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UNITED STATES OPF 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

 

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                   34th MEETING

 

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                      FRIDAY,

 

                 FEBRUARY 28, 2003

 

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      The Advisory Committee was called to order at 8:01 a.m. in the Kennedy Ballroom of the Holiday Inn- Silver Spring, 8777 Georgia Avenue, Silver Spring, Maryland, Dr. Daniel R. Salomon, Chairman, presiding.

 

 

PRESENT:

           

DANIEL R. SALOMON. M.D.         Chairman

JONATHAN S. ALLAN, D.V.M.     Member

BARBARA BALLARD               Patient Representative

JOHN COFFIN, Ph.D.            Temporary Voting Member

KENNETH CORNETTA, M.D.        Temporary Voting Member

JOHN E. FRENCH, Ph.D.         Temporary Voting Member

DAVID M. HARLAN, M.D.         Member

KATHERINE A. HIGH, M.D.       Member

JOANNE KURTZBERG, M.D.        Member

ALISON F. LAWTON              Industry Representative

WARREN LEONARD, M.D.          Temporary Voting Member

CRYSTAL MACKALL, M.D.         Temporary Voting Member

ABBEY S. MEYERS               Temporary Voting Member

RICHARD C. MULLIGAN, Ph.D.    Member

THOMAS MURRAY, Ph.D.          Temporary Voting Member

 

PRESENT:  (CONT.)

 

MAHENDRA S. RAO, M.D., Ph.D.  Member

BRUCE E. TORBETT, Ph.D.       Temporary Voting Member

ANASTASIOS A. TSIATIS, Ph.D.  Member

LINDA WOLFF, Ph.D.            Temporary Voting Member

ALICE J. WOLFSON, J.D.        Consumer Representative

GAIL DAPOLITO                 Executive Secretary

 

NIH REPRESENTATIVES:

 

STEPHEN M. ROSE, Ph.D.

 

GUEST SPEAKERS:

 

CLAUDIO BORDIGNON, M.D.

MARINA CAVAZZANA-CALVO,M.D., Ph.D.

ADRIAN THRASHER, M.D., Ph.D.

 

PRESENTERS FROM FDA:

 

PHILIP NOGUCHI, M.D.

RAJ K. PURI, M.D., Ph.D.

CYNTHIA A. RASK, M.D.

CAROLYN WILSON, Ph.D.

 

PUBLIC SPEAKERS:

 

PAUL GELSINGER

RICHARD JUNGHANS, Ph.D., M.D.

CHRISTOF VON KALLE, M.D.

DONALD B.KOHN, M.D.

RACHEL SALZMAN, M.D.

 

Morning Session

 

Welcome and Introductory Remarks ............... 4

      Daniel Salomon, M.D., Chair

 

Meeting Statement .............................. 4

      Gail Dapolito, Executive Secretary

 

Guest Presentations

 

      Dr. Marina Cavazzana-Calvo............... 34

 

      Dr. Claudio Bordignon ................... 92

 

      Dr. Adrian Thrasher..................... 119

 

      Discussion.............................. 132

 

Committee Discussion of Questions............. 166

 

Public Hearing

      Donald Kohn............................. 177

      Rachel Salzman.......................... 187

      Richard Junghans........................ 191

      Paul Gelsinger.......................... 197

 

Discussion and Voting......................... 199

 

Adjourn....................................... 304

 

               P-R-O-C-E-E-D-I-N-G-S

                                       (8:01 a.m.)

            CHAIRMAN SALOMON:  I want to welcome everyone here to the second day of Meeting Number 34 of the BRMAC, which of course doesn't mean anything to anyone, including me. 

            What does mean something is the topic for today, which is to update the Committee, and to provide advice to the FDA on retroviral gene therapies, particularly focused obviously on the cases of severe combined immunodeficiency disease.  But certainly the discussions need to range somewhat beyond that narrow focus at some point.  The nature of the topic is absolutely important and critical, and I think that does not need any introduction, so I will spare you that.

            The day is relatively compressed, just because it is Friday, and with the snow and trying to get to airports, I would like to be done at 3:00.  Otherwise, I am not making it back to California this evening. 

            So you have got a Chair who is engaged in finishing on time, which is usually a good thing.  So without any other introduction at the moment. We will pick up with the FDA's introduction in a moment. 

            I would like to turn to Gail Dapolito, our Executive Secretary, to read a statement into the minutes.

            MS. DAPOLITO:  Good morning, everyone.  This announcement is part of the public record for the Biological Response Modifiers Advisory Committee meeting on February 28, 2003.  Pursuant to the authority granted under the Committee charter, the Director of the FDA's Center for Biologic Evaluation and Research has appointed Ms. Barbara Ballard and Ms. Abbey Meyers, and Drs. John Coffin, Kenneth Cornetta, John French, Warren Leonard, Stewart Orkin, Crystal Mackall, Thomas Murray, Bruce Torbett and Linda Wolf as temporary voting members for today's discussions.

            Based on the agenda, it was determined that there are no products being approved at this meeting.  The Committee participants were screened for their financial interests to determine if any conflicts of interest exist. 

            The Agency reviewed the submitted agenda and all financial interests reported by the meeting participants.  As a result of this review the following disclosures are being made. 

            In accordance with 18 USC 208, Drs. John Coffin, Kenneth Cornetta, and Warren Leonard were each granted a waiver that permits them to participate in today's committee discussions.

            Dr. Richard Mulligan was granted a limited waiver for today's discussions that permits him to participate in the discussion without a vote.  We also note for the record that Ms. Alison Lawton serves as the non-voting industry representative member acting on behalf of a regulated industry.

            She is employed by Genzyme, and thus has interests in her employer and other similar firms.  With regard to FDA's invited guest speakers and guests, the agency has determined that the services of these speakers and guests are essential. 

            The following interests are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the speakers and guests.  Dr. Claudio Bordignon is employed at the Institute of Science in Milan, Italy.  He is a researcher in gene therapy clinical trials, especially ADA-SCID, and has associations with firms involved with retroviral vectors.

            Dr. Marina Cavazzana-Calvo is employed at the Necker Hospital in Paris, France.  She is involved in retroviral vector gene therapy studies to treat patients with X-SCID. 

            Dr. Adrian Thrasher is employed at the University College in London, England.  He is a researcher in gene therapy clinical trials to treat patients with SCID. 

            Dr. Cristof von Kalle is employed at the University of Cincinnati, and is involved in gene therapy research.  Drs. Amy Patterson and Stephen Rose are employed with the Recombinant DNA Program, Office of Biotechnology Activities, NIH.  NIH funds gene therapy research.

            Members and consultants are aware of the need to exclude themselves from discussion involving specific products or firms for which they have not been screened for conflict of interests.  Their exclusion will be noted for the public record. 

            With respect to all other meeting participants, we ask in the interest of fairness that you state your name, affiliation, and address any current or previous financial involvement with any firm whose product you wish to comment upon.

            Waivers are available by written request under the Freedom of Information Act, and as a courtesy to the committee discussion and those in the audience, and we ask that you silence your cell phones and pagers.  Thank you. 

            CHAIRMAN SALOMON:  Before I turn to Phil and Carolyn to provide an FDA introduction, I just wanted to share with you sort of a brief strategy for today as far as I am concerned as Chair. 

            We have many of us sitting around the table right now, with a few additions to increase the expertise here, but most of us have heard the first round of this issue, with the first child that developed leukemia from the retroviral insertion in the LMO-2 site just before the first of the year.

            And so I think it is very important that the focus of this meeting begin solidly on the framework that the committee set at that time and ask the major question; and that is, what has changed?

            At the time, we talked about what would happen if a second case was found.  How would that change the risk/benefit ratio calculations that we made?  How does that serve the community and affect the stakeholders with severe combined immune deficiency disease?  How does that affect the broader stakeholder community that now includes anyone who might benefit from various kinds of retroviral gene therapy and the companies and academia, et cetera, that are involved.

            So I think the key thing here is to take the foundation of what we did last time. It is perfectly appropriate to say, well, we were right about this, and it incrementally changed in such and such a way, or that we were wrong, and we need to see it.

            But I'd like to see the focus building on what we set up previously, rather than starting all over again and taking everything apart and taking a really long time to go over what I think -- we already plowed a lot of ground here, and I would like to see us go forward from this point onward.  Phil.

            DR. NOGUCHI:  Thank you, Dan, and I would like to thank everyone who is participating today on behalf of the Center for Biologics. Our grateful thanks for coming here.

            This is extraordinarily difficult and is one of a number of things that I would like to just introduce. I presented something like this at the last meeting, but why are we here? 

            We are here to acknowledge that there continues to be extraordinarily difficult diseases and the treatment of them remain hopeful, but are always a problem in terms of balancing risks and benefits.

            And we are here to affirm that the way to get at this ideal is to do rigorous clinical trials.  As we do this, and as we are seeing today, this is not a static evaluation, but it is a continuous balancing of risks and benefits. 

            We are here to further learn about adverse events as they occur, and as they are scientifically researched, and I think some of our discussion should be oriented towards taking what we now know and thinking of strategies for mitigation and elimination of these particular side effects, as well as strategies for side effects in general, where we know more on a molecular basis than we did even just a few months ago.

            And really we are here to confirm that this is exactly where we should be, and we look forward to a very vigorous, a very timely and a very important discussion. 

            Dr. Wilson will now follow this and really step us through a little bit of the background from the last meeting and lay out the framework and the pathway for our discussion today. 

            DR. WILSON:  While they are getting it set up, I am just going to introduce that what I will be doing today is to try to provide an update for the committee since our last meeting in October.

            And that update will include, actually, a revisiting of the discussion that this committee had, so that analogous to what Dr. Salomon was just saying, we can remind the committee what we said in October, and then move forward from there.

            (Brief pause.)

            CHAIRMAN SALOMON:  This is a new California thing where you kind of start the meeting off with a Zen meditation.  I hope you appreciate that. 

            DR. WILSON:  Thank you, everyone, for your patience.  And so, again, what I am going to do for you this morning is to try to provide an update so that you can have all the information at hand in terms of what has happened since the October meeting, so that you can move forward in your deliberations on these important safety issues regarding the clinical use of retroviral vectors for gene therapy. 

            My update will include, as I mentioned, a review of the consensus points from the discussion of the October meeting, subsequent FDA actions that we have taken both in response to the October meeting as well as to the subsequent notification in late December from Dr. Fischer's group of the second child with the T-cell expansion. 

            I am going to provide a quick overview of active clinical trials that are under U.S. IND that use retroviral vectors, and then provide some information from other committees that have been deliberating on these issues, in particular the recommendations from the Recombinant DNA Advisory Committee that met earlier this month, as well as some of the reports from various international bodies as well.

            And then finish with just a quick read-through of the questions for the committee so that you can have these in your mind as we move forward with today's agenda.

            So to start off, the one general consensus of the committee in October was that the T-cell expansion seen in the X-SCID patient treated in France was likely due to an insertional mutagenesis effect of the retroviral vector used in the gene therapy.

            With this as a premise in terms of a major conclusion, then you move forward to address the following question which we asked you in October;  namely, are there additional data or measures that clinical investigators need to provide before future and present clinical trials in SCID patients should proceed in the U.S.?

            Please consider in your discussion each of the following as they pertain to X-SCID or other forms, such as ADA.  And we asked you to discuss six different issues: risk/benefit, informed consent, alterations to cell dose or vector dose, mapping of vector insertion sites, and alterations in vector design.

            And what I would like to do in the next few minutes is just provide for you, again, your committee consensus on each of these points so that you know where you were in October. 

            So regarding risk/benefit, all agreed that, with HLA-identical donors for SCID indications,  the benefits of this particular treatment far outweighed the potential risks of using gene therapy.

            So the committee recommended that patients who have available HLA-identical donors should be excluded from gene therapy clinical trials.  However, the case for haploidentical transplants was not as clear-cut, in that you do get 90 percent survival if the transplant is done in the newborn period.

            Survival rates are lower, depending on the transplant center, when it is done later in life.  But in both cases, you don't seem to get B-cell reconstitution requiring life-long administration of an IgIV. 

            And there was a general consensus that the quality of life for even those patients, quote, "who are surviving" is suboptimal, with recurring infectious episodes and other complications. 

            The other major point that was brought up in the discussion of risk/benefit issues was the analogy to cancer treatments, which often carry risk of secondary cancer, yet are very effective at treating cancer and would not be thought of as being eliminated because of the risk of secondary cancer.

            As far as the risk of gene therapy, all acknowledged the obvious statement that if you don't get gene transfer, then, of course, it is a safe procedure.  But in the case of the trial in France, clearly there is gene transfer and it is having a therapeutic effect.

            And there is actually 100-percent survival at this time, even now with the second child having a leukemia-like illness.  And the other important point that was brought out was that the success of Dr. Fischer's trial may be related to the fact that he treats patients de novo, and he is not using patients who had failed haploidentical transplants. 

            So the committee felt it was important that gene therapy in this context not be considered a salvage therapy but that families be given a choice to have a haploidentical or gene therapy.

            And so, essentially, in October the committee consensus was that trials in SCID indications should proceed, but there were some caveats on that conclusion; namely, that clearly changes to informed consent documents needed to be made.  You felt it was important that all retroviral vector clinical trials should have these revisions to reflect this event.

            The informed consent document should be written in clear language. It should not include mitigating factors, such as issues regarding multiple hits, or number of patients treated, and that it should be clear in saying that gene therapy caused the leukemia, while still emphasizing the unknown quality regarding the risk to an individual patient.

            On the third part of this question regarding cell dose, there was some information provided by the committee regarding, for example, use of cord blood, that you may be able to reduce the numbers somewhat and still maintain engraftment. 

            The number that was thrown out by the committee was one times ten to the fifth CD34 positive cells per kilogram.  I recognize that you had extensive discussions of this yesterday, so you probably are much more informed on this, at this point, than I am, and so I will just leave it at that.

            But, essentially, after going about this issue, the committee felt that based on 30 years of experience that there are certain acknowledged minimum cell doses that are required in order to get engraftment, and that to go below those doses would provide -- would put these children at risk of additional infectious disease complications.

            So, actually, the committee recommended moving forward on researching how to better target the true hematopoietic stem cell, and that would be a more effective way to reduce the cell dose. 

            Regarding vector dose, this was really felt to be a research question.  People also felt this wasn't a huge issue at that time because most retroviral vectors hit about one copy per cell. 

            However, CBER does want to point out that we are starting to see novel vector systems that reach significantly higher copy numbers per target cell, and that this is an issue that the committee may need to revisit. 

            In terms of insertion site mapping, the way that we had phrased the question was regarding lot release of ex vivo transduced cells.  The committee quickly pointed out that this was not scientifically or technically feasible, and this was obviously rejected.

            However, there was a strong recommendation from the committee that patient samples should be monitored closely for outgrowth of single clones, and that if a monoclonal integrant is observed, that it should be sequenced, following with additional phenotypic analyses.  And it was pointed out that this information regarding the integration site may inform clinical treatment, and it may allow earlier treatment.

            The committee recommended that this type of monitoring be performed at approximately a 3- to 6-months interval.  It was thought that this should be done on an active basis, rather than archiving of samples.  And, obviously, if there is no vector positive cells in the peripheral blood, then there is no need to perform this monitoring.  But the committee recommended that each protocol needs to develop a monitoring plan, including trigger points, for additional analyses.

            And, finally, the committee left a caveat that if a particular sponsor felt that it wasn't justified to do this monitoring in their clinical trial, then the FDA should consider this, obviously on a case-by-case basis.

            Regarding vector design, the question here was whether or not you could increase the safety of retroviral vectors by minimizing the effect of an enhancer to activate neighboring or distal genes.  And while everybody on the committee felt this was an important research question and made the recommendation that it should be further studied, nobody felt that this was something that needed to be changed now for clinical trials to proceed.

            And, in addition to that, it was strongly recommended that preclinical models be developed to assess the risk of vector insertion for new vector designs.

            Now, following the meeting in October, CBER then sent out letters to sponsors requesting first of all that all sponsors using retroviral vectors revise their informed consent, and we actually have specific template language that we recommended in that letter.

            In addition, we asked that, in a subset of those trials using CD34 cells, sponsors submit plans for monitoring for integration clonality, and the interval that we recommended was every six months for the first five years, and yearly thereafter for the next ten years.

            And then when a predominant clone is identified, that there be a second test within three months from the first, that the sequence be determined, and that you monitor the subjects closely for signs of malignancy.

            So to summarize then, there were three sets of letters that were sent subsequent to the October meeting.  In the clinical trials in SCID, which were the subset which were on hold at the time we met in October, we required that they revise their informed consent and develop plans to monitor clonality in order for those trials to proceed.

            In indications that use hematopoietic stem cells or other stem cells, these two conditions were recommended, but not a requirement.  And in all other retroviral vector clinical trials, we requested only that they revise their informed consent, and at that time did not recommend developing plans for monitoring clonality.

            And we confined this to hematopoietic stem cells, this issue of looking for clonality, based on the idea that stem cells are by their very nature long-lived, with high proliferative capacities, and therefore more at risk to the effects of vector integration mutagenesis.

            Now, as you know, in late December, we received a second report from Dr. Fischer that there was another subject in his X-SCID gene therapy clinical trial that developed a leukemia-like illness at 34 months post treatment.

            And subsequent to that initial report, preliminary data was provided to us by Dr. Fischer that there seemed to be, again, a monoclonal retroviral vector integration 5' to the LMO-2 locus, which I am sure you recall is the same locus, but a slightly different site within that locus, that was observed in Patient No. 4.

            And so these preliminary data suggested that we were probably looking again at an incident where retroviral vector integration was likely playing a role in the T-cell expansion.

            So in response to these data, we took the following actions:  We again sent three sets of letters to sponsors.  In this case now, we changed the issues of informed consent and clonality -- monitoring clonality plans to a requirement.

            In other words, all clinical trials that used hematopoietic stem cells as their target for ex vivo transduction were now put on hold until they met these conditions. 

            Inactive trials that use hematopoietic stem cells were told that if they ever wanted to resume their trial, that again they would need to meet these conditions.  And then all other retroviral vector clinical trials, we didn't put these on hold, but we made a recommendation that they now would also need to develop plans to monitor for clonality.

            Now, what are the clinical trials that we are talking about?  In terms of target cells, you can see that really fully half of the current active clinical trials are in either CD34 hematopoietic stem cells or bone marrow cells.

            The next largest category are in lymphocytes of various types. Then we have a few in fibroblasts. The other category includes smooth muscle cells as well as a number of different tumor cell types.   

            And then we have two each that are either direct administration of vector producer cells, or of the retroviral vector itself.  In terms of indication, I have broken this down for you two ways.  One by total active clinical trials using retroviral vectors, and in the blue bars, this shows that subset that are in the CD34 bone marrow target cells.

            So in cancer, we have 8 out of 28 total trials using CD34 cells for the ex vivo transduction, 8 out of 12 in HIV.  The miscellaneous, these two are osteogenesis imperfecta and multiple sclerosis.

            And almost all of our trials in genetic disease target CD34 cells.  And these include, of course, the SCID indications, chronic granulomatous disease, and Fanconi's anemia. 

            So at this juncture then, it is obviously prudent to ask whether or not there are additional modifications that we need in order for these types of clinical trials using retroviral vectors to proceed safely.

            And what I would like to do for you now is to just outline some considerations, some which are more theoretical and would require more research before they could be immediately implemented in clinical trials, and others which are potentially more practical and could be implemented more directly.

            So the first, which is a more practical solution, is again to revisit the issue of dosing with the idea that if you reduce the total load of vector integrants that this reduces the risk of integration into a potentially, quote, "bad locus"; a locus that might be tumorigenic.

            And one could envision doing this by reducing the dose of vector used in the transduction, reduce the dose of cells given back to the patient, or potentially changing the dose so it is based on a total number of vector integrants.

            In addition, as was recommended by the committee in October, we want to consider whether or not we might need to have additional preclinical studies to assess the carcinogenic potential of a particular vector backbone-transgene target cell combination.

            And there is one of two ways that one could envision doing this.  One is to perform traditional carcinogenicity testing at an earlier stage of clinical development. This type of testing is usually done at the time a sponsor gets to licensure.

            And the reason for that is because these are multi-year, very expensive studies.  So we don't usually ask people to do this for a Phase I trial.

            Alternatively, one might consider some of the newer accelerated models of tumorigenesis, such as transgenic models carrying oncogenes or knockout models of tumor suppressor genes.  One might also consider a complementary approach of both assays. One might consider doing these concurrently with an early phase clinical trial.

            In terms of cell target or culture conditions, again these are much more on a theoretical, but again coming back to if we could identify what is a true hematopoietic stem cell.

            One issue that is acknowledged regarding retroviral vector or retroviral integration in the genome is that it tends to occur in sites of transcriptionally active genes. 

            So if you could identify a transduction protocol, for example, by studying gene expression by gene or protein microarray that has a fewer number of transcriptionally active genes, this might reduce the number of integration targets. 

            And then, ideally, if you could actually identify cells with vector integrants into known tumorigenic sites, this obviously would be nice to be able to do, but clearly on the realm of way theoretical.

            In terms of modifications of the vector, again, these are things that are in the research phase.  People are starting to look at the addition of insulator sequences. 

            These have really been done more to look at the ability of these sequences to insulate from the effect on the enhancer becoming silenced, and it has not really been studied whether or not these elements would also have the effect of blocking enhancer activation of neighboring genes. 

            But that is something that probably should be studied.  Deletion of retroviral vector enhancer elements within the LTR would clearly reduce the risk of enhancer activation of neighboring genes, and if you could develop a vector with targeted integration, this would be ideal, but again much more on the theoretical.  And it is not known at this point whether or not specific transgenes might also play a secondary role in the tumorigenesis.

            So I want to finish then with recommendations from other advisory committees.  The first is the NIH Recombinant DNA Advisory Committee.

            They have had two meetings on this topic. The first was in December of last year, and the second was just earlier this month on February 10.  And they made the following observations:  The majority of children in this X-linked SCID gene transfer study have had major clinical improvement to date.

            The gene transfer was a cause of both leukemias and the occurrence of leukemia in this protocol is not a random event and constitutes an inherent risk in this study.

            So based on these observations, the RAC recommended the following two main points:  Pending further data or extenuating circumstances, retroviral gene transfer studies for X-linked SCID should be limited to patients who have failed identical or haploidentical stem cell transplantation.