number.  But if you're looking at ball parks, you know, you're looking at several hundred trials and thousands to tens of thousands of people at the present point of time and with a potential for great growth or for no growth, which is a little hard to predict.
CHAIRMAN SALOMON:  Yes.  I was just going to make a ballpark figure of about 4,000 to 5,000 patients, which is I think fairly generous.  Because I mean that gives you a concept to what they're dealing with, which is a lot more.  I mean, you've got 75,000 plus listed, plus they're following what?  You said 200,000 some patients?  A quarter of a million.  250,000.
So I just want to put some reality here.  Now, Phil's point -- and that's not -- I think I'll stop there in the sense that the point of this Committee isn't to help you figure out how much it's going to cost.  But I do want some reality check there in terms of we can do this and it's not necessarily going to take $8 million a year, but you can't make a calculation like that.
DR. SIEGEL:  On the other hand, and it's worth noting, that unlike, say, transplanting a heart if you have a gene therapy that treats a lung cancer or a breast cancer, you may have several thousand people in the study period and tens or hundreds of thousands or millions of people in the post-marketing periods.  So the potential is different than that for solid organs.
CHAIRMAN SALOMON:  No, no.  If gene therapy takes off, Jay, this will be much bigger than organ transplantation.  There's no question about it.
MS. LAWTON:  Can I just ask, we do have another example that I'd like to ask about, and this is the xeno registry database that we've established for long-term follow-up of patients.  And given the relative time periods here, you know, how does that compare and how are we doing on that compared to what we're now talking about doing for gene therapy, which I assume is much larger than the xeno database?
DR. NOGUCHI:  We are in the process of completing the pilot stage and hoping sometime within the next fiscal year to actually be entering data into that on a real time basis.  There are several major differences between this and the gene therapy.
For the xeno database we have elements that would not be required for the human gene therapy in terms of we have a very extensive extra set of data fields for the animal; the animal production facilities, where they come for and an ability to link the particular animals from which organs, tissues and cells are derived to each individual patient.  		So, part of it is a little bit extra than what you'd see with gene therapy.
In terms of the safety data follow-up, we are restricting it at this point in time to those adverse events that we feel would be more related to infectious disease cause because that is our major concern with xeno transplantation.  Above and beyond the usual adverse events in a clinical trial, it's the inadvertent spread of infectious diseases.  So the scope of the adverse event reporting at this point in time is more limited and more specialized.
Some of the other aspects of it that have been put in are not implemented at this time are some of the ideas of being able to actually at a periodic time send out reminders to, in this case is could be either the physician or the organization or the sponsor.  Because it's not implemented yet there would be quite a bit more to do, but that idea has been built into it.
The projected number of patients this would follow at this point in time would be much more restricted, perhaps being generous, in the low to mid hundreds of patients.
CHAIRMAN SALOMON:  Okay.  I think we've sort of covered up until as far as I think we ought to be going in terms of the actual physical implementation of the database.  So it's not off the table, first of all, if anyone has any last comments before I sort of segue back into the tier system, you're welcome to make those now.
MS. LAWTON:  I guess I would just emphasize what I said earlier; that you know if you're looking for the sponsor's commitment for this long-term follow-up I think it's an absolutely critical component that has to be addressed with some level of urgency on how that database is going to be built, who it's made available to, how you search it, how you analyze you, how you provide that information.
CHAIRMAN SALOMON:  What I'd like to do now is segue into the specific questions that Philippe and Carolyn and the rest of the FDA staff have posed to us.  But I'd like to do it is a little different than this question 1, 2, 3, 4, though I promise to get at them specifically.
I'd like to start with looking at table 1 and table 2 of the handouts, which I'm assuming everybody has.  And ask everyone one to sort of pickup where Richard started in terms of the discussion of do we agree with -- I mean, what I would like to hear from the group is comments on the overall strategy of the tier system, but specifically if you wish to start with tier 1.  I mean, just actually looking at the vector characteristics and the fact that participant follow-up past the first year is listed as none.  Because that was kind of one of the issues that Richard brought up.
I mean, my feeling here is that it's a very important to help the FDA come up with a system that is flexible enough that it can be used for a long time and that provides something that the Committee is comfortable with in sort of an over-arching theory that gives sponsors and new investigators some flexibility to kind of slide into these.  And that's a challenge.  I mean, if we don't feel that that's possible, we owe it to the FDA to say no.  You know, this isn't an organizational principle and we can't use it.  So, I think that's kind of where I'd like to end here with the idea of some sort of reassurance or not to the FDA that this is a good way of parsing it out.
Abbey.
MS. MEYERS:  I don't understand the logic behind the stopping follow-up after one year on that lowest level.  Can somebody explain it.
CHAIRMAN SALOMON:  I mean, let's get to that.  Let's talk about tier 1 then, unless there's anymore generic conversation, and then we'll get to your question, Abbey.
DR. SAUSVILLE:  I think that to have this be based solely on the sort of modality or how it's delivered ex vivo as opposed to the nature of the gene deserves some thought.  Because, I mean, it's well known that to pick up the oral immunity example, I mean a relatively brief strep throat can give a lifelong rheumatic fever and it's hypothesized that other elements can, for example, contribute to arthritis, etcetera.  
So, one, I actually would feel uncomfortable about making this blanket exemption just in relation to how it's done.  I think the investigator or the sponsor should justify why their particular gene might be expected to not have this type of long-term consequences.  And I can certainly imagine genes where that would be the case.  But I can also imagine genes where it would not be the case.
CHAIRMAN SALOMON:  I'd have to say that I agree completely, and I think that was what Richard was saying as well.
Again, if I'm not speaking for the Committee, but I really think that right now the public is not willing to accept any sort of gene therapy as having no responsibility to the sponsor for long-term follow-up after the first year.  
DR. MULLIGAN:  Yes. I think on the case that I would characterize as being the perfect case, one, would be an irradiated tumor vaccine.  And definitely some of the thinking behind inducing an immune response is the risk of any autoimmune response because of a local concentration of something.  And that is clearly the case where the cells will go away in a week or two and you'll note DNA persisting.  So I would echo to have no follow-up of that as maybe not wise.
CHAIRMAN SALOMON:  I think there's been  a consensus on that.
DR. SIEGEL:  To reiterate what I said before, we have a lot of traditional drugs and biologicals that as needed, depending on their mechanism of action, we require long-term follow-up, collections off and data registries that exist well into the post-marketing period.  And I think what we were focused on here are the specific needs related to vector class type and properties for follow-up, not those needs that might be related to the specific therapy and specific patient population.  But we'd certainly agree that with any type of vector or even outside the field of gene therapy there are going to be certain types of follow-up necessary for certain types of trials that in some cases may extend to extended periods of time.
CHAIRMAN SALOMON:  One of the limitations we've talked about before in the generic discussion is the tendency that you look at this and you go "no follow-up," and you go no you can't allow that.  So I think that's what you're getting from the Committee right now.
DR. SIEGEL:  I can't imagine a tumor vaccine trial, for example, where if you're treating a tumor and the patient is still alive at one year, you're going to stop following him in that trial.  That's just not the way we do cancer trials.
CHAIRMAN SALOMON:  Fine.
DR. SIEGEL:  Or at least not the way we do most cancer trials.
CHAIRMAN SALOMON:  So our only point is tier 1 has to have some element of long-term follow-up, that's all.  That we don't think that right now in gene therapy the public's going to accept any tier --
DR. SIEGEL:  As a routine, regardless of the nature of the vector or the trial, or whatever, that these patients -- regardless.  And that being the 20 years of clinical follow-up.  So basically tier 1 becomes tier 2.
MS. LAWTON:  No. I understood that it's going to be based on all of the different components in that trial, that the patient population, the vector, everything else, the gene.  
DR. SIEGEL:  Right.
MS. LAWTON:  And based on that you'll decide whether you need long-term follow-up.  You're not automatically saying everybody has to have long-term follow-up, are you?
DR. SIEGEL:  No, but I think that's what the Committee is saying, that everybody has to have that.
CHAIRMAN SALOMON:  This is the problem I have, again, with these generic discussions, and I've said this umpteen times.  I mean if I can imagine that there should be -- if you can put some wording into it here, the problem I have is right now -- right now, not a few years from now with some experience under our belts.  All we can deal with is right now.  And right now I don't know under what circumstance any gene delivery experiment can be exempted from follow-up.  And I don't know how I could defend not producing that sort of follow-up to the public.
Now, from a sponsor's point of view, whether as an investigator myself I know what I'm saying, you know it scars me -- we'll get into this --  to be committing to 20 year follow-up.  And we'll have to talk about that in a minute, but I don't want to contaminate this discussion with that yet.
That's my point.  If someone disagrees with me, then we need to get that table.  But I just don't think we have the kind of information that could be presented to a group of science experts in gene therapy or gene delivery that would convince me that you don't need follow-up.
DR. SIEGEL:  That I think will be, but I'd ask my staff to confirm this, except for retrovirus and mediated gene therapy, that would be radical departure from what's been done over the last 5 to 10 years.  And if that's in fact the recommendation of this Committee, we would be going back to large number of experiments. I'm not sure how much we can do that retrospectively.  But I think -- well, I'll just leave it at that.
DR. NOGUCHI:  Well, I think it may not be as radical as you think in the sense that what the proposal is on the table is that in addition to retroviral gene transfer studies, a large number of the others would have varying amounts of follow-up.  And the specific -- 
DR. SIEGEL:  Hey, that's the proposal we put on the table.  Dr. Salomon, have you not said that for every patient receiving a gene therapy of any type, you think that 20 years of clinical follow-up should be obtained?
CHAIRMAN SALOMON:  That's what I'm trying to say is the consensus of the Committee.  And I've said that we should have discussion if that's not.  I'm not trying to oversimplify it.  That could be by postcards.  And I'm not saying that they have to be in and have multiple tissue biopsies every year.  But, yet.
DR. MULLIGAN:  Yes.  I think that what he is saying was you want to separate the question of what the follow-up was from the discussion right now.  So I don't think I would agree for a blanket 20 year follow-up for everything.  But he was just saying let's defer the issue of the follow-up, but there should be.
MS. MEYERS:  I think the main thing is that the patients have to know their responsibility when they sign that informed consent form.  And that is that they are going to be expected to go back and see the same doctor, at least talk to him on the telephone or have his local GP cooperating with the investigator to give some type of follow-up, at least for the first 5 years.  I mean, you've got to lay it out because the patient has to know what he's getting into.
Now, let's say 5 years down the road we have enough data to know that there isn't any problem from one type of vector, and you want to change the rules.  That's fine, as long as the patient himself has committed to talking to the same doctor every year and giving his data.
DR. SAUSVILLE:  Again, I reiterate my original point was that this as written here seems to be a modality sort of approach; ex vivo, plasmid, what have you.  I think to make it a blanket thing that there should be or should not be follow-up just on that basis.  It should be reconsidered and the matter addressed by, perhaps, the sponsor and the investigator based on the biology of what they're manipulating.  And I think that should enter into it somehow.
CHAIRMAN SALOMON:  That's why I kept saying, I mean if we had a specific in front of us and we could engage in a specific discussion and you could convince us -- I mean not you, Ed, but the sponsor could convince us that they had data that showed that there was no reason to follow-up for 2 years, 5 years, 8 years, 10 years, I'm fine with that.  I mean I'm science driven.  But I was just saying, again, stuck with the generic I think that the message has to be that you can't exclude follow-up under tier 1, that there has to be some follow-up.  That's all I'm trying to say.
DR. SIEGEL:  I think you're missing the question here.  The specific will always be the specific.  Okay?  We are discussing the generic.  Okay?  We're discussing saying if you're using this type of vector, you're going to do 5 years of specimen collection and 20 years; no matter what the specifics of your protocol are.  
And if what the Committee is saying is the FDA should just decide on each protocol how long the follow-up should be, we could do that. I'm not sure that's really the optimal way to do this.
If you're saying that we should decide, they can show us "Well, we think that this particular vector is safe enough, we don't need follow-up," then we'll make a vector-by-vector decision, well that's an interesting approach.
We are talking about generics and what we heard you say, and I guess we heard wrong, in November that there were some sorts of experiments such as these that were so low -- that the specific gene therapy type of concerns were so low -- yes, there are tumor vaccine concerns.  We require follow-up on all tumor vaccine trials.  We're always going to require, depending on the specific issues of a specific vector, the appropriate safety, but the specific risks of gene transfer we were told last time that certain types of products are so low that we didn't routinely need to require long-term follow-up based on the risks directly related to gene transfer.  
And I think you're saying something different now, although I want to make sure that's what you're saying.
CHAIRMAN SALOMON:  I think we're saying something slightly different than -- I remember the discussion in November.  It wasn't quite -- you know, you've come back again very appropriately now, and I congratulate Carolyn and Philippe for doing this.  I mean, this is a really good way to focus discussion by offering something that I think would be very useful to the whole field, and that is when you're planning your studies you can say to yourself and your collaborators "Well, look, is this going to be tier 1, a tier 2, or a tier 3 sort of protocol or a vector, or whatever."  And I think that's very useful.  So we're trying to work with you.
But that's a little different than what we were talking about in November when we were just saying that in some instances where we didn't have any thought that there would be residual gene delivery detectable after several weeks, that that might not require the same degree of follow-up.  And I think all we're doing is choking a little bit on the term none.
DR. CHAMPLIN:  I don't think we had a tier 1 vector presented this morning.  Are there any tier 1 products?
DR. SAUSVILLE:  Well, you can imagine a plasma that encodes MDR.  I mean, that sounds pretty non-enorganic, none persisting.  In fact, it is nonpersisting when people have done these experiments.
So I could probably live quite comfortably with not having a lot of follow-up on that.  I could also imagine a vector that has B7 in the context of some antigen or other, and then I'd be real concerned about that in relation to long-term follow-up.
CHAIRMAN SALOMON:  Richard and then Michael.
DR. MULLIGAN:  Jay, I'm now getting confused because when you talk about the tumor vaccine you say well, of course, you know the FDA is going to make sure there's the appropriate follow-up, and that's obvious that's going to be the case.  So what we're talking about here in that context is whether or not in a way the information that you're asking for ends up in a database, isn't in fact?  Isn't that a way to look at it?
DR. SIEGEL:  No, I don't think so.  Let me state this problem as I understand it.
We will look at a vector that contains B7 and an antigen and determine the appropriate amount of follow-up for that or MDR, or whatever it is.  Just as we look at a given drug and its potential adverse effects and determine the appropriate amount.
What we're focused on here is that there are certain issues that have been raised in gene therapy that have led to specific concerns about long-term follow-up.  Those are largely issues related to the nature -- to viral infection, to insertional mutagenesis, to specific activities that relate to use of virologic vectors and to gene transfer mechanisms.  Those concerns are the types of concerns that led us initially into this area in requiring long-term follow-up for retroviral vectors, a requirement that's evolved over the years and that hasn't always yielded the quality of data we'd like, as was discussed a few months ago.
Further, we've realized that some of those concerns extend well beyond retroviral.  And so we came to a belief that for retroviral vectors we're probably not targeting the right information well enough, and for other areas we're not collecting enough information.  
But I think where the Committee is getting a little bit bogged down is, you know, if you give a treatment to a child, you may want ten years follow-up on it to see if they have normal growth and development; what happens during puberty.
If you treat cystic fibrosis or if you treat Alzheimer's Disease or cancer, the types of follow-up that are specific to that therapy and to that disease may vary tremendously.  There's no notion here that patient follow-up is exempted.  But I think if you're advising us that we should have patient follow-up that's suitable for the nature of what the gene product is going to be and that's suitable for what the patient population is going to be and for what their disease is, well of course. I think that we'll take that advice, that's what we do.
So then the question is those things aside.  So those things aside, should we because it involved gene therapy say regardless you've got 20 years of clinical follow-up or 5 years of clinical follow-up?
CHAIRMAN SALOMON:  Jay -- yes.  So my comment I don't the Committee is getting bogged down.  We've told you already several times that our feeling is that right now at this point, being sensitive to the way the public is looking at gene manipulations of any kind, that we don't think -- and again, I look to my --
DR. SIEGEL:  Well, you've told me that several times.  I think Ed said, for example, with some inserts he wouldn't worry about that and with others he would; that's a different message I think.
CHAIRMAN SALOMON:  Okay.
DR. CHAMPLIN:  I think you might instead of saying the word exempted you could say protocol specific, which we all agree that pretty much what you're saying, that you need to do it on a case-by-case basis but it's hard to envision none ever applying.
DR. O'FALLON:  Well, that's a great segue into my comment.  The fact of the matter is I asked a question right after Philippe was done.  Are we talking about what's happening while the protocols are underway or are we talking about what's happening in a general sense?  And we keep getting them getting confused.
Protocols have to have follow-up in order to establish efficacy.  Efficacy, not necessarily adverse effects, which is what we're primarily worried about here.
Every one of those protocols must be written in such a way that the FDA found them acceptable and when they come here for approval, they will have to have had adequate follow-up to have established efficacy that convinces us that the agent is efficacious, or else it's not going to be approved.
So, we're not talking about the protocol specific follow-up that is necessary for the success of that protocol. We can't be.
DR. SIEGEL:  We would include this safety follow-up within the protocol.
DR. O'FALLON:  Well, that's fair enough.  So we might say there is no safety follow-up necessary, but we certainly aren't saying there's no follow-up necessary to establish efficacy.
CHAIRMAN SALOMON:  Michael, I just want to be clear.  And in this case, you know, there has been times and it's okay, that the Committee doesn't have to have consensus.  I actually think that's important.
I am saying that my opinion is that right now I don't believe that there's any gene delivery protocol that I can at least think of that I could do, give to a patient and then say that don't require any follow-up for safety.  I'm just talking about efficacy.
DR. O'FALLON:  Well, and how long is that minimal period of long-term follow-up that you're saying that they should require?
CHAIRMAN SALOMON:  I was going to get to that next.  But I thought it was -- we're having enough trouble just getting across that.  But I think that should be the next question:  what we're talking about in follow-up.
DR. SIEGEL:  What are you trying to follow-up for?  Latent malignancies, latent diseases, latent neurologic, hematologic?  Because we've tried to focus that follow-up on the particular risks, but you're saying there are particular risks you're concerned about that are there but just because it's gene therapy, independent of what cells and what vector and whatever, and so it's hard to know how long you follow-up for those -- 
CHAIRMAN SALOMON:  We've got to take a biopsy of what the public is thinking about.  I mean, this is a public who absolutely got hysterical when they found out that some genetically modified corn ended up in some tostitos, or whatever it was.  
I mean, I respect that.  I'm not making fun of it.  That's the way the public is looking at this.  And therefore, if we're trying to give you responsible advice, what's driving me is trying to sensitive to the way the public is looking at this field and looking to experts like myself to give them in terms of reassurance.
Personally I think that many of these protocols after 5 or 10 years we'll look back and go "Boy, that was a lot of effort for nothing," and be thanking God that it was a lot of effort for nothing.  But I think that that's what the public's expecting from us today, at least that's what's driving my comments right now.
DR. SAUSVILLE:  I mean, obviously, you know we respect the interest, indeed, the demand of the public to have responsible follow-up.  
I think what you're hearing here is some ambiguity in trying to chart a middle course between exactly that, because this is a gene therapy require, you know, follow-up ad infinitum, which I think plays more to the -- I would use the word -- hysterical aspects  of worrying about a corn in tostitos versus-- I mean, I was reacting to the word exempted.  I mean, and one interpretation of that is that actually a sponsor could choose a particular vector vehicle for an outcome because it would exempt them.  And that I think would be wrong, actually.
I think that one needs to, and I return to, have the nature of the follow-up driven by the biology.  Now what seems to have done is run into yes you always make demands for follow-up based on the biology of what you're trying to accomplish, and we respect that.  Okay.
So let's take off the table the types of follow-up that you would impart based on the nature of the protocol and try and come up with what I would hope would be middle ground generic consensus.  
I mean, I agree with Dan.  I think we're clear.  I don't think we're --
DR. SIEGEL:  I do want to say to Dan that maybe things will change after today.  But it is important to note that much or most of gene therapy research has not had long-term or lifelong follow-up commitments.  Those that have had it, as we discussed in November, have failed to achieve it in any meaningful way.  And perhaps there should be more of a public outcry.  It isn't there.  And I think that as scientists we also have a responsibility to determine what is scientifically appropriate and to educate the public about what is scientifically appropriate.  Because there's always more money you can spend collecting more data to provide reassurances, but if it's not useful, then it's not -- you know, you don't do it just because you --
CHAIRMAN SALOMON:  Yes, I totally agree, Jay.  I totally agree with that.
If I could choose what we talk about, this wouldn't be the topic I'd like to talk about because I find it very uncomfortable because of the implications of it.  
But I've said this before, there are groups in the public who have taken a position no gene therapy, and there are groups that no animal research and no this, and no this, and no this.  But that's a minority.  The majority of the public is willing to give us quite a bit of latitude to do these sort of cutting edge technologies.  And that is based on a trust in us that we are going to do the proper follow-up, and that's what's -- again, just trying to state it a different way.  I feel that that is a responsibility that we have.
MS. MEYERS:  Jay, over 80 percent, my list calculation, of all gene therapy experiments since day one have been on cancer.  And most of those people, of course, are dead.  They've been dead a long time because gene therapy hasn't worked.  So if you start that database today, you're going to have practically nobody in it.
But my long-term memory of this whole thing was that first little girl who went through the severe combined immune deficiency experiment and when that family moved into a new neighborhood, this girl was known.  Her family had gone public.  Her face was in Time magazine.  And the neighbors told their kids not to play with her because she had gene therapy and she might be contagious.
We've got to do something for the people who do survive to assure them that this whole thing is safe.
DR. SIEGEL:  Well, I don't have any problem.  Believe me.  I mean, that's why I'm with the FDA.  I believe in a public responsibility to ensure safety.
I'm simply saying that the amount of safety data we require should be based on scientific considerations.  It should not be based on public expectations that we collect useless data.  If we believe the data is not scientifically important to collect, we shouldn't say that we should collect it because the public expects us to collect it. That's the only point I want to make.
CHAIRMAN SALOMON:  We agree with that, Jay.
MS. MEYERS:  We understand.  I think that public expectations are much more important before we lose this whole field.
CHAIRMAN SALOMON:  We agree with that concept.  And there we get back to that there has to be within any of these sort of things enough flexibility that you can do your job, which you guys do well that part.  I mean, detailing the system for a specific protocol.
DR. SIEGEL:  It will be easy for us to ask everybody to collect everything on everybody for long term.  And if they don't, to put them on clinical hold.  That'll be easy to do for us to do our job.  
This is not an issue of FDA resources.  It's an issue of what's reasonable in order for science to progress.
CHAIRMAN SALOMON:  We agree.  And I think there's just a lot that still needs to be understood about gene therapy before I'm willing to say I recommended that you could exempt whole groups of vectors from follow-up.
So that's tier 1.  One of the things that I wanted to point out, just a practical thing, in tier 1 is less than 2 weeks in vivo.  I think that's probably a little bit too short.  In fact, if you infuse T-cells, they can last a lot longer than 2 weeks.  So I might say something like 6 or 8 weeks just to be a little more flexible within that coverage.  A lot of cells survive longer or can be detected by real sensitive PCR techniques.  And even that you may find eventually has to be changed because of the cell's persistence.
DR. SIEGEL:  If you say that's tier 1, I think -- you said you were going to come around to this issue of time.  But if in fact there is a consensus of the Committee that for all gene therapy there should be clinical follow-up of at least a certain duration, I'd like to find out what that duration is and what the nature of that follow-up is.
CHAIRMAN SALOMON:  All right.
DR. MULLIGAN:  I have a radical suggestion.
CHAIRMAN SALOMON:  Yes?
DR. MULLIGAN:  Which is we move to that issue of the time, because everyone's real nervous about this.
CHAIRMAN SALOMON:  That's what I wanted to do.  So, Richard, why don't you make a comment on that?  Let's talk about that.
I just wanted to make sure I remember to tell you 2 weeks was too short.  That was a practical thing.
DR. MULLIGAN:  Well, I'm not by no means an expert on this part of things, but just reading the document, I read somewhere in the document that the 20 year was an "arbitrary" time.  And so if it really is completely arbitrary, I would throw out 10 just to stimulate discussion.  It's another arbitrary time period.
CHAIRMAN SALOMON:  The way I understand they went after this is you've got a 1 year point, a 5 year point and a 20 year point.  Now, you've thrown in the 10 year point.  Okay.  So let's take this as what you have to do for a year, what you have to do for 5 years, what you have to do for 10 and do you have to do anything for 20?  How about that as a basis for some discussion?
DR. MULLIGAN:  I think 20 makes everyone nervous.  I'm curious to directly talk about 20 versus something like 10 in terms of what's the precedent in terms of toxicities, long-term toxicities coming on in 20 years as opposed up until 10.
DR. CHAMPLIN:  The obvious long-term toxicity is radiation induced cancer.  And solid tumors may take even over 20 years to develop after radiation exposure.  And if you assume insertional mutagenesis, it may in fact have some similar long-term outcome, you need for that end point a long time to evaluate it.
Autoimmune disease, and I couldn't give you the number off the top of my head, but I would think that would be a much smaller -- probably 5 years would be plenty to look at autoimmune outcome.
And so in situations where mutagenesis would not a concern, a none integrating plasmid, perhaps in that situation 5 years might be a sufficient follow-up. 		If mutagenesis is a concern, then you probably do need 20.
DR. SAUSVILLE:  That word exempt is even more pertinent to this field of so-called Von Economos' encephalitis and the latent incidence of Parkinson's.  I mean, what it was, whether it was an exposure or a virus is clearly epidemiologically relevant beyond 20 years.
DR. BISHOP:  Indeed, I wanted to concur with Mr. Champlin. In your briefing document I think we outlined scenarios for Hodgkin's Disease where some of the problems with leukemia may not appear until about 5 to 9 years afterwards and we plateau at 15 years.  Problems with thyroid, breast and other solid malignancies will not become apparent until about 15 years following therapy. And this is data that's pertinent to this conversation because if, for example, as you pointed out you're looking at a single event occurring at the time of therapy that could lead to oncogenesis, this may not be apparent until many years later.
The 20 year period was actually discussed at the last meeting and it was recommended that this would be an appropriate time frame to look at.
The other thing I wanted to point out is the outline that we've proposed in the tier 1, 2, 3 system really pertains to potential policies that would apply to gene therapy for long term follow-up.  It does not at all address the safety data that would be collected as part of a traditional phase 1, phase 2, phase 3 trial which is critical to the development of each product.  
So, clearly, when I used the word exempted there, this was a word that was used by this Committee last time with this particular example and the idea from that is not to exempt patient follow-up from safety follow-up that would be specific to the particular product, but exempted from a requirement, a broad policy requirement or broad requirement that would be outlined in the guidance document that would try to be an umbrella to catch all potential scenarios.
DR. CHAMPLIN:  One would hope that the long-term follow-up beyond 5 years could be like on a post card and nothing that's more onerous than that, because clearly you're looking for major late events.  And the big problem is one gets increasing numbers of people being followed in the long-term is just the enormous amount of paperwork for often a smaller negligible return.  So you really want to make that aspect of the follow-up very simple and straightforward and, hopefully, not very labor intensive.
DR. BISHOP:  I use the word questionnaire rather than post card.
DR. MULLIGAN:  So to try to move ahead -- 
DR. SIEGEL:  If we want a target, it'll be easy to target for those that carry risk factors such as insertion or replication or latency where we know what we're targeting.  For this class you're going to have provide some guidance as to what we're going to want to target in the long-term follow-up for these particular types if we go to long-term follow-up.  
As of yet, the reason for the long-term follow-up we've heard is just that it's gene therapy and we're worried.  And so if we're worried, I don't know is it worry that a post card is going to solve?  Are we worried about cancer and if so, then we don't want 1 or 2 year, we want 20 years? Are we worried about everything, in which case we would want --
CHAIRMAN SALOMON:  Okay.  We gave you that. I mean, Dick proposed that -- and I was just letting the discussion go on before trying to come up with a consensus, and I'm not ready to do a consensus yet.  But what Dick proposed was that if the risk or the putative risk was mutageneses, that you probably needed a 20 year horizon.  That if it was autoimmunity, you could capture that within a 5 to 10 year horizon.  So that was his way of dealing with your question.
DR. MULLIGAN:  I think it would be useful to go back now and look at what is long-term according to the vector, for instance. So if it's a cancer risk, I think there is a consensus that 20 years is a sensible type of thing.  And we could then arbitrarily say for integrating vectors, mutageneses, insertional activation the "long-term follow-up" has to be on the order of that.
If it's a vector that has potential for autoimmune disease, we might decide that long-term follow-up is a 5 year long-term follow-up.
For an ex vivo I think that's a very reasonable way to do it rather than have one long-term follow-up.
CHAIRMAN SALOMON:  I agree.  I think that's where the Committee's going.  
Now, I mean I had some specific questions like why is the plasmid vector looking at table 2 in tier 2?  I mean, it's very low integration potential and it's not replicating, it's not latent and we're not requesting long-term follow-up now.  How did it end up in tier 2 if this as a test for the sense of this system?
DR. WILSON:  That's, I think, what we've been hearing from the Committee that you didn't want to have any gene transfer categories going into a long-term follow-up situation that didn't include collection of this kind of safety data that we've just been talking about.  I thought that was the conversation that we had in November with the exception of the ex vivo cells.  And you've reiterated and actually now expanded that discussion to now include those --
CHAIRMAN SALOMON:  So the way I would think about the discussion today, I would put plasmids in tier 2 --
DR. SIEGEL:  No, no.  That's the opposite of what you're telling us.  That may be why you think tier 1 is too low.
Tier 2 is the low risk products, the ones you told us we didn't need to worry about.  And now you're telling us these low risk products we should be doing clinical follow-up.  That's why they're in tier 2.
Tier 1 reflects that this Committee said that there's some things that are not replicating that are going into cells that are just going to last a short period of time where we don't even need to do that clinical follow-up.  We can eliminate tier 1 if that's your sense.
CHAIRMAN SALOMON:  I think that you're getting the idea here and what you'd exactly end up doing is okay with me.  I mean, in other words, either you put plasmids in tier 1 and you add some long-term follow-up in tier 1 or you leave plasmids in tier 2 and there's nothing that I know of in tier 1 right now.
DR. MULLIGAN:  Well, I think we were on to something before when you're thinking of the different long-term.  If you go back to the tier 1 and make Jay less nervous about what would be some long-term follow-up for a tier 1 thing.  
Let's take a tumor vaccine, you would make the case there's not a risk of insertional activation, therefore there's not this long-term cancer risk.  Therefore, there's certainly not the 20 year follow-up necessary.  And so we come up with what is the long-term follow-up necessary.  And that satisfies, I think, our interest in having some reasonable follow-up.  And so let's say it 5 years or something like that, you happy?
DR. SIEGEL:  I'm happy with whatever advice I get that's scientifically based.  I think that the problem was maybe some misunderstandings about what we meant by tier 1 and tier 2.  But as I'm putting together what the advice of the Committee is, if we were to eliminate tier 1, which is probably an extremely small number of things in any case, but then look at what we've put into tier 2 and say that 20 years may be longer than needed for some of those; that within tier 2 we can recreate a tier 1 of those that we only need 5 or 10 years because they're not significant cancer or latent infectious disease risks but have other risks that could be addressed shorter, that's where we would wind up.
CHAIRMAN SALOMON:  That's fine.  That actually works.  I was just saying that in November the examples that we were giving, which is why I stuck plasmids in tier 1 and was saying all the things I was saying, was that's what the Committee was trying to tell you, was that an ex vivo gene transfer with a plasmid into a cell that had a very short survival in the patient would be an example of what we thought a tier 1 would be.  Not with no follow-up, though.  Okay. Anyway.
DR. SAUSVILLE:  But there are uses of plasmids where they're being put into artificial viruses and run systemically.  It's very different than that.
So, again, merely saying something is a plasmid should be X or Y I think is ludicrous.  I think it needs to be based on the usage that you're contemplating.
DR. MULLIGAN:  I mean, I hate to completely change the way I categorized these things, but if you didn't do it by vectors but you actually did it in terms of the issue; that is there are long-term follow-up issues that relate to autoimmune disease, that relate to cancer.  And although they breakdown somewhat in terms of vectors, I think we're hearing that it really depends.  It depends on what gene it is and so forth.
Couldn't we come up with a tiering system that's more based on the nature of the safety risk and not so specifically tied to that issue?
DR. SIEGEL:  The intent here is basically--
CHAIRMAN SALOMON: To be honest, that's what you're trying to do.
DR. SIEGEL:  That it's not based on the vector per se, but on specific characteristics of the vector that link closely to those risks.  At least that's what the Committee said in November, that whether the vector can be latent, whether it replicates, whether it inserts the genetic material, and the rest of those things.
CHAIRMAN SALOMON:  Right.  And, Jay, I think that the answer is that that is what this tier system is.  I mean, what they've done in table 1 is give you the tier.  It's not by vector.  Then they gave you in table 2 what vectors fell into the tiers.  		DR. MULLIGAN: Yes, but I think we're talking about gene products that are independent of vector that lead to certain sorts of safety issues, right?  You'd have to figure by gene product then and not by vector, right?
So let's say an autoimmune issue can be given by different vectors, then they fall into the different categories, but that risk we may now be saying would require less of a follow-up than the 20 year.
CHAIRMAN SALOMON:  I think the difficulty here, and there's no way to solve it today, is just what you bring up, Richard.  And that is that in addition to the class of the vector and what the vector will do; integrate, not integrate, become latent, not become latent, all of which is relevant risk wise is in addition the gene product being delivered.  But I mean I think everyone here knows that.  I mean, if you put in an anti-A poctosis gene product, that would be completely different than the same vector delivering, I don't know, a cytokine.
DR. MULLIGAN:  I actually just think that the most productive way to go ahead is to talk a little more about the different time periods that would constitute a long-term follow-up, autoimmune versus cancer.  I actually think if we could come to some consensus about that, that's a better template than to add in okay, now what poses a autoimmune risk.
Let's take cancer, what poses a cancer risk is certainly an insertion.  And that'll categorize retrovirus vectors or AAV.
CHAIRMAN SALOMON:  Growth factor, right?  I mean if I put in a growth factor and put it in the liver, just making something up, and it sits there and kicks out a growth factor for the next five years, that's a cancer risk, right?
DR. MULLIGAN:  I think it's the only way to go about this is to -- I think most people would be most comfortable by us, I think, giving a sense of whether there is this blanket 20 year long-term follow-up or whether there's a tier system in terms of the length of time of that long-term follow-up.
CHAIRMAN SALOMON:  I'm okay with the tier system.  I'm just saying that there's a lot of different things, not just integration is going to be risk with cancer.  That was my only point.
DR. MULLIGAN:  If you're treating a metabolic disease where the gene product is not oncogenic, you know, Goucher's Disease or something.  I mean, you wouldn't need 20 years of follow-up for that, per se.  I mean, in terms of the cancer risk you may depending on the nature of the vector, but the gene product, per se, would be considered safe.
CHAIRMAN SALOMON:  Right.  Yes, that's actually a really good point.  That's an example of where the gene product wouldn't be as important or would be relevant, but it would be relevant in a positive way in terms of the risk implications.
So I think what we're saying here, again now trying to bring some consensus, is that what we're concerned about is that we make a reasonable demand of sponsors in gene therapy for long-term follow-up, not unreasonable demands.  And I think in that regard the Committee and the FDA is on the same page.
Twenty year follow-up seems to be a consensus for gene therapy protocols that have a cancer risk, and we would have to take those  -- cancer risk would have to be decided.  Yes, it's certainly going to be influenced by the vector itself, insertional, mutagenesis being the example that we've given several times, but it also could be mediated by the gene product being delivered, in an example of the growth factor I mentioned or an anti-A poctosis gene product.
Then there is autoimmunity, and in that we feel would probably be managed well into a 5 to 10 year follow-up.
And then there would be examples in which 5 years or less intensive follow-up would be adequate.  Be, for example, cells that were modified ex vivo that had relative short lives that could be at least targeted and demonstrated in the patient that it was given.  And under those circumstances that would be, perhaps, suitable for no longer than a 5 year follow-up period.
Are we okay there?
MS. LAWTON:  I just want to say for the record I don't think stating a 5 year follow-up is appropriate for all of those tier 1 level.  I think that still has to be on a case-by-case basis that we look at some of that.  And 5 years may not be appropriate, that's all.
CHAIRMAN SALOMON:  It may not be appropriate being too short or too long?
MS. LAWTON:  Too long.
CHAIRMAN SALOMON:  Well, I mean, I guess there I don't know how to go any further.  I mean if you give us a specific product, then we can have a discussion on what basis scientifically you're going to prove that less than 5 years is okay.  And if you can, I'm a scientist, just show me the data basically.
Suzanne, you give me a desperate look a minute ago.
DR. EPSTEIN:  I think it's kind of hard to put a time limit on autoimmunity and it's hard to put a limit on which products do and don't have a risk of generating autoimmunity.  That's all.  I don't object to your guess.  It's as good as any guess.
CHAIRMAN SALOMON:  I think.
DR. CHAMPLIN:  You know, I don't know off the top of my head the latent period following exposure and the development of autoimmune disease in this type of scenario.  I mean, there's probably data out there.  Vaccine autoimmune diseases that occur.
My impression is that these occur relatively quickly and that 5 years would be on the outside of the risk period.  But if somebody knows more than me, I'd be happy to hear it.
DR. EPSTEIN:  Well, if you look at vaccine, then you're only able to say you think it was causative.  If you assume some kind of temporary relationship, that's very hard to answer and those studies have not really been done properly, and they're being attempted now.
But when the cause of autoimmune conversion is unknown, might be some virus, some environmental exposure and so on, it can be extremely delayed.  It's just not known.
DR. O'FALLON:  In the breast implant controversies there were claims that the autoimmune response was 9 or 10 years after the implants.  I think 10 years is barely long enough.
DR. MULLIGAN:  I think that this issue of the case-by-case is going to be taken care of by the FDA and the IND.  So I think that this policy issue, we can't do on a case -- it has to be kind of a crude sort of arbitrary 5 years, 10 years sort of thing.  And that doesn't effect in any way, really, how the FDA wants to specifically for a particular IND decide how long they want to follow-up.  Because otherwise it would be impossible for us to come up with something.
CHAIRMAN SALOMON:  I think my feeling here is we've given you a consensus.  It hasn't really varied that much from the beginning.
I don't know if it's exactly what you wanted, Jay.  But I think it reflects our best sense of what we're willing to publicly commit to in a field in which there's very little data.  And in fact, I should just point out that my comfort is diminished in that, for example, we heard yesterday that the most common cause of adenovirus infections in transplant patients, and that's also in the paper that we got, was basically reactivation, which means adenovirus is latent.  Yet when we look at table 2 it's marked as no latency.
So, I mean, there just is -- that may be that adenoviral vectors so far as we know has no latency, but that doesn't seem to be the biological situation.  So I'm just saying that even with the most expert people in the world working on this stuff, we're not even really clear about the details.
DR. SIEGEL:  I'm sorry, I'll let you speak in just a second.
But let me just say because you seem -- in asking what I wanted and saying it's the most you're willing to commit to, there seemed to be some inference that I was asking for something less stringent.  I just want to be perfectly clear that I was asking for something that was clear and science based.  And that in fact what you're recommending to us now, as I understand it, is substantially less stringent than what we've designed based on what you recommended last November in the sense that we designed a program in which there would be 20 years of clinical follow-up because of all these uncertainties about what all these -- for the vast majority of trials.  And now you're telling us for significant numbers we should be considering 5 and 10 year follow-up.  The only issue of less stringency is for that extremely small number where we said we didn't even need that, you're saying no those should also have 5 years of follow-up.  
And I hear what you're saying.  If I've said something differently, tell me I'm wrong, but --
CHAIRMAN SALOMON:  One thing you're wrong about is I don't believe that anyone up here has given you any sort of percentages for how many things would we think needs 20 years follow-up and how many specific protocols would need 5 year follow-up, and anything in between.
I think that what the Committee doesn't want to do is tell you every single gene therapy protocol until otherwise notified is a 20 year guaranteed follow-up or a 50 year guaranteed follow-up.
DR. SIEGEL:  You haven't given us percentages.  You've given us science based guidance that if there are not specific oconlogical concerns, that most of the other types of concerns for long-term follow-up don't require that long a follow-up.  And if that's what we're hearing and if that's your opinion, then that's something that we can implement.  And I'm just saying that's a move toward to less stringent.
Because you were asking are you not giving us -- suggesting that I wanted you to give us something less stringent than what I -- I just wanted to make sure we were clear on the motivations.  You heard my  negative reactions to proposals only because I wasn't sure what they were.  I think there was a communication problem.  And because there was a suggestion that they weren't based in science.  And recognizing that, I think you're right.  I know you're right, especially in this field, that we need to address public concerns, not just scientific concerns.  You have to address public concerns in a scientifically valid way because if you simply say we're going to do long-term follow-up not on the basis of scientific concerns but public concerns, you have then not a clue where to start at what you follow-up on.  You know, we should archive every organ specimen and do full examines and x-rays and everything on everybody forever.  If there isn't a scientific basis, then you don't know where to go.  And we're stuck implementing something where we don't know where to go.
I'm much happier where we are now with the discussion that is based on -- can be as conservative as you want it to be, but it fundamentally needs to be based on risk so we know how to design it to be appropriately conservative.
CHAIRMAN SALOMON:  Well, I think essentially that's well said, Jay.  I mean, what the Committee is trying to say is if you're worried about malignancy risks, then we're looking at 20 year follow-up.  If you're worried about autoimmune risks, Suzanne's comment taken into context and appreciated, we're talking about 10 year or so follow-up.  Depending on other risks that might be defined with other projects, maybe 5 year follow-up is okay.  So we're just trying to give sponsors and the FDA the flexibility in a field in which a lot of the rules are not known.
DR. SIEGEL:  Latency and latent infectious risk is one we haven't specifically discussed time lines on, but that's another area where you have to estimate time.
DR. MULLIGAN:  It's just I'm not sure if we want to at this point talk about any of the vectors.  Do you want to do the -- I just had one point specifically about the adeno vector that echoes in a different way what Ann said.
And that is, you know, the vectors, although they're in various stages of getting into work very effectively, those would certainly be a latent case.  There's no question.  And the pox -- I can't cite any studies, but there's clearly nonpermissive pox viruses that upon infection do not kill, necessarily, the cells.  Now how long they persist, I don't know.  I don't know the information.
But certainly adeno would have the potential to give very long term gene in the guttedadeno form.  So I think that's -- I would see that more like an AAV type of situation.
DR. NOGUCHI:  I think what we really are saying is that science can take us to perhaps a couple of weeks ago, because that's when the latest science is.  And that the public concern, there is some basis for the reason that you're right, science doesn't know everything.  We only know what we know.  And it's very hard for us as scientists to know what we don't know and predict what it's going to be.  And that's the precise point about your guttedadeno.
DR. MULLIGAN:  Well, I'm just saying that you actually simplify things since they were kind of out lyers in the old tier 2 system, maybe they shouldn't be exceptions.  It just makes it simpler.
CHAIRMAN SALOMON:  I think we made some progress on that.  
Now there are a series of very specific questions, some of which we kind of addressed.  It's 11:15.  I'm trying to figure out how to do this.
What I would suggest, but again this is for discussion, would be to spend another 15 or 20 minutes and try and go through these four specific questions that haven't been addressed and then -- no.  What do you want to do?
DR. WILSON:  It just seems to me that at this point that may be mute since we really need to go back nd revamp our systems, our proposal.  And so I think for the sake of time, if that's all right with you, Dr. Siegel, that we're happy with the discussion we've had and we need to, obviously, refine our proposal taking into account your comments today.
CHAIRMAN SALOMON:  Jay, that's okay?  Philippe?  All right.
DR. BISHOP:  We'll be back.
CHAIRMAN SALOMON:  I was afraid of that.
DR. SIEGEL:  I think Amy also, she described a process as well that involves a lot of scientific and clinical and pragmatic input into what's collected and how.  And there's no question this is going to be a process.  Nonetheless, while it's being designed we're also doing it.  You know, we don't have any choice but to be implementing while we're designing, and so these are useful discussions and I think we'll come back with something that reflects our interpretation of today's discussions for further discussion.
CHAIRMAN SALOMON:  I think that's great.  And I think that maybe in not the next one, but maybe soon we could get some specific protocols presented to the Committee. I think at this point the concerns that I've expressed before is that there's nothing that sharpens the mind than a real protocol to deal with.
DR. SIEGEL:  Perhaps what we can do is some specific marked up protocols if we want to do it publicly.  Not specific real protocols.
CHAIRMAN SALOMON:  We can do role playing, maybe.
DR. SIEGEL:  There's enough of them that we could do.  
CHAIRMAN SALOMON:  I'd like to play -- well, I'll just tell you later what I'll play.
So at this point I just ask, is there anyone in the audience, the sponsors, that having listened to the conversation today feel that some comment is appropriate?  I certainly don't want to exclude you from all the fun.  Okay. They'll take anything we come up with.
And the heck with you guys.  Twenty years.
I just want to go on record that the problem, and we've said this before, is just practical implications of this is that even if we go to let's say 10 year follow-up -- I don't even want to get into the dramatics of 20 year follow-up -- for an investigator at an institution whose may not even have tenure at the time that they're proposing this sort of thing, to demand that the institution in signing off on that person's NIH grant or -- well, yes.  Or arrangement with a biotech company that isn't a big multinational pharma company that would be definitely around in 20 years, that my dean would have to sign off on this -- I just have no idea how that -- I just can't imagine that happening.  I just don't see how that's going to happen.  And so there's a real practical issue that really scares me here.  I mean, I'm doing what's right in saying these things up here, but the other part of me is going "Oh my, God."
DR. CHAMPLIN:  Realistically what centers are going to have to do is to create an office where you're going to have a staff of people and as part of a contract to do a gene therapy trial is to provide the 20 year funding for that office to do the long-term follow-up.  And the responsible thing is also to be sure that that follow-up beyond the 5 year point is very short and so it doesn't become onerous on anybody.  And so it needs to be are you alive, do you have cancer and have you had a major illness in the last year, and that's sort of it.
And there's sort of an irresistible impulse of organizations to create longer and longer forums and you get a 50 pager for your annual follow-up, and that just is going to be unworkable.  But as long as one can keep it short and sweet and really to the very succinct, it's probably doable.
CHAIRMAN SALOMON:  The frightening thing here is, I mean what Dick's saying is correct.  We could have institutions make groups up that would follow this.  The first question is is that bigger institutions, of course, will have an easier time of doing this than smaller institutions.  And that is not a prejudice or a bias that I'm very comfortable with creating.  But we are going to create that.
A second thing would be right now if we implement these, I'm afraid that these rules will get implemented much more quickly than any sort of change in the way the NIH funds my grants.  And I just can't see how the NIH is going to give me funding for 20 years, you know, based on my follow-up.  And in the absence of that, you're basically knocking us out of gene therapy, and I'm helping in this Committee, which I realize.
DR. CHAMPLIN:  But it could be $10 a patient a year or something if it's a very simple long-term follow-up.
CHAIRMAN SALOMON:  Right.  But correct me if I'm wrong, but I don't think that there's a mechanism right now at the NIH for me to ask for $5 at .50 cents a dollar for the next 10 years -- I mean .50 cents a year for the next 10 years. I don't think I can do that.
I mean, I have to account every year.  So they'd either have to make some congressional thing that a grant could be 10 years long, which I can't wait for that one.  It just worries me here that there's a lot at stake here --
DR. SIEGEL:  Well, it worries us.  That's part of my concern about being science based, because the more that we ask for the less research will be done.  I think there's no question, or the dollars won't be spent and other aspects of research that could have been done.  And so we are defining with the help of this Committee is that minimal amount of long-term data that's necessary to get adequate safety collection -- and certainly our philosophy as discussed in November, it would be to try to simplify the long-term data collection and focus it again scientifically around those items that are of specific concern.  That said, however, first of all we'll focus it around safety, but there are going to be other efficacy and activity questions that people have already raised.  But also I can't imagine we're talking -- what it took to track patients to collect data from them, to put that data together to submit it to an agency in a database, I don't think we're going to be talking about $10 a patient. 
CHAIRMAN SALOMON:  No, I was being facetious and so was Dick, I think.  But the point I'm trying to say is this isn't a science base issue now.  I want to make sure that's really clear.  I'm not talking science.
Yes, everything you said is correct; we want science based reasons for doing things, at least as Phil says, to the extent that we know.  
I'm not talking about science now.  I'm talking about practical policies.  If you go forward as we're recommending you to do, and at anytime in the next year or two, you know, we get this finally down to an implemented policy, that day if there isn't equal efforts on the part of the NIH and other funding agencies to deal with the issue that this creates, an unfunded mandate to the FDA is really annoying.  An unfunded mandate to academic scientists in gene therapy is a tragedy, because you close us down.
DR. SIEGEL:  We won't close you down, you just won't be able to conduct business in a manner that you consider appropriate and safe, right?
CHAIRMAN SALOMON:  We won't be able to conduct business according to a manner in which you'll allow us to hold an IND.
DR. SIEGEL:  And what you're telling us is we should require you to do it, right?  Let's just be clear about that.
CHAIRMAN SALOMON:  I understand.
DR. SIEGEL:  That's why we're here talking to the public so that we don't impose on a community requirements that they think are inappropriate.
CHAIRMAN SALOMON:  We got it. I'm not making you out to be the bad guy here.
DR. SIEGEL:  I misspoke, because sometimes we do inappropriately impose requirements that people don't consider appropriate. But we certainly want input from the communities involved.
CHAIRMAN SALOMON:  I'm saying if you do this appropriately and we don't go to the NIH and Congress and the other funding agencies and make sure that this is done correctly and that we get the support from these agencies, the day you do this it's an unfunded mandate until we do it and it'll kill the gene therapy in academic medicine.
DR. SIEGEL:  If it does funded, then funds will be used for this instead of something else, and that's important to know.
DR. MULLIGAN:  I think that two the event that this was a science based discussion, we did come up with something, I think the next chapter is exactly now whittling that in a practical fashion.  And the practical fashion is titrating now down requirements the nature, the complexity requirements to a point that in everyone's judgment will allow gene therapy to go ahead.  
So I really was looking at this in a very philosophical and a science based way and not factoring in whether this would kill gene therapy.  But I think from my point of view, which may be different than Jay's, I actually think that there is some sort of negotiation, practical negotiation that now has to be done based on this to see whether or not anything we would propose could actually be carried out.
For instance, you know you'd really love to know if all the institutions, how many deans or whatever heads of hospitals would possibly agree to something like this.  
CHAIRMAN SALOMON:  Well, I'm agreeing you will have a lot of difficulty.  So I don't know that we're really disagreeing.  
The question here is if as we discussed it today, we go beyond 5 and start talking about 10 and 20 year follow-ups for specific categories of gene therapy or gene delivery protocol, that's all I'm talking about.  If we do that, that day the absence of funding arrangement to cover that will essentially take many of us out of those types of gene therapies.  That's all I'm saying.
DR. MULLIGAN:  I'm just saying that I think that now the next thing we ought to address, not at this meeting, but we need to address exactly the precise road map for trying to implement something like this.
CHAIRMAN SALOMON:  My point.  Yes.
DR. SIEGEL:  Well, that's important because, in fact, we've had these long term requirements in place for some years and they haven't -- the amount of data for a variety of reasons, many very valid that we've collected, have not really been satisfactory.  And so I think one  of the important, and perhaps the most important condition as we talk about focusing these, is not so much it's not just focusing and so that the research is possible, but focusing as to data that we actually believe can be collected.  And when you talk about that system where the university makes the commitment to do this, the thing that runs in the back of my mind is, you know, there's another concern.  Not whether or not they'll commit to do it, but whether or not they'll do it once they've committed to doing it.  You know, even with the best of intentions if we have a system that without much of an enforcement and that isn't very actually accomplishable, it's not clear how much data we're going to wind up collecting.
DR. MULLIGAN:  In fact, I would argue that this issue enforcement, you're going to have to give us a better sense of that, too, because that'll certainly influence the administrators if they are making obligations and there's a very clear cut enforcement guideline, they're going to be very worried.
DR. SIEGEL:  Well, we're exploring that.  Suffice to say from the FDA point of view our regulatory relationship is largely with sponsors, secondarily with investigators and very little with institutions.  We can require the sponsor to commit to do certain things.  If they don't do it, we can take certain actions.  Although if they're out of business or dropped the product, there are limitations in the strength of that hammer in terms of our ability to require certain actions.  We've sought additional factors in certain cases, like civil money penalties.  We can continue to seek those.
But not to go into details, the importance is to know there's limitations in what we can do, although there's a significant amount we can do.  But, again, it's largely with the sponsor.  And when we're starting to talk about the institution, there's more limitations, although the NIH, obviously, has more relationships with institutions and to some extent may have some other abilities that will need to be further explored.
CHAIRMAN SALOMON:  Amy and then Ed.
DR. PATTERSON:  Yes.  So this is an important issue.  I didn't want to leave untouched Dan's comments about NIH funding.  And as OBA is not a funding entity of NIH, I'll make my comments on this fairly brief.
But I think it's important for everyone to understand that NIH funds a number of long-term follow-up studies longer than 5 years, 10 years, 20 years.  Epidemiologic studies.
Your proposal to do long-term follow-up needs to be part of your initial application, and it needs to be scientifically meritorious and well founded.  And it would be on those principles that long-term follow-up would be funded.
The second point is that I think that this discussion about NIH support and the scientific merit of the studies that are contemplated underscores the need to get much broader input and expert input into the design of these studies and the types of data collected.  I mean, the Committee's discussion here is a good start down that pathway, but I think we really need much broader in depth consideration of how to design these studies; what are the end points, how will the data be reported particularly because again you may be looking for rare events and you're going to have to be able to look at that data critically.
DR. SAUSVILLE:  That in a way does dovetail with a point that I wanted to  make in that in this formulation of how to go after these long-term results we've factored into the participation of institutions, universities.  And certainly where the university was, as we discussed yesterday, party at some level to the generation of the product, one can imagine that being relevant. However, that's not always the case.  And, in fact, some biotech companies have actually not gone through universities but gone to individual investigators at free standing hospitals, etcetera.
So by that way of thinking about it, then this type of mandate falls solely on the shoulders of ultimately the small company that is going to potentially regard that as an additional impediment to being in this field.  And, indeed, what was just injected by Amy, the idea that scientific merit would go into this, obviously if this was put into a study section context, those interests could be quite diverse from those of the industrial sector.
So, I think there are a number of complex relationships here that are being mixed together.  I guess I share the concern that there needs to be broader input because the effects of a rule that is -- or a policy that is not responsive to all these different possibilities could, I think, be very problematic.
CHAIRMAN SALOMON:  I'd also point out that in terms of Amy's point, yes, there are examples of long-term follow-up, but most of us are applying for R01 grant awards in which, as far as I'm concern, there's no way to ask for ten years of funding on a 5 year grant award.
So the point still is that there has to be some sort of NIH decision made, and I hope it's not that every gene therapy protocol has to go to some special type of study section or some special sort of application.  But, I mean, that's the kind of thing that we have to think about.
DR. O'FALLON:  I think there was a passion around the table that if we don't do this, we might destroy gene therapy.  Now there needs to be an equal passion that all of us to work together to keep this simple enough that it doesn't destroy gene therapy.  And I think we really got to concentrate on that simplicity.
DR. PATTERSON:  I would just add one more passion, and that is that we do it right and really design the studies well.
CHAIRMAN SALOMON:  I think we just need to keep straight the idea that designing the studies is not as important as the long-term follow-up issues; that part has to be designed well.  Right?  I mean, I don't think that there'll ever be or is it appropriate to seek consensus on how to design all gene therapy trials for the rest of the world.
DR. SIEGEL:  Well, I assume maybe you're talking about epidemiological studies that go across those studies.
CHAIRMAN SALOMON:  And I was trying to clarify -- I agree with that part.  And that's what I was trying to clarify.
Okay.  Well, a little passion is good.
So, amazing, albeit you could point out that we didn't have the break that we were supposed to have, but I'm going to avoid that and take credit for the fact that we're only 5 minutes off schedule to introduce Dr. Noguchi.
Okay.  I did make a major goof here.  Okay.  No, Dr. Noguchi, you're not introduced.
So what Gail has just pointed out to me is that we have two prior requests to address the Committee as part of the open public hearing, and I would invite anyone else in the audience that this would be a time that they could also step forward.
So, talking about timing here, what I guess that -- and I think, by the way, it makes more sense -- Phil, just before you leave.  What I was thinking of doing was having the open public hearing and then break for lunch, come back and start with you.  Would that be okay?
Then we're going to have the open public hearing.  We're going to have a break.  And then we're going to go to Phil instead of lunch. Okay. We'll work on that.
Okay. Just to show you how flexible we are, I wish someone would tell this to my wife how flexible, I mean.  Is that we're going to have a break now, and then we'll come back and do the open public hearing and go right into Dr. Noguchi's thing.
Thank you all.  See you back in about 15 minutes.
(Whereupon, the meeting was adjourned at 11:40 p.m. until 12:00 p.m.)
CHAIRMAN SALOMON:  Find our seats. We can get started with this last set of the session.
Okay.  One of the things that -- I was told that the break is just from the Committee.  That there was some concern that we weren't being efficient enough in recognizing speakers.  And to that extent, that's my fault as Chairman.  That's one of the things I'm supposed to do well.  So, I apologize to everybody and we'll make more of an attempt to be looking around.
If people can help me by not just sort of jumping in and find the people who are speaking, who want to speak in some sort of order, that would be helpful as well.	
Okay.  So, this last of the session begins with -- I believe we just go in order, right?  Okay. 
So I'd like to ask Dr. Sally Seaver of Seaver Associates to step up and address the Committee.
DR. SEAVER:  Thank you very much for the opportunity to address the Committee.  And since the manufacturing group is being very quiet, I decided I would speak out.  And let me tell you first a little bit about my different affiliations.
I'm, as you realized, a consultant.  I work with people on all sorts of biological products.  And I work with them on issues relating to the manufacturing and control of those products, including working with responses to the FDA.
I'm also chair of a committee at the United States Pharmacopeia, and it's the committee on gene therapy, cell therapy and tissue engineering, and also chair of the whole complex actives division, which includes that committee and five other committees in biotechnology, blood products, vaccines and dietary botanical dietary supplements. 
And finally, many people know me from organizing various conferences, quality aspects and manufacturing aspects in the biological fields.
Today the opinions I'm giving are strictly my own.  I'm not representing anyone or any of these other possible modes, or any client.
And I want to comment on the disclosure, the proposed rule that Dr. Noguchi will be discussing in a few minutes on the disclosure for xenotransplantation and gene therapy.
I read the 70 pages and as with most proposed rules from the FDA or final rules, I very much appreciated the first 61 pages that sort of discussed the rational for the rule and the sections of the rules.  And the message that came through to me was that what the FDA was asking for people to disclose were things that were not confidential, that were very often disclosed anyhow.  And that it would help assure the patients of the safety of trials.
Therefore, the issue I have that I'd like to address today is a section that's on page 67 of that whole long 70 page disclosure, and it's section 601.52(c)(6) where it actually lists the information you disclosed.  And it's a multi-inch paragraph on what they want.  And one of the things listed is ancillary products used during production.
And let me back off a bit and bring people up to speed on what ancillary products are.  And basically they are components used during manufacturing that really should not be present in the final product.  And so they can include growth factors, cydicines, media formulations, antibodies used to purify a cell fraction or a gene therapy product.  The actual bioractor and cell culturing device has been suggested by the FDA as possibly an ancillary product.  Agents used to purify the product, which could include the columns, the enzymes you might use, and as I said, media components.
So, in general this if you really -- one iteration of this is basically everything you use to manufacture this product.  
Now the conflict comes in in the other wording where the FDA said that you can hold confidential information back.  And let me give you some examples in this area and let me state right here that most companies consider this information highly confidential.
So, for instance, if I'm in adenovirus and I've been producing and my 293 cells beginning, the fact that I've now moved to a "better less replication competent producing cell line" like PerC6 cells potentially would have to be disclosed.  The fact that I've moved away from using cesiumchloride to separate by virus two columns and how many columns I use because after all, none of the column resin should be in the final products so that they are by definition an ancillary product.  What enzymes I might use to chop up my xenogeneic product or remove DNAs from my product, both gene therapy and xenogeneic might have to be disclosed, and quite frankly sometimes if it's simply benzonase, it has been disclosed.
But in organizing conferences, I can tell you that our ability to get people to discuss in detail their production schemes is usually not that successful.  And even for approved products most of the time if the company goes and discusses in particular a purification process, they very often don't disclose which product it is.  If you're clever, you can figure out which one it is.  But in the general disclosure it's not there.
If they disclose which product it is, they very often don't disclose all these details like media formulations, exactly what purification they did, etcetera.  And I'm including companies that have really delivered a lot of information to the public, including Genentech.  If you watch very closely when they exclude some really important details, they don't tell you which product.
And what I'm concerned about this rule is that it links the product with the exact media you might use, saline, etcetera, etcetera, and method of purification.  And when I'm concerned is that this is going to cause a lot of disputes, a lot of extra time both on the part of the client and the FDA, and potentially even some appeals.
Some of my clients, they don't have a lot of problem disclosing media because they say fine, I'm just using the standard media or something like that.  But they're very sensitive about the way they purify.  Other clients I have are like no, I'm not going to tell them anything about the media.  I consider that highly confidential because we've discussed what we might in a response to this rule.  But I don't mind on purification because it's the same purification that I've heard Joe Blow talk about.
So, it's very company-to-company dependent on what people consider confidential.  And it's also not clear how much detail the FDA is asking for ancillary products, and it's not clear that it will be applied uniformly for each reviewer to reviewer for an application.
So, in conclusion -- and finally, even if it were -- if you do give some of these ancillary product, it's not clear to me personally, and therefore I can't explain it to my clients, how the patient is necessarily going to be able to interpret this information.  All right.  How do they know the difference between DMEN F-12, somebody's proprietary media?  Okay.
So, in conclusion, number one, I'd really urge the FDA preferably to delete ancillary products from this list of things to disclose.  And if they want to include it, to please define exactly what you mean by ancillary products.  And I hope, Phil, you'll do that in your next section.
Please help the sponsors understand why you want this info and for what purpose.  And please expect some appeals.
I believe ancillary products should be disclosed in the IND.  They should be discussed with the FDA.  They should be shown to be safe before you start the trials.  That's not what anyone is disagreeing with.  What we're disagreeing with or concerned about is the disclosure of information that's often which most people consider highly confidential.
Thank you.
CHAIRMAN SALOMON:  Thank you, Dr. Seaver.
The next speaker whose requested time is Dr. Michael Werner and representing BIO.
MR. WERNER:  Thank you.
I'm actually not a doctor, but thank you.  It's the easiest -- I'll take an honorary degree.
Well, good afternoon.  Thanks for the opportunity to provide comments on the proposed rule from FDA concerning disclosure of certain data from human gene therapy an xenotransplantation experiments.
Michael Werner.  I'm Bioethics counsel for BIO, the Biotechnology Industry Organization.  BIO represents more than 950 biotechnology companies, academic institutions, state biotechnology centers and related organizations in all 50 states and 33 other nations.
The biotechnology industry, as many of you know, has historically supported public discussion about the implications of new technologies.  Company have recognized the need for and the value of this kind of public discussion and public dialogue.  And this principle has been taken to heart in particular by gene therapy and xenotransplantation companies.
Biotech companies doing gene therapy research have participated in public discussions about their clinical trials at meetings of the NIH Recombinant DNA Advisory Committee for many years.  And when appropriate, companies doing xenotransplantation have also participated in public meetings about their experiments.
Although BIO supports public dialogue, we have some very real concerns, however, with the FDA proposal.  According to its preamble the proposal calls for the vast majority of material submitted along with an IND to be made public.  The proposal seems to be predicated on the notion that this information is already in the public domain, and that is simply incorrect.
Although gene therapy and xenotransplantation companies have made some information  publicly available, the type of information to be disclosed under the FDA proposal is much broader in scope.
Release of the vast majority of IND data would provide potentially misleading information to the public and could also lead disclosure of trade secret and confidential commercial information.  This could cause serious competitive harm to the companies trying to develop products using gene therapy and xeno transplantation to cure disease and reduce human suffering.
Now, over the years companies engaged in gene therapy and xenotransplantation have been forthcoming about their research.  However, as the industry matures and companies get closer to commercializing products, issues concerning public release of confidential commercial information become more salient.
Simply put, routine disclosure of this information will make it significantly more difficult to develop products that can be brought to market.  In the end, patients will suffer because potentially lifesaving products either will be delayed or won't be commercialized.
For decades FDA has kept the information contained in an IND confidential.  In fact, the existence of an IND is confidential information.  The Congress and the courts have consistently endorsed the public policy reasons for this approach.  But this proposal represents a dramatic, and to our way of thinking, troubling change in FDA policy.
It's important to note that BIO has proposed a plan regarding the disclosure of data from gene therapy trials.  Under the BIO plan oversight agencies would have access to data from clinical trials according to FDA time tables for reporting of adverse events and serious adverse events.  
A committee of experts at the agencies would analyze the data, recommend regulatory action if necessary, and make a public report.  And we continue to believe that this would provide the agencies and the public with important data while protecting trade secrets.
BIO and its member companies are engaged in a thorough scientific, legal and competitive review of the FDA proposal.  We'll be filing official comments that lay out our thoughts in more detail.
Thank you very much.
CHAIRMAN SALOMON:  Thank you very much.
Is there anyone else in the audience today that would like to add their comments to the public docket?
Yes, sir.  If you can step up and identify yourself.
MR. McKAY:  I'm Malcolm McKay, Vice President of Quality and Regulatory Affairs for Cell Genesis, a gene therapy company.
Very briefly with regard the proposed system for long-term follow-up, we urge you to consider the original plan that FDA put forth with the three different tiers and then allow the sponsor to have individual discussions with the FDA based on scientific merits as to whether or not that company fell into tier 1 and was exempt from long-term follow-up, or tier 2 or 3.
It might be that we might be in tier 2 for phase 1 and phase 2 and then go back into tier 1 for phase 3.
With regard to the public disclosure of INDs, Cell Genesis supports FDA's ability to discuss these issues in public, and we intend to write to the docket with our comments.  But we are concerned about the issue of publishing an entire IND, the amendments and the annual reports on the Internet.  We believe that that form, sharing the information with the public, will not serve the public. 
An IND is a very complicated document.  The flavor of the IND often changes with subsequent of submission.  And so the public wouldn't know where to look to find out what's current about a particular IND or a particular clinical trial.  And we've proposed that the FDA allow us to use integrated summary format.  It's friendly, it's consistently familiar with NDA's and it would give the company an opportunity to summarize the pertinent information in a succinct and easy to follow manner.
Thank you.
CHAIRMAN SALOMON:  Thank you very much.
I certainly won't comment on any of the stuff that we're going to talk about now, but just in terms of your comment on the long-term follow-up rule, I think it is the intention of the Committee to allow the FDA based on scientifically driven data reporting to negotiate what the follow-up for a vector should be.  I don't think anyone on this Committee suggests that as data evolves and our understanding of gene therapy improves, that that shouldn't be an option.
Dr. Noguchi.
DR. NOGUCHI:  Thank you very much for staying as long as you have, and of course, for the continued public comments that we've heard.  While I won't speak directly to the comments because, after all, we're still awaiting an evaluation of all the comments submitted to the docket, I would encourage everyone here don't let Florida happen again.  We take all comments.  We look at each one carefully.  There are no chads and each voice counts.
It is my privilege, actually, to be able to talk to you about the proposed rule.  This is an effort that has involved literally tens if not close to a 100 different individuals both currently at FDA and previously at FDA, including several of our guests around the table.  
And I'd like to go through, first, a little bit of the philosophical aspects of it and then to go through some of the details in, I hope, a short time.
Now just to speak to the complexity, in fact Dr. Seaver correctly points out many things are involved in a gene therapy experiment.  This is an example of a report that was in Nature several years ago, or I guess last year, in which there was very encouraging data presented that perhaps a certain type of immunodeficiency disease, that GammaC-R for X-SCID or severe combined immunodeficiency might actually be treatable by a gene therapy.  But to do that peripheral blood mononuclear cells were taken out of the -- in these cases, these are the type of individuals that literally live in bubbles, cannot leave the hospital and there is no treatment for them, unlike the first gene therapy patient in this country.
They run over an FDA approved or an FDA regulated column that has monclonal antibodies and other regulated product into a Petri dish, which is another FDA regulated device.  You take a viral vector, obviously another FDA regulated biologic, put it on fibronectic coated plate.  Fibronectin itself is a regulated product, as is the flash.  This is transduced, but that can't be done unless you also have stem cell factor, Fit-3, Interleukin-3, PEG-MDF, all of which have or will be used in clinical trials as a single entity.
You put those altogether and what you come out with, with a fairly high level of transduction are cells which are now expressing the gamma-c receptor.  And in several cases very encouraging results are seen.  Several of these children that actually left the hospital, they've been vaccinated, they're going to school.
Desirable outcome, extremely complicated background on how we get there.
Part of the reason and the need for a disclosure rule on gene therapy and xenotransplantation is that these are products of nature as biologics.  Even as far ago as Sr. Francis Bacon, "Natura enim non imperatur, nisi parendo," or basically "Nature cannot be ordered about, except by obeying her."  A different way of looking at that is we only know what we know as of yesterday and tomorrow we'll probably be shown that we're wrong.  Or another way to put it is "In nature there are no rewards or punishments; there are consequences."  And our FDA reviewers and others always say "For every intended consequence, there are a 100 mostly unknown unintended consequences that we must address."  
And I'd like to go through some of those that we've seen through the years.
Edward Jenner, for example, was a brilliant scientist.  He said he saw some -- the maids who milk cows never got smallpox, but they had these funny little pox marks on their arms.  And he said I'm so convinced that I can vaccinate people and prevent the disease, that I'm going to do the classic experiment.  I'll treat my children first, then myself.  Which he did.  And fortunately, his children were protected.  And this became a fairly widespread type of treatment, but it almost died an early death because in Italy there's an epidemic of syphilis because the transmission was done from lesion to lesion to lesion.  And the needle got contaminated with syphilis somewhere along the way.  Again, we didn't know what we didn't know.
In 1901 was the start of biologic regulation where a horse named Jim was used to prepare antiserum for diphtheria.  Now diphtheria was a therapeutic that was very, very useful and could reverse diphtheria.  More children died from diphtheria than has ever been effected by polio, so it was a devastating disease.
12 children died not of diphtheria, but they died from tetanus because poor Jim, the horse, contracted tetanus in the meantime and it was transmitted through that antitoxin.
Jonus Salk successful himself inoculated over 11,000 men, women and children with his killed vaccine.  Once it was commercialized, the very first lots that were prepared when you go from a 10 liter carbide to about a 10,000 liter fermented, every forgot you had to stir the virus or else you wouldn't get inactivation of it by formaldehyde.  And in fact, many of the first people that were inoculated with the first commercial version of the vaccine came down with polio.
This continues on.  Once you knew how to inactivate polio, RSV, respiratory syncytial virus, was the next one to be attempted.  After all, we know how to inactivate, keep everything stirred, simple. 
The first time that was done when the next season came around for RSV, men, women and children died who were vaccinated, whereas the controlled group didn't.  That was because that we think now that there was something to do with T1 and T2 immunity.  There is no RSV vaccine to this day.  There is a monchrominal antibody as a therapeutic, but as preventative, we still don't know how to do this.
University of Pennsylvania this last year or two years ago now, an 18 year old patient died in experimental gene therapy, others received the same dose, did not have this type of an adverse event both in this trial and other trials.  Do we know what killed the patient here?  Human subject -- we really don't at this time.
Even a toavirus vaccine, approved in the year 2000 was with withdrawn when it was widely used.  It prevents infantile diarrhea, but in a very few select cases it causes intussusception. 
All this is merely to say that for biological products mother nature will let us push her a little bit, but she always comes back and tries to tell us "You know, maybe you don't want to go this particular route."
Now, this is the proposed rule to get into that.  They short named it FDA as the proposed rule on public disclosure.  This is the longer official title, Availability, etcetera.  It was published on the 18th of January with a 90 day comment period, so that'll be sometime this month on April 18th will be the final comments.  And, again, we encourage everyone to please respond to the docket either in writing or by email.  At last count we had something like 40 written comments and close 90 email comments, all of which will be read, evaluated and used to reformulate and see where we need to go with this proposed rule.  Remember, it's a proposal.  It's not a final.
The scope and the purpose is for gene therapy and xenotransplantation.  Mr. Werner did point out that FDA for decades has had a policy for INDs.  We are speaking specifically for gene therapy, which is a decade old.
Part of the reasoning behind the rule is, in fact, that gene therapy and xenotransplantation have a different experience than other areas of clinical research with FDA regulated products.  They represent unique areas of clinical research that have potential for risks that are really unusual; that is it's not just the human subject or patient that may the subject to adverse.  It could be the surgical team, as in the case of xenotransplantation you could have transmission to offspring whether they're verdant or inadvertent, and things of this nature.
We've seen what the complexities of products are.  It's not just a single product, it is a therapy with multiple aspects to it.
Part of the reason of the rule is to provide, actually, a consistent amount of information for public discussion and public access.  
This rule, by the way, was not promulgated in response to the 1999 death of a gene therapy individual.  It started in 1994 when there was this public discussion and a departmental committee, the National AIDS Task Force, that asked the question whether or not there was duplication of effort between the NIH RAC and the FDA review process.  We went through a number of discussions with this, but the critical question that was asked at that time is even by 1994 there was a tradition and I would say global public acceptance by the community, by the sponsors, by the academic and especially the pharmaceutical industry to present a large amount of data that would be available publicly.  This did include things that we'll get into later.
The issue at that time was could be transfer review, sole review responsibility to the FDA and guarantee that access.  And the answer is no.  As you've heard by our own laws, even the existence of an IND is traditionally and by our own laws not acknowledgeable unless it's been publicly disclosed elsewhere.  This, as we said, provide a consistent amount of information, it will enhance patient awareness and consumer protection.  After all, if you're entering a gene therapy trial and you're not up to date on all the types of adverse events that can happen, whether they're large or small, and this goes for the sponsors, by the way.  Up to date information needs to be available by one means or another.
It will help, we think, ensure accurate and up to date informed consents as they're being written and updated.  And a small but a significant part of the rule is allow FDA to fully participate in public discussions.
Now, for gene therapy and xenotransplantation, we do have that full access to discuss things.  Part of it is because the sponsors have been exceedingly well versed and have been willing to discuss these things knowing that the issues are going to be primarily safety related at this early stage of the game.
Now what is disclosable, and this is an important aspect of it.  Patient information not disclosable under any federal statute.  
Trade secret information is not disclosable.  We used the narrow definition that was I think 1968 by the district court.  It's a productive process, it's not the idea; that is as things like incipients, and we will concede that certain types of ancillary products very well would fall into this sort of a category.
There's a limited amount of commercial confidential information and we're basing this on our experience with the National Institutes of Health Recombinant DNA Advisory Committee, the departmental Xenotransplantation Working Group and its various meetings that it's had, public meetings.  And now the Secretary's Advisory Committee for Xenotransplantation.
The key factor here, commercial confidential means that information which can give a competitive advantage to a competitor that will disadvantage the innovator.
What is disclosable or what we are proposing to be disclosable. This will be product and patient safety data and related information.  Included in this will be the preclinical data, animal data that very often can help define or help guide us away from situations in which there may be potential and adverse risk.
Name and address of sponsor.
Clinical indications to be studied and the protocol for each planned study.  We have heard in the past as an example that even the design of a clinical trial is commercial confidential.  It puts us in a bit of puzzlement since most of the trials and certainly many of the trials in gene therapy are only gone forward when FDA has had extensive modifications implemented in that, and in many cases FDA will consider some of this to be our intellectual property rather than anyone else.
There is written informed consent for as provided in 50.27 of this chapter.  Although FDA does not in itself regulate informed consent, we clearly view this as an important means of assuring adequate patient safety as we go forth.
Identification of the biological products.  Dr. Seaver is correct, if we just looked at this there are a number of subparts here.  I think that the question of ancillary products is a good one that we will need to address.
While we would acknowledge that some ancillary products or things that might be considered ancillary such as a design and types of columns and how many columns are being used could be considered in the nature as commercial confidential.  
In terms of the producer cell lines, what we have seen just from the few examples I've shown you, is that a cell line or a biological material that is thought to be "better or safer" very often is not.  That does not mean that it's disqualified, but what this does mean is that we need to know and have everyone know what the risks of any particular biological product area.  In fact, many with the exception of the RSV vaccine that we saw before where there is no present one, we have gone through many different tragedies with biological products, but it's always been on the basis of understanding, knowing the adverse events, the risks and getting actually the acceptance by the public who participate in these trials, which sometimes have very adverse events associated with them.
Biologics are different from drugs in the sense that there may or may not be a dose related phenomenon.  It very well may be idiosyncratic and the person's response.
IND safety reports.
And then information submitted in the annual report.  Now, if we look at the actual requirements of the annual report, the amount of information required is rather sketchy.  We've gone further in this proposal to outline the types of information that has been required by the NIH guidelines which sponsors have been routinely submitting information.
One aspect that we're talking about here is the regulatory status of the INDs, such as whether it's on hold, in effect, inactive or withdrawn.  Some of this comes down to the fact that far too much of our time is spent over the phone with the media trying to save "Well, is such-and-such on hold" and "Is such-and-such on hold.  What does that hold mean.  Does that mean somebody has done something bad."  And the reality of the administrative mechanism that FDA has to really say wait a minute, we want more information is the clinical hold.  
We think that in many respects, actually, this kind of information can help demystify the fact that clinical hold is not a good or a bad thing, it's a part of the process.
Then finally there is number ten, which is a clause which allows the Director of CBER on very unusual, very rare occasions to require that even if all safety information has been provided and we have no objections on a safety basis to disallow an IND to move forward, that in fact we can invoke only by petition to the Director, a lengthy process.  And if it's  determined that we need ethical issues to be discussed, we need to ask the question this can be done, we think it can be done safety but should it be done at all, this would be the clause that we would invoke in order to have a public discussion such as the RAC, such as at this Committee, such as at other advisory committees.
We're making a proposal on this could be disclosed.  The reason that it reads this way is for several reasons, the first of which is that it's simple to say get all this data, put it in a database and then make it public on a periodic basis.  That's a useful concept if, in fact, the population is small.  We anticipate that the number of patients and the number the trials for gene therapy will grow. We anticipate that some day there will be products, we could be wrong.  As we do that the amount of information is going to grow, FDA is not.  That can we can guarantee you.  
What we are asking, therefore, and part of this is to help assure that the sponsor will be able to look at what is trade secret, always what patient information is there and to determine what commercial confidential information is there and official and redacted version of each submission to an IND including the original IND.  The redacted document would not contain patient information, trade secrets and a certain limited amount of commercial confidential information, certain limited amount.
The idea, and this again is because we don't want to get in a position where everything has to go through a Freedom of Information request, but to rather make it in a publicly available format, a proposal, is that after a certain amount of time being used to make sure this is administratively correct and is accurate, it would be forwarded to a public docket.
Now, our public dockets office has said that each IND number will be used to create an IND docket with the same number.  Through the life of the IND then, this information of redacted form would be submitted to the docket, the official document which has both confidential commercial, patient information and trade secrets would continue to be submitted.
Now, this is a radical change in a way, but what it is also is a recognition that ten years of experience of gene therapy and xenotransplantation have suggested to us that in fact public disclosure has not been detrimental to commercial development; that in fact very often even those things such as an adverse event help to shape how the field moves forward.  And that in fact currently it has lead to the public confidence that up to recently we have enjoyed in the area of gene therapy.
We believe that for all the reasons given before, that if we can learn, especially from the lessons from the past throughout the history of biologics regulation that biologics are different, that they require a certain amount of openness and that science is always evolving, then in fact what can be imagined will be done.  And we know this will be done with hope.  It must be done with humility, and by this we mean not the hubris that our scientific decisions must be the end point, they are a part of the end point, but we have to also acknowledge that today's science, today's dogma, is going to be tomorrow's dog meat.  As science changes, so does our interpretation of what is important.
And finally, as we move forward, it always needs to be done with compassion.
Thank you very much for your kind attention.
CHAIRMAN SALOMON:  There'll be T-shirts on sale in the lobby with that last one.  It'll help the database.
Thank you, Phil.  That was, as always, done extremely well.
I have no official questions to guide what happens now and yet there is a provision for discussion here.  And so I very much have no agenda and my objective is that everyone get a chance to speak.
Abbey.
MS. MEYERS:  Well, I just want to say from the patient community this is probably one of the most important that FDA has ever done.  It's extraordinarily important.  
And I was at the last RAC meeting and they voted unanimously that there should be more disclosure.  There's some type of regulation that went through the RAC.  And one of the problems is, of course, that there seems to be a general secrecy in the field.  And the only thing that people get is basically the news that's released to Wall Street.  And writers pick that up and they reprint it in the newspapers.  And while on the one hand industry is saying we need to attract more patients into these clinical trials, they still want FDA to keep the whole thing secret.  So if you call up and ask FDA is there a clinical trial on gene therapy for some disease, they can't even tell you if there's an IND.
So, I think that the lessons that we've learned in the last 10 years since gene therapy started, which is actually a little more than 10 years, is that if biotech, agriculture industry had been as opened and there had been a forum for public discussion like the RAC for biotech foods, then we wouldn't be facing this big problem we are today.  I mean, people are scared to death of biotech engineered foods.  Why?  Because it was done behind closed doors and it was in secret.  And we can't afford that to happen with gene therapy.
I mean, nobody's going to die for lack of an engineered tomato, but you know people are going to continue to die from these horrible diseases, especially genetic diseases, which is my area of concern, unless this field moves forward. And because of the death of this young man at the University of Pennsylvania, I think that we're teetering on the edge here.  That the public is losing its faith in the government handling these things right, and this is the solution to put this out on the Internet so that people can see that 100 people went into a trial and, hopefully, 95 of them are still alive.
What frightens people is the fact that they read about it in The New York Times or they see it on 60 Minutes that 100 people were in the trial and a 100 of them are dead.  
So, this is the solution.  And I urge you all to support this solution.  I agree perfectly; take out the things that might be patentable or the trade secrets, but let us know the trial is going on and let us see what the adverse events have been.
CHAIRMAN SALOMON:  Alison, you looked like you wanted to make a --
MS. LAWTON:  Yes.  Thanks.  
I actually agree with your last comment there, Abbey.  Although we're probably coming from opposite sides here, I think generally I would say that we recognize the need, absolutely, for public debate and for the FDA's need to have public debate as well.  And for that very reason industry's need to have public debate.
I think the big question I have is is this proposed rule the right way to do it.  And my perception of the proposed rule as it is is, no, that's not the way to do it.  And I would like to see more time allowed to have more discussion around the best way to do it to provide the patients and the public with that information in the best possible form.
One thing we talked about earlier in discussing the follow-up of clinical trials, for example, we talked about the need for the scientific aspect of advising what's needed versus just what's required from a public perception point of view.  And I would come back to similar type of thing around this.
During the last couple of days we've also heard, for example, there's over 200 INDs on gene therapy trials.  And I'm not sure if people have any concept of just to try and get the information that you're talking about, Abbey, to go through that docket room and to look through volumes and volumes of data of 200 INDs is not the best way to get this information out to the public.
So I think from the safety perspective and what trials are ongoing, there's a better way to do this.  I don't have the solution here. We will definitely be commenting to the docket. But what I really encourage FDA is that you allow the time.  And I know that you will be reading the comments to the proposed rule, but to make sure that we have the appropriate time to look at the best way to do this for all of the industry, public, patient and FDA needs.
DR. NOGUCHI:  Thank you for those comments.  And, of course, we are going to look very carefully and see what the next step is going to be.
Just one slight correction.  The actuality of the docket is that, in fact, it will be electronic.  You may come and look at it in person, but each submission as of right now for about the last six months, everything coming in is both available in hard copy as well as electronically.
MS. LAWTON:  I'm just trying to get across the amount of information for somebody to have to go through to actually try and come up with a question around the safety of a gene therapy trial, for example.
DR. NOGUCHI:  That is a good point.  This is not at all examining any database or search capabilities.  It's simply saying we have determined that for these two areas we think this is a limit of what is commercial confidential and what is not.  But not anything about retrieving the information.
MS. MEYERS:  Do you agree, though, that adverse events are not proprietary information, or you think they are?
MS. LAWTON:  Adverse events currently are not proprietary information because they're reported.  Investigators have to report them through to the NIH anyway.  And, obviously, with the establishment of the safety database that is something that will be publicly available.  And so that is very definitely a very important aspect that should be made publicly available.  The question is again how do we do that and is it better to have expertise in looking at those adverse events and analyzing it and, again, putting it into context within the types of patient populations.  All of those aspects, I think, we have to think very carefully about.
MS. MEYERS:  Well, I want to just register my feeling that there should be no delays in this.  These regulations or changed regulations, whatever you do about all these little questions, the main thing is information about adverse events should go on the Internet.  And the reason is that when the Gelsinger family agreed that their young son should go into that, they had no idea that animals had died in the preclinical testing.  They had no idea that people who were in the test before them had abnormal liver enzyme levels after the test.  And they need a fighting chance.  Patients need a fighting chance.
And when you're sitting there and thinking about whether you should put your child or your mother, or your spouse into a trial and if you're not getting the whole truth in the informed consent document because, of course, IRBs are overworked and under funded and everything else, we need to know the whole truth.  The patient community needs it. Otherwise, it's going to end up on 60 Minutes and the whole field is at risk.
CHAIRMAN SALOMON:  Again, I have no agenda today but to make sure that everybody gets a chance to comments.  There are lots of issue that we could get into that I don't think really we're set up with the time today to do that and to try and define, for example, a universe of what should be in a public disclosure or how it should be shown to families, should be on a web, you know, what is it that you'd find when you opened the website.  I think those are the kinds of details that have to be worked out between the FDA, between the sponsors in industry and done in a way, Abbey, that responds appropriately to your concerns that accurate, interpretable, accessible information be available to patients.  And I think that's, from my limited view at this point, where the real concerns are.
You're not going to be able to allow a family member going to a website to interpret complex results in an animal model. It's not appropriate.  It's not fair.  It's not going to communicate, nor is it going to contribute, I think, to what you want; a sense of reassurance that everything's on the table.
So I think those are the issues, those are the details that are going to need to be worked out.
DR. SAUSVILLE:  I'd like to share those thoughts and actually extend them to the extent that in both biologics and in so-called small molecule drugs the nature of the preclinical toxicology studies are actually to cause, if possible, toxicology, toxic effects.  And I must say I'm very concerned that the undiluted and uninterpreted and unfiltered information of that type could be very problematic and actually hinder patient access to otherwise very reasonably constructed clinical trials.
DR. SIEGEL:  What, of course, would go on the website would be -- what is proposed is some redacted versions of what comes to the FDA.  And I think for a similar --  notwithstanding the fact that we have rather sophisticated scientist sponsors in general for similar reasons don't like to send us undiluted, unexplained animal data.  Our animal studies come with explanatory summary reports and interpretations.
DR. SAUSVILLE:  Right.  What I just heard is that there was a desire for an Internet disclosure at one level of either of what actually is, and even if you extend this to adverse events, the initial occurrence of one adverse event in a clinical trial, again, taken out of a clinical context, could be very problematic.  		I mean, the usual rules for stopping clinical trials actually call for more than one adverse event. 
So I think this is a very complex area.  And while I -- I mean to be clear, I mean I'm very both personally and professionally amenable to the idea of a constructive dialogue to how to do this.  One has to be concerned that access that without interpretation could ultimately be deleterious.
CHAIRMAN SALOMON:  Richard and then who else.
DR. CHAMPLIN:  So I always support that the patient should have access to reasonable information and be aware of pending adverse events.  One has to keep in mind a couple of things.
The specific organ toxicities in animals often are not reproduced in man. It's very dependent on the species and the metabolism of drugs.  And so if liver toxicity occurred in the dog, that doesn't necessarily mean that it's going to happen in humans.  So one can be mislead if there's detailed information about toxicology data in other species.
The other issue is you're of course interested in the observed versus the expected.  And in given disease state there's a background of adverse events happening in leukemia patients, for example, undergoing chemotherapy.  And that when you get the raw adverse event data, it's not clear exactly how much is truly attributable to an investigational agent and how much is to be expected in the standard treatment of those patients.  And so one has to somehow keep this all in context, and whatever information is provided has to be given with the balance of that overall discussion.
CHAIRMAN SALOMON:  Amy.
DR. SIEGEL:  Well, the rule suggests that trade secret information and patient identifiers would be redacted.  Other than that, the documents would be essentially what is submitted to the FDA would be submitted also and redacted form for posting on the Internet.
Is there some commercial redaction?
DR. NOGUCHI:  A limited amount, yes.  That's the proposal.
CHAIRMAN SALOMON:  Any and then --
DR. PATTERSON:  I wanted to make a comment because I think it's an important issue about providing an analysis and context for information that's provided to the public on what Ed was just talking about.
There has also been out for public comment a perhaps synergistic or complimentary proposal from NIH regarding the reporting of adverse event and other safety information to NIH.  The interplay of these two proposals is something that I think needs to be explored further.  But part of our proposal that would involve FDA cooperation or collaboration and input is the establishment of a national data assessment board that would meet in close session and would look at all the data reported, would look at the data being entered into the comment database between the two agencies, and would report out perhaps on a quarterly basis to the RAC and on an annual basis in some sort of written summary report of the findings and report the information in context, do analysis across trials, across vector class, across clinical indications.
So, I just wanted to put that on the table that I think the federal agencies are sensitive to the fact that merely putting up raw information is not necessarily beneficial.
MR. GROSSBARD: Elliott Grossbard.
Something that Dr. Siegel said prompted me to think of unintended consequences.  And you're quite right that on many submissions sponsors in describing toxicology studies, for instance, indulge in a fair amount of what might be called spin control, and the FDA reviewers are very sophisticated and I've over the years come to see how it just kind of gets ignored or blown off and handle in appropriate matter.  Reasonable people can disagree.
In a redacted version if companies were to indulge themselves in this kind of activity around safety studies, this could lead to an interesting interchange with FDA, something short of a labeling meeting perhaps, but a discussion about whether the company's interpretation is appropriate for presentation to the public and lead to kind of an ongoing engagement around a scientific interpretation that could be a distraction in many ways.
CHAIRMAN SALOMON:  Alison.
MS. LAWTON:  Just to follow-up on that comment.  I think that's part of what I was trying to get at as far as we need more time to work through how we do this and how the timing of the information is made available, how the information is made available.  Because that's one example where information that could be made publicly available immediately would be with a company's perspective that might change in the future once the FDA's had a chance to look at it.  And so the timing could be key.
Likewise, with adverse events.  You know, a serious adverse event may have a very different perspective when you first get that to having follow-up information to find out actually the reason that serious adverse event occurred.
So, they're both examples of why we need to really sort out the details around the processes and how the information is made publicly available.
CHAIRMAN SALOMON:  I just think a point following sort of where Abbey was going, is that yes, of course.  And I support that, as I already said.  However, we also shouldn't go so far as to say that if data is there that maybe isn't fully interpreted or understood, often times because it might take a year or two or 20 more events to really put it into context, that's not necessarily an a priori argument not to have that in the public domain in some form.  Because we shouldn't assume that patients and patients' families can't go to the investigator in the process of a true informed consent and say "Well, you know, at the website I read about such-and-such and I'm concerned about it."  
 I don't necessarily see that as any sort of a negative thing.  That is, in some sense, very positive aspect of a partnership between the physicians -- we're asking the patient and the patient's family to take a risk.  And I think that what we have to fight for, too, here is reasonable, responsible information transfer, but still not fight for no information transfer until it's 5 years later and it's happened 25 times, and we know the exact molecular mechanism. 
DR. SIEGEL:  Well, it should be noted it's not envisioned that the patients would be the only consumer of this information.  There are other investigators, that there are physicians and so forth.
CHAIRMAN SALOMON:  That's important context.  Thank you, Jay.
Michael.
DR. O'FALLON:  Phil, I think you said this process which lead to this massive document which I memorized every word of, of course, has been 6 or 7 years in the making, right?  So certainly sponsors have participated, is that not correct?
MS. LAWTON:  No, that's incorrect.  No.
DR. O'FALLON:  They have not?
DR. NOGUCHI:  No.  This particular rule, as many rules do, they go through a number of interactions.  While we can say it started a number of years ago, events certainly propel it one way or another.
We have indicated that we would be proposing this rule for some time, and even on that scale other events have interfered or gotten in the way, other priorities come in there.  So, it's -- no.  In this particular -- this is a proposed rule.  This has no part of a public discussion and it's not by any means meant to be the final, but it is meant to be the beginning.
DR. SIEGEL:  It's the nature of the rules we have by which we can make rules, which are governed by law.  They're not just rules.  And that in order to ensure that there's a fair public input and we're not getting input from some people and not others, and whatever, that while it was several years in the making internally there were broad general discussions.  It's at this point that the proposal is out, which is really only a limited period of time, for more formal input on the specific proposal.
MS. CHRISTENSEN:  Janet Christensen with Targeted Genetics.
I think that one of the issues that -- I've actually read this so many times I could probably give you chapter and verse.  I think a lot of us have in preparing our comments to the docket.
One of the concerns, however, is that when you start talking about criminal prosecution for perjury if the redaction is not appropriately carried out, I find that personally very scary.  You know, I'm going to do my very best job, but if we don't see eye-to-eye, I may be criminally prosecuted.  And that's one of the aspects of that proposal that I find very concerning.
When you do that in there, besides being the full employment act for regulatory lawyers and regulatory professionals, which I must say I have some bias towards, we have to start bringing in legal staff. And we are in order to be prospectively protecting our interests and keeping me out of jail, okay.  I like my freedom.
I think that you inadvertently lay on a tremendous amount of additional bureaucracy and legal review to ensure that we are following the law.  And for that reason I believe that there's a figure in -- as proposed as having an impact of about $840 a year to each company. I would suggest that with this additional legal review, not only for intellectual property, not only for securities and exchange information, and as well from the regulatory law perspective, that figure is going to be significantly higher.
So, that would probably -- and I would encourage everybody on the Committee to take a good look at that particular aspect. Because I think that can have -- I think it has a potential to significantly have a negative impact on working with the agency.  I think we've worked very well with the agency, as well as NIH, but we'd like to continue to maintain those relationships.  But when you put the threat of prosecution in there, it has a quelling effect.
Thank you.
CHAIRMAN SALOMON:  So the question I had in follow-up to that is who will do the redaction?  I guess in one version that I had heard, and this is by no means quoting anyone in the FDA, but in one version I heard was that reaction would be actually done by the companies, which I thought was brilliant because that way the companies (a) could control what they redacted and therefore you didn't have to have any fights or issues, and of course it was a tremendous savings in FDA activity, which I also thought was positive given the sparse amount of funds.
So if redaction is being done by the companies, and again this is a question not that I'm saying that anyone from the FDA told me they would do that, why is this an issue then of perjury and -- I didn't follow that.
DR. NOGUCHI:  Any laws that are -- or any regulations that are put forward by FDA are sanctionable; that if you don't follow the regulations, there is this whole series of steps that are available, those being one of them.  If you lie to the FDA, that is against the regulation and is sanctionable.  So it's in that nature where to be fair that where industry and sponsors are talking about legal counsel, we have legal counsel as well.  And that was one of the -- it's not a stipulation, but they felt that it would be worth reemphasizing that this is not meant to be a voluntary kind of a thing that it would be nice to do, but that it is in fact something we've spent a lot of time and effort determining and we feel that it's in the public interest to do that.  For the out lyers there are these sanctions which are not unique to this particular rule.  They apply to all FDA rules.  That's really the nature of it.
I will say about the redaction, part of this it's not really -- it's on certainly CBERS part, but the device industry does have -- all 510Ks have redacted version.  This is one level of clearance that is approved.  And I believe it's being implemented for PMAs as well.  So part of it is based on other FDA experience.  The redaction is done by the companies.
DR. SIEGEL:  But as part of the reasons for the underlying question, it's anticipated under this proposal that the FDA would do some checking of the amount of redaction.  That, you know, some companies for competitive reasons or other reasons might choose to redact more materials than we thought were appropriate.  And if that became extensive, it potentially could undermine the whole point of the rule.
On the other hand, if you acknowledge there's limitations on FDA resources, so there have been no -- the anticipation would be that the chore of redacting would be by the sponsors with an expectation that that would be largely sufficient and with spot checking and with appropriate remedies which, in many cases, would simply involve just a telephone call and a discussion of what happened.  But in some cases, it might involve more severe actions if there were problems.
CHAIRMAN SALOMON:  Alison.
MS. LAWTON:  Yes. I was actually just going to make a comment on the redaction as well along the lines that Jay just said, around as we heard from Sally as one example around the different level of redaction that might take place by companies.  And I think one of the questions around this proposed rule is what's acceptable and what's not.  And that's not clear at the moment.
You know, in the proposed rule there are definite ways to deal with that, such as putting companies on clinical holds if the level of redaction is too much or inappropriate.  So those are the types of things we still have to work out the details.
CHAIRMAN SALOMON:  Yes.  I think in thinking about this, the concern that you'd actually face potentially criminal investigation for perjury is -- that was good.  I like drama. I didn't mean that to sound a criticism.
But I'm not quite sure that that's a very large risk over what exists right now.  In other words, what I could see you being accused of perjury for is if there was an existing rule that you disclosed adverse events in animal trials or in clinical trials and you didn't, then you would of course be against the rule.  But I'm thinking that's not too far from where you're at today.
So I guess I'm -- in part of this discussion not quite sure what the incremental injury is here vis-a-vis a perjury charge.
MS. CHRISTENSEN:  I think the thing that caught me is in looking at previous proposed rules I've not found that language, per se, included in there.  And so perhaps this is a newer trend we're going to see in proposed rules.  So it's more of you don't usually find, for example, that there's -- for example, those proposed rules for GMPs issued in May of '96, there wasn't a thing in there that if you don't comply with this you'll be potentially up for criminal prosecutions.  I think Phil and Jay's comments are on the mark.
But again, you know, we have to react looking specifically at the proposal as published in the Federal Register.  So whether or not it's high drama or not, it certainly got my attention, as well as a number of other people's attention.  And I think I just wanted to float that out there just so people get an idea.  Because what I don't want to have happen, and this is me personally, I don't want to have happen that the synergistic relationship that we have with the regulatory agency -- the relationship we have with NIH/OBA is harmed or teased apart in an unhelpful way for the patients, for product development and moving forward.  That was my point.
CHAIRMAN SALOMON:  Abbey.
MS. MEYERS:  It's so interesting because I run a charity, a nonprofit and I can't negotiate with the IRS.  I can't tell them what I think should go into the regulations for nonprofit.  IT's crazy, you know, to hear that the regulated industry wants to tell the regulators how to regulate them.  That I can't adjust to it.  But I wish I had that kind of relationship with the IRS.
But when you're looking at this, understand the way this happens on Main Street.  People are sitting out there saying "Ah, the FDA controls my food, my drugs, the cosmetics, the x-ray machines, the mammograms and everything," and each one of those we go in there and tells them how to regulate it.
Another thing.  All of my children have been in clinical trials.  I had to signed informed consent documents for all of them.  The drugs they went on had killed animals.  I looked at the sentence and I said to the doctor "Explain this to me.  What happened here."  And after I had all the knowledge that I could, I made the judgment to put them on the medicine.  I'm not stupid.  You can't be so paternalistic.  Doctors are learning that everyday.  If the patient doesn't learn enough from the doctor, he goes home and he gets on the Internet, and he finds out the truth anyway.  And if I want to find out the truth about 99 percent of these people's products, I go on the Internet and I look at what they've been releasing to Wall Street.  I find out more from Wall Street than I can from the FDA.  Something has got to change here. Consumers won't stand for it anymore.
So tell them that the animals died and put a little footnote next to it that says "They died because they fell out of their cage, not because of the drug."  But tell them the truth, because if you don't, you increase your liability and you lose the public faith.
DR. SIEGEL:  I just wanted to make clear, and I know you know this, Abbey, but when we make new regulations we are compelled and we are not compelled in the sense that we do so reluctantly to consult publicly.  We consult publicly with regulated industry, and I must say in many cases we hear important perspectives from regulated industry of the implications and impact of the regulations that we may not always have appreciated.  But we don't consult just with public industry -- with regulated industry, that's why we are here. We are a consumer protection organization.  We're regulating industry.  We want to hear from consumers, we want to hear from academicians, we want to hear from scientists.  We want to hear from all concerned parties inn order to do what is in the best public interest.
I don't know how the IRS operates in that regard, but if they are able to make rules without public consultation, I would be a little bit surprised because that wouldn't seem appropriate to me.
CHAIRMAN SALOMON:  Well, I think actually the comment about the IRS isn't is fair since we know that in Congress, which is a public environment, that there is all kinds of input from the regulated industry, which is the public.  And they're in the process of changing the tax laws as we sit here discussing these regulations.
So, I don't think that it's quite an unreasonable situation to have regulated industry trying to work in a partnership with the FDA as long as we realize the FDA isn't bound by anything that a specific company or a group of companies demands, but it doesn't mean you can't be heard.  I think that's probably a very positive aspect of things, not a negative.
I think that from what I'm hearing here, again, this discussion wasn't intended to finish, but it seems like the dynamic that Abbey and Alison in a way have kind of set up is the right one for the next discussion.  And that is how much and what kind of data should be available to the public that addresses really well exactly what Abbey wants, and that is a sense of confidence, a sense of participation, a sense of partnership and how much of that is going to be -- how much information is not going to be put on there that would be considered private, competitive.  And by the way, I don't think most patients really care whether you use a real complicated growth factor mix to get out gene transcribed trials. I mean, I don't think that's the kind -- so I think that when you really -- you know, well there isn't going to be a fight, "Well, I really want to know about the stem cell factor."
DR. SIEGEL:  But, no, the patients may not care, but public discussion of safety concerns.  If you want to start doing aggregate data and be able to discuss in a public forum what is the safe or an unsafe way to proceed, it might be quite critical that you know which growth factors went into which product.
And so, again, it's not simply that the patient is the sole consumer of these data, which isn't to undermine the issue you're saying, and I do think we need to carefully look at everything.  But it's important to realize all the perspectives.
CHAIRMAN SALOMON:  Well, I guess, Jay, what I was -- what maybe isn't either quite clear here is -- I agree -- I understand what you were saying back to me. 
My thinking is is that if there's really an issue that gets brought forth to a committee like this, whether we have to close it to get at part of it, you know, that there's some secret factor that we need to know about for us to make a decision, yet maybe isn't going to be shared with all the other competitor companies, I certainly agree with that.
My thinking was that this public disclosure policy and what we've been talking about isn't really for that sort of a user.  I thought it was more for the daily experience with the whole field of gene therapy and xenotransplantation. What trials there are and what they're about, and who needs them.
DR. SIEGEL:  That's a wrong perception.  It's important to note that feeding into this rule is not simply making sure that things are available on the Net that patients can read or investigators, but also facilitating our ability to share with NIH data that they wish to be able to present in public, facilitating our ability to share with this Committee data that we would prefer to be able to discuss in public rather than behind closed doors, facilitating our ability when symposia are held, you know, why do these mice die at the last RAC meeting, what's going on with adenoviruses, why did Jessie Gelsinger die in a RAC meeting of November '99.  Facilitating our ability to speak to information that we have in hand which may well involve a lot of that type of detailed information, and that's an important underlying reason for this.  This is not to be viewed simply as a way to put all this information for public consumption in a raw form for people to read on the Internet, although it does involve doing that and we're hearing some comments that there might be other ways to address other concerns without doing that.
You know, I want to reiterate what Phil said, and I'm here trying to explain not particularly defend any one position at this point in time.  Although, obviously, I was involved in development of the proposed rule.  But I want to repeat what Phil said that it's very important to us that we have as much input from as broad a spectrum as possible to encourage people.
We can insert, and I suppose insert these proceedings into the docket so that what is said here will be part of the formal record considered.  But I know that there's a lot that's underlying what people are saying that isn't going said, and I would encourage people to put that out.  To put that in paper in whatever detail they wish to communicate and get it into the docket, because we really do want to be able to consider all of the concerns and options as we work on this rule.
CHAIRMAN SALOMON:  I think that's an excellent clarification, Jay, and that actually helps me see it in a broader light.
I would tend to bring this to a close now.  I would also invite any other comments from the panel or from the audience.
If not, I want to thank everyone who attended the meeting and contributed.  
I'd like to thank Gail Depolito and Bill Freas and Rosanna Harvey, and the others of the FDA staff for whom work an incredible amount of time and energy into making these things happen.  And I certainly appreciate it.
We'll see you in the next FDA meeting, which will have a title next time, right?
(Whereupon, at 1:17 the meeting was adjourned.)