> 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BIOLOGIC RESPONSE MODIFIERS

> ADVISORY COMMITTEE MEETING #31 - VOLUME I
>
> Wednesday, October 24, 2001 9:00 a.m.
>
> Holiday Inn Gaithersburg Two Montgomery Village Avenue
>
> Gaithersburg, Maryland

2

PARTICIPANTS

Daniel R. Salomon, M.D., Chairman

Gail Dapolito, Executive Secretary

Rosanna L. Harvey, Committee Management Specialist

Members:

Richard E. Champlin, M.D.

Katherine A. High, M.D.

> Richard C. Mulligan, Ph.D.

Alison F. Lawton, Industry Representative Mahendra S. Rao, M.D., Ph.D.

Consultants:

David W. Gaylor, Ph.D.

Katherine E. Knowles, Consumer Representative

Guest:

Amy Patterson, M.D.

FDA Participants:

> Jay Siegel, M.D. Patricia Keegan, M.D. Steven Rosenthal, M.D. Philippe
> Bishop, M.D.

3

C O N T E N T S

Opening Remarks and Introductions,

Daniel Salomon, M.D. 4

Conflict of Interest Statement, Gail Dapolito 7

Long-Term Follow-up: Gene Transfer Clinical Trial Participants, Philippe
Bishop, M.D. 11

Epidemiologic Considerations in Developing a

Database

for Long-Term Follow-up of Subjects,

Steven Rosenthal, M.D., M.P.H. 27

Open Public Hearing:

Ms. Malissa Tice 40

Committee Discussion of Questions 43

> 4 1 P R O C E E D I N G S

2 Opening Remarks and Introductions

3 DR. SALOMON: Good morning, everybody, in

4 the beginning of a three-day session that begins

5 today, Wednesday, October 24th. If you were

6 expecting anything but the FDA\'s BRMAC committee

7 meeting, you are in the wrong room. I just can\'t

8 imagine anyone coming all the way out to

9 Gaithersburg thinking they are coming to a

10 different committee. My wife is happy. Supposedly

11 this is safer.

12 Before doing anything else this morning, I

13 wanted to begin something I just feel a personal

14 responsibility to. We have been together, many of

15 us, for a very long time and in a way that kind of

16 creates a type of family, and one of our family

17 members, unfortunately, was caught up in the

18 September 11 tragedy. What you see here is a

19 picture of Lisa Raines, who was vice president of

20 government relations for Genzyme. The picture was

21 kindly provided by Alison Lawton, to my left. Lisa

22 was often in the audience. She interacted with

23 many of us. I have met her on several occasions

24 here. She was very active with FDA and Bio, and

25 before she went to Genzyme, she was very involved

> 5 1 in a lot of different things. So, her interactions

2 went far beyond just the BRMAC committee. Anyway,

3 just at a time in which so much has happened to us,

4 it just seems inappropriate not to take a second to

5 recognize this woman and the tragedy that engulfed

6 her along with the rest of the country.

7 Well, on to hopefully better things today.

8 I think what we will do just to start off is

9 quickly go around the table and introduce

10 ourselves, and then we will get the meeting going.

11 Can we start on the left?

12 DR. RAO: I am Mahendra Rao. I am at the

13 National Institute on Aging. I work with stem

14 cells in development.

15 DR. CHAMPLIN: Richard Champlin, I am the

16 Chairman of the Department of Blood and Marrow

17 Transplantation at the M.D. Anderson Cancer Center.

18 DR. HIGH: Kathy High. I am the Director

19 of Research in the Hematology Division at the

20 Children\'s Hospital in Philadelphia.

21 DR. GAYLOR: David Gaylor, Sciences

22 International. My area is biostatistics and risk

23 assessment.

24 MS. LAWTON: Alison Lawton. I am the

25 industry rep on the panel. I chair the solid and

> 6 1 gene therapy committee for PhARMA and work for

2 Genzyme.

3 DR. SALOMON: Dan Salomon. I am at the

4 Scripps Research Institute and work in experimental

5 medicine. My interests have been in cellular and

6 organ transplantation and tolerance to gene

7 therapy.

8 MS. DAPOLITO: Gail Dapolito, Executive

9 Secretary for the committee. Seated to my right in

10 the FDA section is Rosanna Harvey, committee

11 management specialist.

12 MS. KNOWLES: I am Kathy Knowles and I am

13 with a small non-profit company in Seattle,

14 Washington, Health Information Network. I serve as

15 a consumer representative for the VPAC committee

16 and I am serving in that role today here.

17 DR. PATTERSON: Amy Patterson, Director of

18 Office of Biotechnology Activities in the Office of

19 Science Policy at NIH.

20 DR. ROSENTHAL: Steve Rosenthal, medical

21 officer, Division of Vaccines, FDA.

22 DR. BISHOP: Philippe Bishop, medical

23 officer, CBER, oncology.

24 DR. KEEGAN: Patricia Keegan, Division of

25 Clinical Trials, CBER.

> 7 1 DR. SIEGEL: Jay Siegel, Director, Office

2 of Therapeutics at CBER.

3 DR. MULLIGAN: Richard Mulligan, from

4 Harvard Medical School.

5 DR. SALOMON: Thank you all, and I would

6 like to greet Dr. Gaylor, joining us from

7 biostatistics. We will need you, and Ms. Knowles,

8 thank you. Let\'s move right along to Gail,

9 providing us with the conflict of interest

10 statement.

11 Conflict of Interest Statement

12 MS. DAPOLITO: This statement applies for

13 all three days of the meeting. This announcement

14 is part of the public record for the October 24-26

15 Biological Response Modifiers Advisory Committee

16 meeting.

17 Pursuant to the authority granted under

18 the committee charter, the director of FDA\'s Center

19 for Biologics Evaluation and Research has appointed

20 Dr. David Gaylor and Ms. Katherine Knowles as

21 temporary voting members for the discussions on

22 October 24. In addition, the CBER director

23 appointed Drs. Jonathan Allan, Kenneth Cornetta,

24 Michael Emerman, David Gaylor, Katherine Knowles,

25 Jeffrey Kordower, Clifford Lane, Bruce Torbett, and

> 8 1 John Zaia, as temporary voting members for the

2 committee discussions on October 25 and 26.

3 To determine if any conflicts of interest

4 existed, the agency reviewed the submitted agenda

5 and all financial interests reported by the

6 committee participants. As a result of this

7 review, the following disclosures are being made:

8 In accordance with 18 U.S.C. 208, Drs.

9 Richard Champlin, Katherine High, Richard Mulligan,

10 Clifford Lane and Jeffrey Kordower have each been

11 granted a waiver which permits them to participate

12 in the committee discussions.

13 Drs. Champlin, Cornetta, Lane, Mulligan,

14 Salomon, Sausville and Torbett have associations

15 with firms that could be affected by the committee

16 discussions. However, in accordance with current

17 statutes, it has been determined that none of these

18 associations require the need for a waiver or an

19 exclusion.

20 Ms. Alison Lawton is serving as the

21 non-voting industry representative member for this

22 committee. She is employed by Genzyme and, thus,

23 has interests in her employer and other similar

24 firms.

25 In regards to FDA\'s invited guests, the

> 9 1 agency has determined that the services of these

2 guests are essential. The following interests are

3 being made public to allow meeting participants to

4 objectively evaluate any presentation and/or

5 comments made by the guests. The following

6 individuals are employed by industry and have

7 interests in their employer and similar firms:

8 Drs. Dale Ando and Gabor Veres are

9 employed by Cell Genesys. Dr. Inder Verma is on the

10 board of directors of Cell Genesys and Dr. Susan

11 Kingsman is the founding shareholder of Oxford

12 Biomedica.

13 Dr. Amy Patterson and Dr. Marina O\'Reilly

14 are employed by the National Institutes of Health,

15 Office of Biotechnology Activities. Dr. O\'Reilly

16 also has a financial interest in an affected firm.

17 In the event that the discussions involve

18 other products or firms not already on the agenda

19 for which FDA\'s participants have a financial

20 interest the participants are aware of the need to

21 exclude themselves from such involvement and their

22 exclusion will be noted for the public record.

23 With respect to all other meeting

24 participants, we ask in the interest of fairness

25 that you state your name, affiliation and address

> 10 1 any current or previous financial involvement with

2 any firm whose product you wish to comment upon.

3 A copy of the waivers addressed in this

4 announcement is available by written request under

5 the Freedom of Information Act.

6 DR. SALOMON: Before we get started again

7 formally, again, in terms of ground rules here, I

8 have always started by encouraging the audience to

9 participate. My feelings are that the purpose of

10 this advisory committee is both to focus the

11 expertise on the panel, but also to bring to bear

12 as much of the community\'s opinions and thoughts on

13 these complicated subjects, particularly the one

14 today on long-term follow-up. So, I hope that

15 nobody in the audience will be inhibited to get up

16 and I will do my very best to recognize you

17 promptly, and would encourage that at all times.

18 To the committee members, I would also

19 just say that we will attempt to reach consensus

20 whenever consensus is possible. If my attempts to

21 reach consensus are failing or I am wrong, then I

22 am expecting you guys to, you know, bring that to

23 my attention. I certainly never would want to

24 pretend I was reaching consensus and not do it.

25 The other thing that I think would be

> 11 1 important is that a vigorously defended minority

2 opinion is absolutely appropriate. So, even if I

3 am saying something at the end of a section that

4 sounds like a committee consensus if, at the end,

5 you don\'t personally believe it, then I think it is

6 very important to stop and articulate those issues

7 and not feel that there is any pressure from me as

8 chair to hold any particular party line.

9 Then I guess we should get started. To

10 begin with, Philippe to begin the discussion of

11 long-term follow-up: gene transfer protocols for

12 clinical trial participants.

13 Long-Term Follow-up:

14 Gene Transfer Clinical Trial Participants

15 DR. BISHOP: Dr. Salomon, members of the

16 committee, good morning.

17 \[Slide\]

18 This morning\'s presentation pertaining to

19 long-term follow-up of subjects in gene transfer

20 studies has been broken down into three parts. The

21 first part, I will read you briefly, is a summary

22 of prior BRMAC discussions focusing on statements

23 or at least generalizations that are pertinent to

24 today\'s discussion.

25 \[Slide\]

> 12 1 I will move on then to discuss areas of

2 clinical concerns that pertain to gene therapy and

3 are relevant to the long-term follow-up of subjects

4 enrolled in these trials and, I will turn it over

5 to Steven Rosenthal who will discuss issues of

6 special considerations when discussing

7 epidemiologic databases.

8 \[Slide\]

9 So, first some background information and

10 summary of prior discussions.

11 \[Slide\]

12 It is important to understand that today\'s

13 discussion is in the context of current FDA

14 guidance pertaining to long-term follow-up of

15 subjects in gene transfer studies. It is important

16 to realize that as of today the only guidance that

17 we have pertaining to long-term follow-up of these

18 individuals is limited to studies that involve

19 retroviral gene vectors. This guidance document

20 has been discussed at great length at prior

21 meetings here, at BRMAC, and is also available on

22 our web site. For those of you who have not had

23 opportunity to get intimate with this particular

24 document, I would invite you to visit the FDA web

25 site for that.

> 13 1 \[Slide\]

2 It is in that context that discussions in

3 November, almost a year ago, November of 2000, took

4 place. At that time, I think it was clear that the

5 committee told us that efforts to gather

6 information pertaining to the long-term risks of

7 exposure are necessary not just for retroviral

8 vector studies but for all of gene transfer

9 products and, rather than focusing on vectors

10 types, it is important to maybe consider the

11 properties or the characteristics of vectors, and

12 maybe this is what we should utilize as the basis

13 for further discussion when discussing long-term

14 risks for participants.

15 \[Slide\]

16 With that in mind, FDA proposed a

17 three-tier system based on vector characteristics

18 at the April, 2001 meeting.

19 \[Slide\]

20 Let me review this three-tier system. The

21 three-tier system essentially categorizes vectors

22 according to their characteristics or their

23 properties into one of three categories. The first

24 category would be considered low risk; the second

25 category intermediate risk; and the third category

> 14 1 higher risk.

2 Encompassed into the first tier would be

3 essentially all vectors that would be new licensed,

4 ex vivo that would be non-replicating and

5 essentially fit into cells that demonstrated

6 limited survival.

7 The third tier, the higher risk tier,

8 would encompass vectors that had the potential to

9 replicate or were known to be replicating, had high

10 integration potential, altered tropism or a latency

11 potential.

12 Now, because of experience with pox

13 viruses and adenoviruses, although they are

14 replicating or have the potential to replicate, we

15 felt that these vector types would be better put

16 into tier two, or the intermediate category.

17 Essentially, tier two encompasses all other gene

18 transfer products that are not in tier one or tier

19 three.

20 \[Slide\]

21 Generally, in the discussions that took

22 place and ensued it was felt that in order to

23 really be fruitful and have a successful long-term

24 monitoring program, it was essentially for this

25 committee and for the FDA to really identify and

> 15 1 focus on the most important information that would

2 be relevant to long-term follow-up of subjects

3 involved in gene transfer studies.

4 In part, there is a notion that there is a

5 critical need for the gene therapy community to be

6 an active participant in these efforts, and in

7 order to include compliance we really need to be

8 able to zero in on those issues that are most

9 critical.

10 \[Slide\]

11 With that in mind, the FDA left the April

12 meeting and put together a working group to further

13 define the clinical concerns that relate to gene

14 transfer studies. In addition, we wanted to be

15 able to address the duration of clinical follow-up

16 that would be appropriate for the specific areas of

17 clinical concern.

18 \[Slide\]

19 Additionally, this working group was asked

20 to take into consideration some of the advice that

21 came out of the April meeting, which is not that it

22 is just important to vector characteristics but it

23 is also important to take into consideration the

24 duration of gene product expression, the mode of

25 administration, the targeted tissues and, of

> 16 1 course, patient-specific vectors.

2 \[Slide\]

3 With that in mind, we put together a

4 multi-disciplinary group at the FDA, involving

5 individuals with varied types of expertise in

6 oncology, hematology, neurology, immunology and, in

7 addition, we involved our experts in clinical

8 toxicology and molecular biology as well as

9 virology. Because we are talking about

10 epidemiologic databases as maybe one of the future

11 goals, we also involved Dr. Rosenthal, who will

12 address you a little bit later this morning. It

13 was important to keep our liaison, RAC liaison,

14 informed of our activities and, therefore,

15 Stephanie Simek was also apprised of our

16 discussions.

17 \[Slide\]

18 The working group met and agreed that the

19 four clinical areas of concern is consistent with

20 what the committee had already previously

21 articulated, and that is, namely, that

22 malignancies, hematologic disorders, autoimmune

23 diseases and neurologic diseases are the areas that

24 we should be focusing on when discussing risks of

25 gene therapy studies, long-term risk of gene

> 17 1 therapy studies.

2 \[Slide\]

3 So, what I would like to do this morning

4 is to go through those four categories and

5 highlight the information that has been already

6 discussed in your briefing material, and maybe

7 highlight those important examples that you may

8 find useful to today\'s discussion.

9 \[Slide\]

10 DNA and RNA viruses have been studied as

11 important causes of human cancers. For example,

12 the HTLV-1, the human T-cell leukemia virus is

13 known to be the causative agent for adult T-cell

14 leukemia, or there are other viruses such as HIV,

15 HPV and hepatitis C viruses that have been

16 associated, or strongly associated with several

17 malignancies, such as non-Hodgkin\'s lymphoma,

18 Hodgkin\'s disease, cervical cancer and hepatocell

19 carcinoma. It is important to note that DNA and

20 RNA viral vectors are commonly used in gene

21 transfer studies.

22 \[Slide\]

23 Some mechanisms for viral oncogenesis have

24 been described. Among these, I have highlighted

25 four potential mechanisms. The first,

> 18 1 transformation by transgene expression, and I have

2 highlighted here HTLV-1 tax, interacting with the

3 NF kappa-B and potentially other transcription

4 vectors to up-regulate the transcription of a large

5 number of cell genes like cytokines or cytokine

6 receptors such as IL-2 and GMCSF, as well as

7 transactivating the expression of c-myc, c-fos,

8 c-jun Ap1 and others that could essentially lead to

9 a clonal outgrowth and a malignant transformation.

10 Insertional mutagenesis \-- probably the

11 prototype or example would be ALV integrating in

12 the vicinity of c-myc and then leading to an

13 up-regulation of c-myc transcription, eventually

14 contributing to the development of a non-Hodgkin\'s

15 lymphoma.

16 Hepatitis C virus can cause chronic

17 inflammation and the release of inflammatory

18 molecules that recruit maybe other inflammatory

19 cells. Maybe the generation of toxic reactive

20 oxygen radicals can trigger proliferation and

21 responses by surrounding tissues and may represent

22 an important pre-condition for carcinogenesis or

23 the development of de novo cancers. In this model

24 the increased proliferation potential of cells

25 increases the opportunity for replicating the

> 19 1 errors that can occur over time and the loss of

2 normal cell function leading to oncogenesis.

3 The \"hit and run\" hypothesis is more

4 controversial but here I have highlighted a recent

5 example for adenoviruses. Here, the adenovirus-5

6 E1A protein with the open reading frame E4, open

7 reading frame 6 can potentially lead to an initial

8 insult to the cell that eventually can lead to

9 transformation. So, in this instance I think it is

10 important to understand that this concept raises

11 the possibility that an initial event triggered by

12 this viral agent can lead to tumor development in

13 the absence of detectable viral genes or protein

14 expression, viral protein expression.

15 \[Slide\]

16 An example of retroviral-induced

17 insertional mutagenesis leading to T-cell lymphoma

18 has been discussed previously at this meeting.

19 This has occurred in non-human primate studies that

20 were published in 1992 by Donahue.

21 As a result of recombination events

22 between the vector and packaging and protein

23 sequences and a replication competent retrovirus

24 was produced. These viruses were incubated in

25 purified immunoselected CD-34 stem cells from

> 20 1 rhesus monkeys who were used then to reconstitute

2 these myeloablated non-human primates. Six to

3 seven months later after the transplantation, three

4 of eight of the stem cell recipients developed a

5 rapidly progressive T-cell neoplasm. The analysis

6 of the lymphoma showed that they were clonal; that

7 there was common to these lymphomas the insertion

8 of the retroviral DNA. I think it was concluded

9 from these studies that there was a clear

10 association between the replicating viruses and the

11 development of lymphoma.

12 \[Slide\]

13 It is important to understand that we have

14 experience in oncology with second cancers or

15 treatment-induced cancers that can take years

16 before clinical presentation with a second

17 malignancy. For example, in Hodgkin\'s disease it

18 is well known that leukemia can appear five to nine

19 years following initial therapy, but these

20 leukemias can appear up to thirteen years following

21 the treatment for the Hodgkin\'s disease.

22 Leukemia is not the only cancer that can

23 appear in Hodgkin\'s disease \-- bone cancers,

24 thyroid, lung, stomach have all been described as

25 second cancers related to the Hodgkin\'s disease

> 21 1 therapy.

2 Breast cancer is another example where it

3 is well-known that second cancers can arise.

4 Second cancers of the uterus, the lung, the

5 esophagus, connective tissue and thyroid can appear

6 up to fifteen years following the initial breast

7 cancer therapy.

8 Testicular cancer is the third example

9 that I have chosen for you and there leukemia,

10 lymphomas, stomach, colon cancer, pancreas,

11 prostate and kidney cancers and also thyroid

12 cancers can appear up to twenty-five years

13 following the testicular cancer diagnosis.

14 \[Slide\]

15 Before moving on to hematopoietic

16 disorders, we would infer that some of the

17 mechanisms and some of the injury that occurs

18 secondary to chemotherapy could be similar to some

19 cellular injuries that could arise out of gene

20 transfer studies and, therefore, it is plausible

21 that second cancers will not appear until years to

22 decades following the gene transfer protocol,

23 participation in gene transfer studies.

24 \[Slide\]

25 Moving on the hematopoietic disorders, it

> 22 1 is well-known that viruses can induce hematologic

2 disorders. As an example of an acute event,

3 parovirus B19 can cause anemia and it is usually

4 associated at the same time that you have viral

5 infection. However, HBV can cause aplastic anemia

6 months following the HBV initial infection. With

7 HIV, isolated or combined cytopenias can appear

8 months to years following the HIV infection.

9 \[Slide\]

10 When discussing hematopoietic disorders,

11 it is important to understand that the progenitor

12 cells are self-replicating and can give rise to HPC

13 descendants. These progenitor cell descendants are

14 very important and critical components of the blood

15 and the bone marrow, and these cells are essential

16 to human life.

17 \[Slide\]

18 Cytopenias could be related to gene

19 transfer-related hematologic disorders, as well as

20 malignant leukemias, all conditions that could

21 appear months to years following the initial

22 exposure. There we would invoke mechanisms that

23 would be similar to what is known of viral-induced

24 hematologic abnormalities.

25 \[Slide\]

> 23 1 Moving on to neurologic disorders \-- gene

2 transfer vectors and the administration strategies

3 that can lead to neurologic disorders that we

4 identified are highlighted on this slide:

5 integrating vectors, vectors with long latencies;

6 vectors with prolonged transgene expression; and

7 vectors with immunogenic reactions are all gene

8 transfer strategies likely to represent the gravest

9 risk to the CNS.

10 \[Slide\]

11 When talking about the central nervous

12 system, it is important to realize that the CNS is

13 a highly specialized organ that has a lot of

14 redundancy in functional capacity. Many known

15 neurologic disorders require significant damage

16 before being clinically evident.

17 \[Slide\]

18 Neuronal injury may go on for years before

19 being clinically detected, and I have highlighted

20 three examples for you. HIV dementias can occur a

21 long time after the initial HIV infections. It is

22 well-known, because of latency, that prions can

23 incubate for a long time before CJD becomes

24 apparent. Then, I have highlighted diabetes to

25 demonstrate that it is not just the CNS that we are

> 24 1 concerned about but also peripheral neuropathy

2 being one of the concerns and, again, you know, the

3 same principles that it can take a long time and a

4 lot of neuronal injury before you have clinical

5 symptoms.

6 \[Slide\]

7 Moving on to autoimmune disorders,

8 environmental and other xenobiotic agents that can

9 cause autoimmunity have been described. For

10 example, viruses and bacteria can induce

11 antibody-mediated autoimmune diseases via molecular

12 mimicry. Group A strep causing rheumatic fever and

13 infectious mononucleosis causing ITP are two

14 examples of such infections that can cause

15 autoimmune diseases by molecular mimicry.

16 \[Slide\]

17 But there are other mechanisms for

18 autoimmune diseases. For example, the unmasking of

19 the autoimmune disease gene may be a similar

20 mechanism that an insertional vector can unmask an

21 oncogene. Here we are unmasking a gene that can

22 essentially be up-regulated to cause autoimmunity.

23 I have already described examples of molecular

24 mimicry. There are also examples of humoral

25 autoimmunity and T-cell mediated autoimmunity.

> 25 1 T-cell mediated autoimmunity is an important

2 mechanism for autoimmune diseases. For example,

3 the down-regulation of T-cells can normally

4 suppress responses to cell proteins, essentially

5 causing a shift from TH-1 to TH-2 cell balance to

6 predominance of the TH-1 cell subsets. This

7 imbalance of TH-1 and TH-2 is thought to be a

8 general mechanism that is associated with many

9 autoimmune diseases, including multiple sclerosis

10 and the Hashimoto parovirus virus.

11 \[Slide\]

12 Immune responses to gene therapy vectors

13 or transgene products are possible, and similar

14 mechanisms as those I have highlighted in the

15 earlier slides are plausible. The risk may relate

16 to vector characteristics, the duration of

17 transgene expression, route of administration, as

18 well as the host specific factors.

19 \[Slide\]

20 The clinical manifestation of autoimmune

21 diseases that result from environmental insults may

22 take months to years before they are clinically

23 detected. For example, systemic lupus may appear

24 with a median of 19-25 months following the

25 exposure to minocycline, but the clinical onset can

> 26 1 range anywhere from three days to up to six years

2 following initial therapy. Another example would

3 be exposure to silica which would cause scleroderma

4 which could occur several months following the

5 environmental exposure. Similarly, we would think

6 that gene therapy-related risks of autoimmune

7 diseases could take months to years before they

8 become clinically apparent.

9 \[Slide\]

10 So in summary, the long-term follow-up of

11 gene transfer participants should focus on four

12 clinical areas, and I think we would agree with the

13 committee\'s prior recommendation that these gene

14 malignancies and neurologic disorders with the

15 notion that they may take years to decades before

16 clinical diseases or disorders become apparent.

17 Whereas hematologic disorders and autoimmune

18 disorders are likely to represent risks and

19 clinical disease development that would be maybe

20 with a shorter time frame, maybe months or years

21 following the gene transfer study therapy.

22 \[Slide\]

23 We have previously proposed a three-tiered

24 system to assess the risks to subjects that were

25 based on vector characteristics and, still today,

> 27 1 we believe that this three-tiered system should be

2 the basis of our ongoing discussions.

3 With that in mind, I will turn the podium

4 over to Dr. Rosenthal who will address special

5 considerations pertaining to epidemiologic

6 databases.

7 Epidemiologic Considerations in Developing a

8 Database for Long-Term Follow-up of Subjects

9 DR. ROSENTHAL: Thanks very much.

10 \[Slide\]

11 Determining causality of exposure to drugs

12 with certain outcomes can be problematic,

13 especially in the context that we are talking about

14 today, with outcomes that they may develop many

15 years after the initial exposure, and also outcomes

16 which are generally rare in the population, such as

17 cancer, autoimmune diseases and neurologic

18 diseases.

19 \[Slide\]

20 In general, when we try to make

21 conclusions about causality we generally use the

22 following criteria, and none of these criteria are

23 sufficient in themselves for determining causality

24 but the more of these criteria where certain

25 associations can be made, then we are more

> 28 1 confident that causality does exist between

2 exposure and outcome of interest. For example, is

3 the association consistent? Do we observe it among

4 different populations or among different studies?

5 Is the association strong? Is there a very high

6 relative risk? If the relative risk is high, that

7 is a good argument for causality unless the

8 methodology of the study is severely flawed. Is

9 the association also seen in studies that are very

10 rigorously done, for example, randomized,

11 controlled clinical trials? If we see an

12 association in that context we can be pretty

13 confident that there is a causal association. Is

14 this association specific? Do you often see an

15 outcome with a certain exposure and vice versa? Is

16 the temporal relationship between exposure and

17 outcome consistent with what we know? And, is

18 there coherence or biological plausibility? Is the

19 outcome consistent with what we understand about

20 the pathophysiology and consistent with data

21 perhaps obtained in preclinical studies and in

22 vitro studies?

23 \[Slide\]

24 Epidemiologists like to use the following

25 tools to determine causality, and when we go from

> 29 1 the top of the list to the bottom of the list the

2 study designs become much more convincing. On the

3 other hand, they become much more logistically

4 difficult and much more expensive.

5 Case reports, case series are easy to

6 obtain and very inexpensive, and sometimes they can

7 lead to good, interesting data which can help us

8 determine causality. Case-control studies, cohort

9 studies and randomized clinical trials \-- the last

10 really is the gold standard but is the most

11 expensive.

12 \[Slide\]

13 Now, cohort studies and randomized

14 clinical trials we consider analytical studies

15 because they have control groups and we can safely

16 come to certain conclusions. Now, randomized

17 clinical trials are the most expensive and the most

18 convincing, but these aren\'t the studies that we

19 are talking about today really. These will be

20 carried out in the future with gene therapy

21 products, but now we are concerned really with

22 developing a database where some long-term adverse

23 events can be investigated.

24 \[Slide\]

25 A cohort study would be a reasonable study

> 30 1 design and has many advantages. You can study

2 multiple outcomes from a given exposure. You can

3 study uncommon exposures. Selection bias is less

4 likely. Unbiased exposure data, we are confident

5 that everyone in our database has received a

6 certain product, and incidence data in the subject

7 group is available. There are some disadvantages.

8 There may be biases in obtaining outcome data, and

9 cohort studies are very expensive.

10 \[Slide\]

11 One reason they are expensive is,

12 depending how you designed a study, often rates of

13 disease in the subject group are compared with

14 populations that do not receive the exposure, and

15 what is usually lacking is data in populations with

16 the underlying disease. Comparison cohorts can be

17 created but you need to develop a subject

18 controlled cohort which is similar to the

19 experimental group. You need to have the same

20 underlying disease and, again, developing this

21 control cohort is really very difficult, very

22 expensive, and not readily available outside the

23 context of randomized clinical trials.

24 In addition, for rare outcomes, the

25 outcomes we are talking about today \-- cancers,

> 31 1 autoimmune diseases, neurologic disease and

2 associations which may have small relative risk,

3 cohort studies are usually not of value.

4 \[Slide\]

5 This chart is just an example of sample

6 size calculations, just to demonstrate that for

7 diseases with very small incidence, such as cancers

8 and neurologic diseases, and if we are going to be

9 looking at associations which may be small or

10 moderate, sort of in the upper left-hand quadrant

11 of this table, cohort studies are going to require

12 very large sample sizes, in the order of tens of

13 thousands in both the study cohort and the

14 controls.

15 As the disease becomes more frequent, as

16 you move down the table, and when the relative

17 risks of the associations are much stronger, then

18 associations can be made with much smaller sample

19 sizes.

20 \[Slide\]

21 Case series or case reports have some

22 advantages. It is very easy to obtain this data.

23 It is very inexpensive. For a case series or

24 developing a series of patients that have received

25 gene therapy products, it is very easy to quantify

> 32 1 the incidence of certain outcomes. The problems

2 both with case series and case reports is that

3 there are no control groups and, therefore, you

4 can\'t really use these study designs to test

5 hypothesis. But they are useful in many cases for

6 generating hypotheses.

7 \[Slide\]

8 However, there are contexts in which case

9 series and case reports can very strongly suggest

10 causation. An example historically is when the

11 outcome is so rare and so rare and so

12 characteristic that we can make with very high

13 confidence an association that is causal. For

14 example, clear cell vaginal adenocarcinoma in young

15 girls that were exposed in utero to

16 diethylstilbestrol, this cancer which was so rare

17 and associated so consistently with its exposure,

18 that we are all very confident that this drug is

19 causally related to this outcome. Another recent

20 example, which may not apply to gene therapy

21 studies which we are talking about today, is when a

22 change in the event of a course is reversible when

23 the exposure is withdrawn, and the event returns

24 upon retreatment. A very recent example is

25 alopecia following hepatitis B vaccination where a

> 33 1 child lost its hair after receiving the first dose.

2 The hair grew back; came back for a second dose and

3 the outcome repeated itself.

4 For gene therapy it is very possible that

5 for certain outcomes if there is vector persistence

6 or vector sequences and/or gene products can be

7 found within a target organ of toxicity \-- data

8 like this can help us conclude perhaps with a high

9 degree of confidence that there is a causal

10 association.

11 \[Slide\]

12 So in conclusion, to develop very

13 elaborate, detailed databases for long-term

14 follow-up of gene therapy for analytical studies to

15 determine causality of adverse events may not be of

16 value. It may be a waste of a large amount of

17 resources, especially when the events are uncommon

18 in the general population, such as the events we

19 are talking about today. It would be of value if

20 the events are more common in the general

21 population, unlike the events we are talking about

22 today, and if the relative risks are very high.

23 However, developing a database more on the lines of

24 developing a case series could be very useful to

25 reveal causality for events that are characteristic

> 34 1 and are biologically plausible. They would also be

2 very useful to generate hypotheses that later down

3 the road could be further explored in more detailed

4 ad hoc analytical studies, and those decisions can

5 be made later and be more focused, and usually can

6 have a high probability of obtaining very useful

7 information. Thank you very much.

8 DR. SALOMON: Thank you, Philippe and

9 Steven. I want to acknowledge my gratitude to the

10 staff, all of whom were recognized at the beginning

11 of Philippe\'s talk. I read this paper that you

12 created and outlined now these last two talks and

13 it represents a tremendous amount of thoughtful

14 work on the part of the FDA staff in this instance

15 and I think, certainly as chair, I would like to

16 recognize that. We appreciate it.

17 This is a problem that won\'t go away, and

18 it is apparently, to all of us, critical to come to

19 some sort of grips with at this point after a year

20 of working on it in the committee. I think as a

21 base I am finally convinced that I am not going to

22 be able to slide by with the kind of

23 generalizations that, you know, it is kind of a

24 good idea but we are not sure of the details sort

25 of thing that we have tried twice now. So, I think

> 35 1 that is our challenge in the next couple of hours

2 really, to put it into a context that the committee

3 feels has sufficient detail to allow a response to

4 interested parties, in this case to Congress who is

5 not letting this drop, to consumer groups, to the

6 public who is not going to let this drop, and to

7 all of us in the field from the biotech industry

8 sponsors to the individual investigators that are

9 going to need to figure out how this is going to

10 fit into our plans in terms of funding, in terms of

11 politicking with our funding agencies. I think

12 that is our task, to get on the public record the

13 fact that there are no easy answers here, that we

14 are going to have to make some judgments. I think

15 that in this case this is probably the one time in

16 which vigorously defended and well articulated

17 minority opinions are perfectly appropriate to put

18 on the record today.

19 So, that is my introduction. I have

20 struggled with this for a while and I am going to

21 really try and do it right. I think the last

22 comment I have is that, you know, any soldier

23 looking at a campaign will talk about the low

24 point. So, I think the low point so far, as chair

25 of this committee, was achieved with this

> 36 1 particular question when, at one point in

2 frustration with the implications on research, I

3 came to the brilliant conclusion that the FDA

4 should do it, at which point Jay very vehemently

5 pointed out to me that not only I just violated the

6 basic principle of the FDA, which he was absolutely

7 right in pointing out to me that point. So, if we

8 can get through this, I will feel like we have

9 really gone beyond that low point for me.

10 DR. SIEGEL: I don\'t remember saying quite

11 that, and I don\'t think it was a low point. I

12 think what I was pointing out is that our opus

13 operandi, what we do and what we are funded to do

14 and the way we operate is collect data from

15 sponsors who sponsor clinical trials, not to

16 collect data from patients. To move in that

17 direction would represent a major step out of our

18 normal roles with important implications \--

19 financial, social, legal, ethical and so forth,

20 which isn\'t to say necessarily that all of those

21 are negative, just that it is not a simple

22 consideration.

23 I have reflected a lot on the things you

24 have just commented on, and I do want to make a

25 comment or two before we get into committee

> 37 1 discussion of these issues just as a matter of

2 context.

3 Dan is right that this is a problem that

4 isn\'t going to go away, but that also means it is

5 not a problem that is going to be finally solved at

6 one point, solved at one point in time and then we

7 are living with that solution. We feel that it is

8 time to move forward to ensure that sponsors have a

9 better focused approach to getting the right

10 information than has existed in the past and we

11 want guidance so that we can make progress in that

12 field.

13 We recognize that we are constantly

14 learning and that there are many other areas for

15 input, that we are not making decisions today, for

16 the most part, that we are going to be permanently

17 stuck with for several decades; that we need to

18 make decisions, vet them, have further discussion.

19 You know, maybe implement some of them but also

20 have further public discussion of them with various

21 interested parties and fine-tune them as we move

22 along.

23 The other complex thing about this issue

24 that we have discussed and that I think needs to be

25 sort of in the back of everybody\'s mind is that the

> 38 1 presentations you have heard, both presentations,

2 are focused on what sort of information we think is

3 important to collect. There are a lot of closely

4 related issues. Who is going to pay for collecting

5 it? Who is going to store that information and

6 how? And the pragmatic issue, as we have discussed

7 frequently at other meetings, how do you make sure

8 that you get a high rate of collection of

9 information after a decade or two when people move,

10 patients move, companies go out of business,

11 funding runs out and all the other issues that we

12 have discussed at some length?

13 It is important to note that, although you

14 didn\'t hear those issues mentioned, we haven\'t

15 forgotten that those are important issues. So,

16 while we are dealing with this interplay of issues,

17 it is very hard to build the information systems or

18 the infrastructure without knowing what you are

19 going to collect. It is very hard to determine

20 what you should collect without knowing what the

21 information systems and the infrastructure are, and

22 so forth. So, suffice it to say that we have been

23 working hard within the agency and with our sister

24 agencies to explore all of these questions and to

25 move forward on all of them, and you see that our

> 39 1 focus in this discussion is on the piece of what is

2 the right information to collect, but I want

3 everyone to be cognizant that we are well aware

4 that there are important issues as well in related

5 areas.

6 Finally, the only other comment I would

7 like to make regarding this discussion we are about

8 to enter in is that the questions you have before

9 you were actually radically changed a number of

10 times over the last few days. In my mind at least,

11 that is not that important. So, we have asked you

12 to at least comment on certain things. Maybe we

13 haven\'t asked you to comment on other things, but

14 what we need is your input on any areas pertinent

15 to this matter that you feel would be helpful for

16 us and that you have expert opinions on. So, as

17 Dan has said a couple of times, minority opinions

18 count. Consensus is important but voting doesn\'t

19 necessarily matter on all of these. These are

20 complex issues and we really want to integrate as

21 much of the expertise we have available to us in

22 this forum and others into the whole process.

23 So, please feel free and strongly

24 encouraged to offer opinions and comments

25 regardless of whether we specifically solicited a

> 40 1 comment on a particular question or not. I don\'t

2 see anything in here saying, for example, are these

3 the right four clinical areas to focus on but if

4 you are sitting there, thinking how come they are

5 not going to do cardiovascular disease, the fact

6 that we haven\'t asked for that opinion doesn\'t mean

7 that we wouldn\'t very much welcome it. So, really

8 feel open and free and strongly encouraged to

9 participate and contribute in any way. That, by

10 the way, applies also to the public.

11 Open Public Hearing

12 DR. SALOMON: In fact, you anticipated,

13 Jay, what I was going to say right now. I think

14 very appropriately for something that has been

15 discussed two times already over the last year and

16 this is the third time, I think it is one of the

17 situations in which I would welcome some general

18 comments from people, just as I have kind of given

19 you a little bit of my sense of it. So, if there

20 is anyone in the audience that would like to give

21 us their sense, just identify yourself.

22 MS. TICE: My name is Malissa Tice, and I

23 am the regulatory liaison for Schering-Plough \[not

24 at microphone; inaudible\] and we have conducted a

25 number of Phase I and Phase III trials in gene

> 41 1 cancer. Let me just give you a little background

2 of Schering\'s involvement and I have a statement,

3 and I have a statement from Schering-Plough.

4 Long-term follow-up is defined as the

5 collection of data on study participants that occur

6 at least one year after the treatment period of the

7 clinical trial. Numerous factors must be

8 considered, ranging from practicality and

9 feasibility of obtaining the follow-up data, the

10 scientific merit of the information gathered, the

11 analysis of the data, the creation and maintenance

12 of the database, the financial and administrative

13 burden on the investigators, academic institutions

14 and sponsors. Furthermore, there is a significant

15 burden on the patients.

16 As previously discussed, these factors can

17 be overwhelming and may discourage participation in

18 \[not at microphone; inaudible\] research. One more

19 practical and efficient way to capture this

20 information may be the creation of a patient

21 registry sponsored and maintained by the FDA, which

22 would allow patients to be voluntarily contacted.

23 Data reporting would be in a standardized format in

24 the registry to allow pooling of information in an

25 attempt to draw any meaningful conclusions or

> 42 1 trends. It is important to define what information

2 is being required above and beyond the safety and

3 efficacy data collected during the clinical trial.

4 When a clinical trial is conducted,

5 patient follow-up is included to determine the

6 efficacy of the drug product. Additional requested

7 data beyond the protocol prescribed length of time

8 raises concerns that patients will be lost to

9 follow-up, thereby rendering the data

10 uninterpretable. In most cases there will be all

11 these problems in determining the relatedness of

12 the gene transfer product to adverse events

13 detected a few years after this treatment.

14 Overall, the FDA needs to clarify and

15 state what the objectives are for the long-term

16 data. Examples are survival status, occurrence of

17 new malignancies, as presented today, autoimmune

18 disease, hematologic disorders or neurologic

19 disorders. We support the basic principles of the

20 proposed three-tiered system and feel that the

21 length of follow-up must be determined on a case by

22 case situation through communication and discussion

23 with the FDA.

24 Each vector construct is unique and the

25 variables associated with its use, such as route of

> 43 1 administration, the underlying condition and the

2 patient population. A rigid guideline is not

3 flexible enough to accommodate the various gene

4 transfer clinical trial scenarios. The rationale

5 for determining what data collection is needed must

6 be defined. Currently, as was discussed here for

7 the retroviruses and in the guidance, laboratory

8 specimens are required for five years with

9 questionnaires and telephone calls beyond that

10 time. The rationale needs to be evaluated based on

11 the biology of the vector. If the half-life of the

12 vector \[not at microphone; inaudible\] laboratory

13 specimens are burdensome to the patients. They

14 have to travel, lose work time, etc. Managed care,

15 insurance companies, academic institutions and

16 sponsors, along with the extra paperwork and

17 procedures find this provides little extra

18 information or useful information.

19 In the case of vectors that do not

20 persist, such as plasmids and adenovirus laboratory

21 specimens are \[not at microphone; inaudible\].

22 Thank you.

23 Committee Discussion of Questions

24 DR. SALOMON: Thank you very much.

25 Richard?

> 44 1 DR. CHAMPLIN: Reflecting on the data

2 being collected, certainly the four disease groups

3 that you looked at have precedent but this is an

4 area when unpredictable things can certainly

5 happen, and I would think almost anything goes in

6 terms of organ targets for toxicities. Clearly,

7 examples of late liver and kidney failure, and

8 chronic glomerulonephritis are mostly in the

9 autoimmune category perhaps but, clearly as one is

10 screening for toxicities one needs to look for

11 those things. I would think an approach would be

12 to try to use a broad-based toxicity scale, sort of

13 like the NCI common toxicity criteria that is used

14 for a chemotherapy drug. As one collects

15 information from patients, obviously you want to

16 make that as simple and easy to pull out as

17 possible so that somebody on the receiving end

18 would need to translate the patient\'s description

19 of their medical problems into categories by either

20 that toxicity criteria or some other instrument.

21 DR. SALOMON: So, right now anyone is

22 there anyone else who had a sort of general point?

23 Richard?

24 DR. MULLIGAN: I have an issue with the

25 definition of long-term follow-up. In the briefing

> 45 1 document there is a comment that clinical concerns

2 restricted to a specific vector for a given study

3 agent for a given study would be addressed in the

4 study protocol would not be material to any

5 guidance. I am thinking that this may be a very

6 important key to separating the formal definition

7 for long-term follow-up and many of the concerns

8 people would have may well be covered by the

9 individual protocol.

10 So, one of the clarifications in the sense

11 of maybe a sample or two of what would be the

12 closest kind of information for the clinical

13 protocol that you are talking about would be like a

14 long-term follow-up because I think if we can

15 separate as much as possible those two things it

16 may be easier to see the real long-term follow-up.

17 DR. SIEGEL: I think that is a very

18 important issue. In fact, I think the April

19 discussion or confusion over that was fundamental

20 to some diffuse discussion in terms of what was

21 needed. Each protocol for any drug, biologic or

22 device under study includes an amount of follow-up

23 that is dependent on both the nature of the drug,

24 its anticipated effects and the nature of the

25 disease. In traditional drug studies with

> 46 1 short-acting drugs that typically follows to

2 approximately a month after the end of the

3 treatment period. In biological studies, because

4 they often have much longer lasting effects and

5 they may have persistence of both desired effects

6 and undesired effects, such as immunogenicity

7 issues well after the administration of the

8 product, it is quite common that studies persist

9 significantly longer than that.

10 In our current experience for the vast

11 majority, if not all, gene therapy products we have

12 been asking for follow-up that extends to at least

13 one year after the final administration. So, for

14 the purposes of these discussions, and as reflected

15 in the footnote on page one, and also consistent

16 with the comment that you have just heard, we have

17 decided to define long-term follow-up as follow-up

18 that occurs beyond the first year after final

19 treatment on protocol.

20 With that said, however \-- and I think

21 that is functional for what we are looking at when

22 we are talking about the risks that may cross over

23 broad varieties of gene transfer products that

24 might share common vector characteristics or other

25 characteristics that might call for long-term

> 47 1 follow-up such as we have been discussing. But, as

2 your question is asking, we would all presume,

3 regardless of the discussions about general

4 principles for long-term follow-up, that if the

5 nature of the disease being treated or the nature

6 of the insert and the vector product being produced

7 raised specific concerns regarding safety relevant

8 to that specific product or, for that matter,

9 efficacy regarding that particular product, we

10 would require follow-up. Even when those concerns

11 require follow-up beyond one year, we would require

12 that regardless of this discussion.

13 So, the fact that you might imagine a

14 particular insert in a particular disease where you

15 think you would want to have, you know, five years

16 of follow-up because of the nature of what that

17 insert is doing, unless that is a broadly

18 generalizable characteristic that shouldn\'t be

19 driving our discussions of generalizable issues of

20 vector characteristics as we would expect for a

21 given disease and a given insert. We would make a

22 case by case determination about the nature of that

23 risk, and the duration of that risk, and the

24 appropriate way to deal with that risk in the

25 setting of a clinical trial.

> 48 1 In addition, in some sense all of our

2 determinations will be case by case but we feel

3 that as we look across broad classes of vectors to

4 look for shared risks, we need to develop the

5 guidance regarding the common expectation based on

6 the factors that we have discussed.

7 DR. MULLIGAN: I think we can just say it

8 is very, very key. It makes me feel more

9 comfortable that we might be able to look at the

10 long-term follow-up discussions in a slightly

11 different way than maybe some of us have in the

12 past because I think you are giving comfort that

13 the good old-fashioned process of reviewing a

14 protocol will identify things that probably would

15 be of most concern. I think we could all come up

16 with several specific points of things that will be

17 done in the near future where that five-year

18 follow-up may well be very, very important.

19 So, I would propose that we might want to,

20 based on that, think of the nature of the other

21 information. What is the other kind of

22 information. I was struck by Dr. Rosenthal\'s talk

23 because at the finish there is a suggestion of an

24 analytical importance of the follow-up information.

25 That is, I think you were making a point that some

> 49 1 of the data collection may not be that useful

2 because it doesn\'t really tell you whether it

3 really is associated with the gene therapy.

4 I am struck because I am not sure, in the

5 context of the overall value, why we are doing

6 this, why that necessarily would be the goal. That

7 is, another goal might be simply to get raw

8 information. From the political point of view,

9 when something bad happens people are not going to

10 want to know that you didn\'t know, no scientist

11 knew, why this happened. They are just going to

12 want to know that you identified this, or if you

13 didn\'t identify this people are going to be very

14 upset. So, a system that is too sophisticated

15 because you are kind of getting rid of things where

16 you don\'t really know what is going on is probably

17 not the right system for this kind of follow-up.

18 So, maybe I am just trying to fantasize about

19 getting over this whole thing over the next hour or

20 two.

21 DR. SALOMON: I would like to share your

22 fantasy, Richard. Certainly, at the end of the day

23 it will mean a lot more to me than now.

24 DR. MULLIGAN: But I am not so sure that

25 maybe it is all that complicated if we begin to

> 50 1 separate things on the basis of real clinical

2 information and analytical information and raw

3 information.

4 DR. SALOMON: I agree very much with what

5 Richard has been saying just now and as Jay put it.

6 I spoke with Jay earlier this week to just get some

7 idea about where these questions were going and, as

8 Jay points out, they evolved quite a bit.

9 I think that what we ought to do now is

10 try and follow a path to get to the end of this and

11 the guidelines I think, Richard, you have kind of

12 articulated. The first question and the first

13 issue I think we need to just have some sort of

14 official opinion on is do we agree \-- you know, do

15 we advise, not getting yet into the details of what

16 long-term follow-up us but just in some form that

17 we can feel comfortable with, can we say to the

18 FDA, to the public, that we believe long-term

19 follow-up for gene therapy clinical investigation

20 is appropriate? If we can get past that first

21 question, and then begin to get at what would be

22 the appropriate context and kind of information

23 and, in so doing, try again to articulate where the

24 issues are and some of the practical obstacles that

25 sponsors, individuals and biotech industry

> 51 1 experience. Then, maybe we can get to the end with

2 talking about what database, or what we would

3 require in terms of long-term follow-up in order to

4 be responsive.

5 DR. RAO: I just wanted one more

6 clarification. So, if we just take an example

7 using something like lentivirus and say that that

8 is retrovirally induced, it is going to persist and

9 the hope is it is going to persist for the life

10 span of the individual in some sense. Then certain

11 long-term follow-up will be covered just by the

12 clinical protocol itself as an individual protocol

13 and we are not going to worry about that as an

14 issue. Right? If this is just a follow-up for

15 unanticipated effects, in some way can we be

16 preemptive in collecting information which might

17 give us clues to what would be common effects

18 across many such viruses or many such drugs?

19 DR. SIEGEL: Well, I guess there are two

20 ways in which I could look at your question. One,

21 there are issues that are specific to a specific

22 trial and those things that you want to collect for

23 all lentivirus and that is, in fact, what we are

24 answering. There is another issue, and I am not

25 sure if it is what you are asking, is it collected

> 52 1 as a matter of in the protocol or some other

2 matter? I am not sure if that was inherent in your

3 question.

4 DR. RAO: Yes.

5 DR. SIEGEL: I guess what we would

6 envision is that if we feel for lentiviruses that

7 it is appropriate to collect information about

8 malignancy for some period of time, at the present

9 point in time we would ask that protocols would

10 include that as part of the protocol. That is the

11 way we, in the FDA, see that things happen. At

12 some future point in time some group may put

13 together some multi-center cohort study and

14 database that deals with that in some other way.

15 You know, we have heard discussions and suggestions

16 about that and, as I have said, we have discussions

17 and lots of different avenues at the same time.

18 So, if you are saying protocol specific issues

19 versus general lentivirus issues, yes, that is what

20 we are focusing on but we would think either issues

21 would essentially addressed in the protocols we

22 would expect to see.

23 DR. SALOMON: I think what is critical

24 here is that nothing that we do today is going to

25 change the fact that each protocol that comes to

> 53 1 the FDA for an IND and, for that matter, to the RAC

2 for review, is going to be looked at for the

3 specifics of that protocol; for the specifics of

4 that vector class. Things are going to change.

5 There are going to be new technologies that we

6 can\'t anticipate today. Nobody and nothing we are

7 going to say or discuss now is going to try and

8 change the flexibility of the regulatory agencies

9 to deal with case by case issues now and in the

10 future.

11 With that said, there are some principles

12 that we need to decide are appropriate, and the

13 principle that is on the table right now is just

14 the simple principle of do we agree that long-term

15 follow-up beyond the current one year after the

16 last dose is generally appropriate? That is the

17 question that I would like to hear from the

18 committee on. If you think, gee, that is obvious

19 and simple then, you know, we can go through this

20 quickly.

21 DR. CHAMPLIN: I mean, just the precedent

22 of, you know, chemotherapy administration and later

23 the incidence of acute leukemia, in some types of

24 patients it is a 15 percent actual rate that

25 secondary leukemia develops after intensive

> 54 1 chemotherapy of various types, and this occurs

2 usually in a period of a decade. So, clearly

3 envisioning products that damage or rearrange DNA,

4 that is a possible outcome and it would be

5 inappropriate not to be monitoring for that in some

6 fashion. I think the practical issue is how can

7 you do it in an effective way and we will come back

8 to that.

9 DR. SALOMON: Yes, I promise we will come

10 back to that.

11 MS. LAWTON: Your question is, is

12 long-term follow-up necessary and I guess I would

13 just come back to I think we all agree that some

14 level of long-term follow-up is necessary, but that

15 comes back to the tier approach and we then get

16 into what is long-term follow-up for the different

17 categories.

18 DR. KNOWLES: I think long-term follow-up

19 is essential. I think things have changed a lot in

20 medicine over the last ten, fifteen, twenty years.

21 I think the American public is going to demand it.

22 So, I think this is an issue that needs to be

23 addressed.

24 DR. HIGH: Disagreeing with this is like

25 disagreeing with mom and apple pie. I mean,

> 55 1 obviously for a new therapy like this it is

2 important to acquire long-term follow-up and I

3 would only make the point that as we do accumulate

4 data, so when there is twenty years of follow-up on

5 4000 patients, then I think the requirements change

6 unless necessary.

7 DR. SALOMON: I think one thing I promised

8 to the committee \-- I promised to myself is that

9 before we are done we are all going to make sure

10 that we have articulated all the problems with this

11 as well. Well, if I don\'t have anything, then I am

12 actually going to say there is a consensus of this

13 committee that long-term follow-up beyond one year

14 after the last dose of a gene transfer vector is

15 appropriate as a starting principle. Do we need to

16 vote on that? Are we going to dispense with votes

17 today? I just want guidance from you.

18 DR. SIEGEL: I think if a critical issue

19 comes up and it looks like it would be useful, that

20 might be useful. I think in general, as a general

21 rule, advice is \-- you know, votes seem to somehow

22 discount minority viewpoints. People come from

23 different perspectives and you need to hear voices

24 from different perspectives. I am not sure we are

25 really in a voting situation. We might come to a

> 56 1 situation where we are going to have to make an

2 immediate decision and it would be useful for us to

3 have a better record but I don\'t foresee that per

4 se.

5 DR. SALOMON: I just want to do things

6 right in the official sense as well. So, the

7 second question is an important factor for

8 determining the nature and extent of follow-up are

9 the characteristics of the vector. I think

10 everyone would agree with that. As well as, when

11 we talk about the vectors, the class of the vector,

12 what kind of gene is in the vector, what kind of

13 disease the vector is being given for, I think we

14 all agree that you can make it very complex.

15 The FDA has proposed dividing gene therapy

16 products into three tiers. Everyone here is

17 familiar with the general concept of the three

18 tiers. So, let\'s deal with that next. Does

19 everyone have the three-tier system? So, the

20 three-tier system, tier one is low; tier two,

21 intermediate; and tier three, high. And, I am not

22 going to read the rest of it. You, guys, have it.

23 So, comments on the three-tier system?

24 DR. SIEGEL: Let me first say we welcome

25 and invite any comments on how the tiers are

> 57 1 defined or used. One particular area where we are

2 really eager to get clarification on, and that

3 relates to the last question, is we thought we

4 heard in November that for the low risk products if

5 a vector doesn\'t replicate and the cells aren\'t

6 going to survive so it is really not too much to

7 distinguish from any other types of therapy for

8 which we don\'t have specific, generalizable

9 concerns about long-term effects. Neither the

10 vector nor the cells containing them are expected

11 to be around for very long except where, as we have

12 discussed, there might be an aspect of a particular

13 protocol that required long-term follow-up, that

14 one-year follow-up might well be adequate.

15 We went back to the committee to check if

16 that is what we heard and I think we perhaps

17 phrased the question somewhat differently because

18 what went up on the board is something that

19 suggested that such patients would have no

20 follow-up, and I think that made a lot of people

21 anxious. But I think the question we thought we

22 were asking then was if you are in this lowest risk

23 group and if you are followed for a year after the

24 last treatment, which could be many years if it is

25 a recurring treatment and most gene therapy today

> 58 1 there have been short courses of treatment \-- if

2 you are followed up for a year after the last

3 treatment, and if you have a vector that falls into

4 these low risk groups, and if there is a specific

5 reason in a specific protocol for longer-term

6 follow-up where that would be implemented, the

7 question is, is long-term follow-up necessary in

8 that group?

9 Again, I don\'t want to limit the

10 discussion to that area but we are looking for some

11 clarification. I think we asked different things

12 and we will take full responsibility for confusion,

13 but we are not really sure what we have heard and

14 what we are being advised to do.

15 DR. SALOMON: Well, my sense of it, just

16 to start this off, is that there are two circles

17 here and I am trying to figure out where the two

18 circles intersect. The first circle is, I feel

19 very strongly, that the FDA, in its approach to

20 this, has to have the flexibility that if

21 approached by a sponsor with a specific vector and

22 a specific trial where there is \-- and I am not

23 going to define how that should be because I don\'t

24 think we can define that here, but where there is

25 really compelling data that the vector or the

> 59 1 gene-modified cells don\'t survive, except for a

2 very short period of time as, for example, in the

3 case of irradiated cells or in the case of certain

4 vector classes, the FDA and the sponsor should have

5 the flexibility to suggest that there should be no

6 long-term follow-up. That is one circle.

7 The second circle is this question of a

8 generic public anxiety that extends through

9 regulatory agencies, Congress and the public that

10 the minute you mention gene modification,

11 recombinant DNA, etc., that you have to do

12 something, that that is out of the ordinary. That

13 is the other circle. Richard?

14 DR. MULLIGAN: Well, I have a radical idea

15 that may seem like we are going backwards but I

16 don\'t think so. Based on the discussion that we

17 have just had, if I look at the different tiers

18 there may be a way to make essentially one tier \--

19 you know, no tiers essentially. I note that in the

20 high risk the only difference really from category

21 two is essentially an annual physical for five

22 years. I would propose that we talk about why we

23 propose this and why that should be the case, and

24 wouldn\'t that be something that would fit into a

25 protocol-specific requirement? That is, based on

> 60 1 what you think those issues may be, wouldn\'t you be

2 likely to have an annual physical? If that was the

3 case and you dropped that, then you really look at

4 all the tiers being comparable except for the

5 lowest tier where, based on this very recent

6 discussion, there is the question whether there

7 should be any long-term follow-up.

8 So, the radical proposal is you might say

9 that everyone is going to have \-- and we would have

10 to discuss what this would be, you know, the

11 clinical question, but whatever that is going to be

12 for anything from the point of view, as I think you

13 articulated, you know again, if something happens

14 to someone who has had irradiated tumor virus

15 vaccine over ten years and has some autoimmune

16 reaction, people are not going to care or they are

17 going to think that it is pretty silly that, you

18 know, the wisdom of the FDA and the group was that

19 this was something sent from those reporting

20 requirements, and that would be silly because,

21 again, things might happen. If we have a system

22 for getting this information and it is an easy

23 enough system, a questionnaire system, then it just

24 unifies the ability to get the information and

25 probably gives us the most valuable thing we could

> 61 1 get from this which is raw info. I think just

2 having info so that people will know that we have

3 been looking for these things, even though we can\'t

4 necessary articulate what we are going to do with

5 that information or whether, indeed, that

6 information is every going to draw us back to

7 really what happened.

8 DR. GAYLOR: One thing that may be obvious

9 to everybody already is that almost any late effect

10 \-- you know, the first one you won\'t believe is

11 related to the study drug or vector. It is only

12 when you have observed greatly greater than the

13 expected that, you know, a bell rings in your mind

14 to say, yes, this encephalitis was related to drug

15 X or vector X. So, causality aspects really can

16 only sort of be ascertained in the short term

17 around the time that you are giving the drug, and

18 if you give it and something happens you assume

19 there is a causal relationship. As you get further

20 and further from the exposure other things are

21 going to happen to patients. They are going to get

22 other medical problems and the challenge is to sort

23 out is if that new medical problem is in any way

24 related to the vector. So, almost never will it be

25 obvious that it is unless it is a previously known

> 62 1 association.

2 DR. SIEGEL: We do have an advantage here

3 though. Given some of the putative mechanisms of

4 long-term effects, if insertional mutagenesis gives

5 rise to a tumor ten years later you should be able

6 to find in that tumor, you know, a clonal

7 insertional site of the vector. You might be able

8 to. Or, if you expect an autoimmune response as a

9 toxicity, you might be able to find in that patient

10 evidence of a response to the gene product.

11 So, I certainly agree that for the most

12 part, except for very rare \-- and this applies to

13 everything we see, all rare events in drug studies,

14 you know, you get one case with a rare event and it

15 is very hard to know what to make of it and you

16 look a little more closely. But in addition to

17 looking for other cases and related cases, we may

18 have molecular mechanisms to look at as well here

19 that may, in fact, even in a single case point to

20 causal association.

21 DR. RAO: Just in the interest of time, as

22 you said, to move things along discussion, is my

23 sense then correct that there seems to be some sort

24 of consensus, at least for tier, one that there be

25 no long-term follow-up required or mandatory after

> 63 1 one year? Is that correct?

2 DR. SALOMON: I think we have two things

3 now on the table. One question was appropriately

4 raised by Richard, are the tiers useful and I think

5 we haven\'t answered that. The second question was

6 what I started with, and that was, you know, these

7 two circles. One circle is that there is a concept

8 that we ought to leave open the fact that

9 appropriately argued scientifically based decision

10 that certain things don\'t require any follow-up.

11 The other circle is when you say recombinant DNA

12 and gene transfer in the same sentence requires

13 follow-up.

14 DR. RAO: I thought that it may be useful,

15 because even Dr. Mulligan said that in terms of

16 doing away with the tier system, he would just

17 suggest that there be this one tier which would be

18 this low level tier one which, as you suggested,

19 would give the FDA flexibility to say that this is

20 not something for which you need follow-up. And,

21 he proposed that at least in terms of long-term

22 follow-up we can consider tier two and tier three

23 as one. The difference in the follow-up is just

24 that you have a physical annually. In that case,

25 for long-term follow-up we can consider that as one

> 64 1 and then discuss it separately later. If that

2 seems to be a reasonable consensus, then we should

3 at least say that, yes, we all agree with the tier

4 one idea and say that there isn\'t any required

5 recommendation for follow-up and move to the next.

6 DR. SALOMON: That is an interesting way

7 of taking both our questions and putting them

8 together, and we can discuss it.

9 DR. BISHOP: Yes, I want to make one

10 clarification. In tier two and tier three there is

11 an additional very important aspect that is

12 different in terms of what is required. Tier

13 three, being the highest risk, was modeled upon

14 current recommendations for retroviral vectors

15 which includes a laboratory component to that.

16 There, we felt that at least in the first five

17 years it would be important to this discussion to

18 evaluate whether or not it would be necessary to

19 have this laboratory component. It may be a tissue

20 or may be some blood sampling to be done. Along

21 with that thought, really the discussion at the

22 time that we put this together was based on the

23 current recommendations for retroviral vector

24 studies.

25 DR. GAYLOR: Maybe another way of looking

> 65 1 at those is whether or not those would be better

2 put in a protocol-specific fashion. It depends

3 what the basis for doing that over the five years

4 is. I would say in the case of retrovirus vector

5 that that is not just collecting random long-term

6 follow-up. That is a real highly relevant,

7 technical issue that I think would be very, very

8 important. I can\'t conceive of any gene transfer

9 with hemopoietic cells using retrovirus vector that

10 people wouldn\'t be, over a five-year time period,

11 trying to assess whether or not the vector was

12 still present.

13 DR. MULLIGAN: What we are talking about

14 today is what the requirements are for those

15 protocols. I mean, this is the way the FDA \-- this

16 is their guideline to approve a protocol or give at

17 least advice on the construction of the protocol to

18 be sure it contains these elements. So, it is not

19 like there are two different processes here. This

20 is a process of considering protocols, whether they

21 are acceptable or not and if they need these

22 criteria.

23 DR. SIEGEL: I would like to address a

24 couple of comments about public expectations, not

25 to address what the public expectations are but the

> 66 1 comment that it is gene therapy so we need to be

2 doing something, just to make sure that at least in

3 the context that we have been viewing this in is,

4 of course, we need to be doing something but we

5 need to be doing the right thing. You can always

6 do more. Not just in the long-term but even in the

7 first year you can say, well, we are only doing

8 blood tests once a month, why not once a week? How

9 come we are not getting electrocardiograms once a

10 week and thyroid function studies once a week? Why

11 are we only getting all the routine blood screens?

12 So, there are two things that I think one

13 needs to reflect on in making these decisions. If

14 you are talking about not collecting information,

15 it is not a decisions that, first of all, we are

16 talking about decisions to focus resources in those

17 areas that are going to provide the most safety

18 rather than in those areas where they would be less

19 efficiently used.

20 The other perspective, especially if we

21 talk about long-term as a perspective we have

22 discussed before, and most epidemiologists I have

23 talked to believe, and I think is a matter of

24 common sense, is given the practical difficulties

25 of getting information, especially out many years,

> 67 1 asking for less may in many cases mean getting

2 more. If you ask everybody to come in twenty years

3 later and have blood tests and scans I think most

4 are just going to say no way. If you ask for a

5 one-page questionnaire you are probably going to

6 have more of them return than if you ask for a

7 twenty-page questionnaire.

8 So, the issues are not so much whether we

9 need more or less safety information but how to get

10 the best and most important information. I just

11 want to make sure we are all on the same page there

12 because I don\'t think we should feel some

13 compulsion to ask for things that don\'t make sense.

14 That would be harmful. On the other hand, we need

15 to do the best job of collecting those things that

16 will tell us what we need to find out.

17 DR. SALOMON: In terms of pages, I think

18 the only thing I would say is you are a page ahead

19 of me right now in terms of my outline for this

20 campaign. I am hoping to get to what it is we are

21 going to demand in the third question, and just get

22 past this sort of concept now of do we go along

23 with the tiers. So, just to focus on that, I know,

24 Katherine, you had a point you wanted to make \-- I

25 would like to say two things, one directly along

> 68 1 the lines we have been discussing this morning.

2 One is, Richard, I personally am okay with

3 this tier system in the sense that I don\'t think

4 the substance of what you are suggesting is wrong

5 either. I don\'t see any big disagreement between

6 us. For me, the tiers I think may be useful to the

7 FDA and also the sponsors approaching the FDA, and

8 will also allow, as new information comes along,

9 sort of picking up on something Katherine said, you

10 could move a whole vector class down a tier and

11 that, to me, would be a good thing as well. So, I

12 think just from a practical point of view the tiers

13 have some value, but I don\'t disagree with anything

14 you said actually in terms of the fact that some of

15 these things should be specific to a trial.

16 DR. MULLIGAN: I think in the spirit of

17 reducing bureaucracy, I would like to have more

18 arguments why you would want to have the tiers.

19 That is why I am focusing exactly on what is the

20 difference, the relevant difference, and the thing

21 that is in the high tier is something that I would

22 like better discussion of what the rationale for

23 that is.

24 DR. SIEGEL: I would like to ask some of

25 our FDA scientists to comment about this. What we

> 69 1 are proposing here, the nature of this tier system

2 is that these are, based on the discussions we have

3 had with the committee and our analyses of the

4 system, these are the characteristics of a vector,

5 the ones that you see under high, that would

6 specifically warrant value in general for annual

7 medical histories and archives, that it is those

8 integrating, replicating and so forth where you

9 might want to do that. That is what we want

10 comment on as to whether that is an appropriate

11 linkage. Now, there will be case by case decisions

12 and, while not wanting to get bureaucratic, we

13 don\'t want to be arbitrary. There is a value for

14 industry and investigators to know what the

15 expectation is before they plan what it is they are

16 going to study and how.

17 DR. SALOMON: Can I make a point along

18 that line? I am thinking to myself how would this

19 work in practice. So, the way I would see it

20 working in practice, let\'s say I have a retroviral

21 vector that I was putting into macrophages ex vivo

22 and I could demonstrate that the macrophages had a

23 relatively short half-life, I would then ask, as a

24 sponsor, to have that phased as a tier two study

25 when I came in to do my IND. Whereas, next week we

> 70 1 might be dealing with one that was a retroviral

2 vector or lentiviral vector in a hematopoietic stem

3 cell in which there would be no question today that

4 that would be tier three, but maybe five, ten years

5 from now we could get rid of the tiers because they

6 would collapse on each other. So, that is the

7 value I see in the tier system.

8 DR. MULLIGAN: I don\'t see that. This

9 question comes back to this issue of what should be

10 dealt with in the individual protocol, and I am not

11 sure I see why the specific cases that you made

12 wouldn\'t be in the protocol. So, I am not seeing

13 the generic kind of global issues for this

14 particular point, that is, the five-year annual

15 physical for these particular cases. I don\'t see

16 that they are particularly distinguishable. I

17 don\'t have a good sense of why that would be

18 particularly necessary as a generic requirement as

19 opposed to a case by case within a protocol

20 requirement. That is, if you thought that there

21 was something about the macrophages that was

22 different than the stem cells, in the protocol you

23 would probably want that addressed, and I would

24 think the FDA would view the protocol and see a

25 difference between the macrophages or the stem

> 71 1 cells. But, in fact, according to this thing the

2 macrophages would be considered a tier three.

3 Right? That is, if you are not irradiating the

4 cells and using a retrovirus, and you are putting

5 these into patients, even a cell with a short

6 half-life would be considered a tier three.

7 DR. SALOMON: That is fair. I guess my

8 point here was to give some flexibility that that

9 could be a tier two but, I mean, you are right. If

10 it turns out that in doing it this way we

11 complicate things, then I am also not for it. So,

12 that is the kind of discretion we need to have.

13 Katherine?

14 DR. SIEGEL: Before you do that, because I

15 think this is important because part of the

16 question you have raised in your last two or three

17 comments is an important one, which is why not just

18 do all of this on a case by case basis based on

19 good scientific judgment? And, there are

20 attractive reasons to do that, but there are

21 important considerations for why we would seek

22 general principles and general guidance, if not

23 general rules that are inviolable, and that is,

24 first of all, people who are planning to do

25 research, whether are commercial sponsors or

> 72 1 academicians, benefit tremendously from having

2 advance knowledge of regulatory expectations. If

3 you know when you are designing a protocol or

4 seeking a grant or funding a research study, or

5 whatever, that you are going to have to bring

6 patients back and archive specimens and examine

7 them for five years you have a better idea of what

8 your costs are and whether or not you are willing

9 to do that. So, it is a lot easier for people to

10 pursue research in an efficient manner if they have

11 some general idea of expectations.

12 A second reason is that when we don\'t put

13 out those general principles that we work from

14 there is often a perception, whether correct or

15 not, that we are being arbitrary and capricious.

16 We say we think your study requires five-year

17 follow-up and they say, well, the guy down the hall

18 doesn\'t require five-year follow-up. Why is that?

19 And we say we can\'t tell you; that is confidential

20 information. You know, they may do a different

21 study with their irradiation machine or something.

22 Frankly, it also is a more difficult job for us to

23 ensure that that doesn\'t happen, to ensure

24 consistency. Then if we have guidance, it would

25 serve not only sponsors but ourselves.

> 73 1 Finally, it helps you understand what is

2 in that database that you have accumulated. While

3 there may always be exceptions, if you have a

4 database that in general has these sorts of data on

5 these sorts of protocols, then when you go back to

6 analyze for incidences or occurrences, or whatever,

7 you know that that is what is there.

8 So, those are some of the reasons why,

9 although from a scientific perspective it would

10 always be best to try to just say, well, let\'s deal

11 with each one in the most appropriate way as it

12 comes, there are advantages to try and spell out

13 general rules, not to mention, of course, the

14 opportunity to have public discussion, which is

15 hard to do when everything is simply done on a case

16 by case basis.

17 DR. MULLIGAN: But I think what we are

18 trying to do is separate the kinds of information,

19 and we are still having trouble. I mean, there is

20 confusion. Just from what you said, you know,

21 sponsors will want to know what kind of archival

22 sampling but, I mean, I think that should be built

23 into the scientific and medical review and

24 separated from \-- I think this is why we have been

25 doing this for such a long time, we haven\'t

> 74 1 articulated a real distinction between that and the

2 murky stuff that might or might not be put in a

3 clinical protocol, and I am just saying that one

4 way to do that is to make sure it is very clear

5 that the long-term follow-up information is

6 different. Still, based on the years of talking

7 about this, you obviously have a lot more guidance

8 based on all the discussions you have had about the

9 clinical protocols and what might go into

10 individual clinical protocols.

11 But I think that is the key to resolving

12 this, separating as best we can those two classes

13 of info. Otherwise, we are worrying about how to

14 collect the information that probably should be in

15 a clinical protocol in this long-term follow-up. I

16 am just trying to set the stage so we get to the

17 point of talking about what information we want and

18 don\'t get confused with, oh gee, we can\'t get this

19 information because it is too complicated; we can\'t

20 be tracking these patients and getting samples for

21 twenty years, and so forth.

22 DR. SIEGEL: The two classes of

23 information you are referring to are?

24 DR. MULLIGAN: The information that I

25 would say is more medical, scientific long-term

> 75 1 follow-up, things that are more technically

2 directed to a protocol, issues like retrovirus,

3 integration, persistence, from, I would say, the

4 value of the long-term follow-up, we will come down

5 to eventually, has to be just collecting raw

6 information, keeping track of gene therapy patients

7 and make it very, very simple. At the end of the

8 day we will want to keep track of these patients.

9 We will want to identify things that happened and

10 it will undoubtedly be in an unorganized fashion.

11 It will have to be, but there is greater value to

12 it.

13 DR. HIGH: I would just say that actually

14 I agree with the points that Dr. Mulligan made and

15 it might be useful to collapse the intermediate and

16 high tier groups. When I look at the field, it

17 seems to me that the way most clinical trials are

18 structured now, one does elicit information on

19 short and medium term consequences of the

20 intervention.

21 What is really lacking in the field are

22 data about long-term consequences of the

23 intervention, and what would be most valuable I

24 think to all of us in terms of eventual licensing

25 of products would be to begin to collect

> 76 1 information about long-term consequences, and the

2 information we need I think could really be

3 acquired through a simple questionnaire rather than

4 \-- I don\'t see the purpose or archiving samples and

5 doing annual physical exams between one and five

6 years. I think it is much more important to

7 collect data out through twenty years, very simple

8 kinds of information that is just essentially

9 patient follow-up.

10 DR. SALOMON: Good. Let\'s go back to a

11 question that I think we can\'t go forward with this

12 discussion until we answer, and that is, are we

13 agreeing that there are going to be cases that

14 don\'t require any long-term follow-up?

15 DR. CHAMPLIN: I guess I have been

16 bothered a little bit by this. I would like to say

17 yes because we would all like to simplify matters,

18 but the question is can you be truly sure that a

19 non-integrating virus doesn\'t have a small fraction

20 of integration going on? Or, if you are treating

21 macrophages, you know, 99 percent macrophages, that

22 the one percent stem cells that are in your

23 preparation aren\'t going to transduce? So, even

24 when the objective might well meet the tier one

25 objective, is the reality of the manufacturing of

> 77 1 those cells totally safe in terms of the potential

2 for long-term consequences? I would like to be

3 assured that that would be the case and that we

4 could do things in a simplified manner but I am

5 just uneasy that that is truly possible.

6 DR. GALORE: I am probably getting ahead

7 of the question here, but follow-up doesn\'t have to

8 be an all or nothing situation. We could do a

9 sample of 200-300 people and do physical exams on

10 them, and depending on what we see there we may

11 decide to increase that sample size or we may

12 decide to discontinue physical exams. So, it

13 doesn\'t have to be all or nothing. I think we can

14 make use of sampling.

15 DR. SALOMON: Okay. I guess the reason I

16 am pushing this, and I could be wrong, is that if

17 we agree that everything needs long-term follow-up,

18 then there is no tier system. Right?

19 DR. MULLIGAN: I would agree with Dick. I

20 have to agree with him that if the level \-- well,

21 just what you said that basically even with a

22 non-integrating virus I think it would be

23 ridiculous at this point to say that we can predict

24 that there would be no reason to collect this.

25 And, if you make the eventual question very simple,

> 78 1 or whatever, then it is not an impediment to have

2 that information and it would be inconsistent with

3 the concept not to include all gene therapy

4 activities.

5 DR. SALOMON: Okay, that is a clear

6 statement. So, taking my two circles, that could

7 bring the two circles together. So, we have two

8 things on the table still, but progress. It is

9 really I think up to the FDA staff at this point to

10 tell us what they think of the three-tier system in

11 the context of the conversation we have already had

12 this morning.

13 DR. SIEGEL: Well, I guess I hear mixed

14 opinions. I certainly hear some subset quite

15 concerned about the notion that there is a group

16 where if you have one-year follow-up, you would be

17 comfortable just to do one-year follow-up. I think

18 we could target not too complex follow-up beyond

19 that on that group. Although I certainly heard

20 opinions to the contrary, I think that is something

21 that we can work with.

22 One of the areas I am still seeking more

23 input on for the tier system is the implication

24 between tier two and tier three, and as I read this

25 \-- although, again, I would ask the experts who

> 79 1 devised the system to comment or elaborate or

2 correct, some of this, it seems to me, was driven

3 in part by a desire for samples and that, in fact,

4 the issue of whether somebody is viremic, has an

5 immune response or has an insert for some of these

6 classes of viruses, even if they are doing well,

7 whether they have those things going on over the

8 first few years may be important information to

9 have, particularly if they develop toxicity later

10 on.

11 I have not heard this but I am reading

12 between the lines that, to some extent, there is

13 probably a thinking that if you are going to bring

14 somebody by for a sample, rather than just send

15 them a questionnaire, you might as well examine

16 them and take a medical history while they are

17 there. I don\'t know what drove what there, but I

18 guess having heard some comments that seem to

19 allude to whether there is a difference between

20 these high and intermediate risk categories, one

21 thing that might be worthwhile focusing on is while

22 they are, in fact, high or weak, overestimating the

23 potential value of getting samples beyond the first

24 year in some these cases, or are we saying it

25 should be in all cases? Bringing patients back, I

> 80 1 think we all agree, is a bigger endeavor than

2 sending questionnaires. Philippe, do you want to

3 comment on that?

4 DR. BISHOP: I think that when we

5 initially envisioned this three-tier system there

6 was a notion that there would be vector

7 characteristics that would present a higher risk in

8 the long-term for these subjects. The notion that

9 coming in to the clinical institution where the

10 expertise lies where, indeed, there is going to be

11 a specimen collected, maybe a physical examination

12 and maybe a directed interview of the patient by

13 the experts that are well aware of what is

14 happening in the field would have some value.

15 So, I think in terms of trying to identify

16 flags or signals that a certain strategy or gene

17 transfer may represent a long-term risk, we thought

18 that certainly the clinical centers where this took

19 place would probably be the best suited to

20 recognize those signals. Hence, the physical exam

21 and the direct patient-physician contact that would

22 take place at the same time, maybe an archival

23 specimen would be collected which could have some

24 value for the reasons that Dr. Siegel outlined.

25 DR. SALOMON: So, that we be a tier three.

> 81 1 You are making the argument for why tier three

2 would be different than a tier two.

3 DR. BISHOP: Tier three, and we felt,

4 based on discussion that this committee had and the

5 advice, that maybe the concerns would not be as

6 great beyond the first five years, especially when

7 it comes to autoimmunity and maybe hematologic

8 disorders, although malignancies and neurologic

9 disorders could occur much later, but most likely

10 these would be captured in the questionnaire and

11 would not necessarily necessitate the level of

12 expertise that the physician at that center may be

13 able to provide.

14 So, that is the distinction between tier

15 two and three, tier three being the highest risk

16 and maybe requiring that within a certain period \--

17 we picked arbitrarily five years; I don\'t know if

18 that is a correct number for follow-up, maybe a

19 year is sufficient. I don\'t know. But we picked

20 that, number one, because we thought that this

21 could potentially be manageable and doable, and

22 would probably provide the most specific

23 information.

24 We had entertained at some point, if all

25 gene transfer products needed to be monitored,

> 82 1 maybe combining tier one and tier two. However, I

2 think we had heard the committee here previously

3 expressing a need to have the flexibility that you

4 articulated for us and, therefore, we were

5 uncertain after the last meeting whether or not we

6 had heard you correctly and whether or not we

7 really needed to leave tier one intact, or whether

8 or not we needed to combine tier one and tier two,

9 again, tier two being just the clinical

10 questionnaire as being a useful tool here. All of

11 that, of course, was a thinking exercise for all of

12 us and certainly your comments are appreciated.

13 Carolyn, do you want to address maybe some

14 of the value of sampling, especially as we

15 understood it for retroviral vectors and how that

16 may apply to the high risks?

17 DR. WILSON: Yes. I am Carolyn Wilson,

18 Center for Biologics. I wanted to give a little

19 bit of a historical background of how we got to

20 this particular recommendation. Actually, to go

21 back to almost ten years ago, 1993, after the

22 Donahue report came out there was a letter that was

23 issued to sponsors that actually asked for lifelong

24 follow-up of all patients who were treated with

25 products involving retroviral vectors, and that

> 83 1 lifelong follow-up involved active obtaining and

2 testing of samples for evidence of RCR infection

3 and we recommended that three different methods be

4 used, serologic, PCR methods and infectivity

5 assays.

6 It became evident very shortly that that

7 was a very onerous burden on sponsors to fulfill

8 that particular request. So, back in \'97 and \'98,

9 starting sort of in 1996 and 1997 actually, I think

10 it was, we were having FDA-sponsored gene therapy

11 forums, and in those forums we were having sessions

12 to address those concerns with the guidance at that

13 point.

14 We had proposed one of several different

15 options regarding how to scale back that kind of

16 lifelong follow-up for patients in retroviral

17 vector gene therapy trials, and we were focusing

18 again primarily on the issue of RCR and the

19 clinical manifestations of the potential infection

20 by an RCR. We felt that if testing during that

21 first year of follow-up was all negative, one

22 potential would be that you wouldn\'t do any

23 additional physical examination but that you would

24 do just data collection but not archiving of

25 samples.

> 84 1 Interestingly enough, during the

2 discussion, because we had an extensive panel

3 discussion with extensive input from audience

4 members, there was a strong feeling that people

5 weren\'t ready at that point to give up archiving of

6 samples, at that point. So, this was really sort

7 of a compromise position between not doing anything

8 past the first year if all the of the RCR testing

9 was negative and doing everything lifelong. So, I

10 don\'t know if that helps the discussion.

11 CHAMPLIN: Is there experience now with

12 archiving all that dead tissue that has been

13 worthwhile in any way? Have you find evidence of

14 persistent virus that would then be meaningful?

15 DR. BISHOP: In November I think I

16 presented to this committee some of the limitations

17 that followed an attempt by sponsors, and I think

18 there were legitimate attempts by most of our

19 sponsors to comply with the guidance, and we

20 presented an outline, and it was a pretty long

21 outline, of the limitations that were identified in

22 the course of a survey. We attempted to contact

23 almost everybody that was doing retroviral vector

24 studies at that time. So, I think that conclusions

25 in terms of the value of having done that are

> 85 1 difficult to state because I think there was a lot

2 of information that had not been collected that

3 precluded us from really knowing whether or not

4 there was any value to this exercise.

5 But there was a general sense from almost

6 everybody that had this been done, then maybe today

7 we would know and we would be in a better position

8 to make statements, more definitive statements

9 about whether or not this was a valuable exercise.

10 In addition, I wanted to come back to one

11 comment that Carolyn had made, which is the

12 collection of specimens and archiving them, one of

13 the values of doing this is in the course of

14 following individuals three years following gene

15 transfer studies who develop an autoimmune disease,

16 we now have yearly archival that has occurred where

17 you can go back and start looking at whether or not

18 antibodies have become apparent, or there was maybe

19 the presence of viremia. So, I mean there are

20 various studies that can be performed that, at the

21 time of collection may not be obvious that would be

22 extremely valuable once a particular clinical

23 disorder had been recognized.

24 DR. SALOMON: Yes, Doug Jolly?

25 DR. JOLLY: My name is Doug Jolly. I work

> 86 1 for Biomedica \[not at microphone; inaudible\] \...

2 respond to the gentleman\'s question \[not at

3 microphone; inaudible\] \... HIV infection and \[not

4 at microphone; inaudible\]\... in the final go-around

5 we had 250 patients approximately from two HIV

6 trials and we tried to do follow-up for three

7 years, three to five years out from the initial

8 start of the trial, and we got about 66 patients

9 out of the \[inaudible; not at microphone\] \... which

10 is about 25 percent of patients.

11 I guess I would agree with what Dr.

12 Mulligan was saying, that I think for those kind of

13 protocols \[not at microphone; inaudible\] \... not

14 too much to worry about. \[Not at microphone;

15 inaudible\]. So, I would say that you really have

16 to look at the clinical experiment to try and

17 categorize the \[not at microphone; inaudible\].

18 DR. SALOMON: Can you enlighten us on the

19 reason why out 350-some patients you only go, I

20 think you said 64?

21 DR. JOLLY: Yes, 250 patients.

22 DR. SALOMON: But why? What happened to

23 the others? Why didn\'t you get follow-up on the

24 others?

25 DR. JOLLY: Because the way that trial was

> 87 1 run \[not at microphone; inaudible\] \... cystic

2 fibrosis patients there are not particular centers

3 where it is common to follow \[not at microphone;

4 inaudible\]. These are patients that were recruited

5 at various sites referred from other physicians,

6 and so just the whole process to find these

7 patients again is much more complicated \... \[not at

8 microphone; inaudible\].

9 DR. CHAMPLIN: If we are getting into

10 practical issues here, sort of doing annual

11 physical examinations at the treatment center for

12 five years becomes a very difficult thing to

13 actually accomplish. We try to do this with our

14 bone marrow transplant patients and the fall-off is

15 just dramatic even after the first year. So, if

16 what you really want is blood samples. You can get

17 that without the patient having to fly across the

18 country to come to the treatment center, and it is

19 good to have some sort of organized interview by a

20 physician to collect interim history and medical

21 information and potentially get a chemistry panel

22 to check for creatinine levels etc. that might not

23 be symptomatic in the patients if they had mild

24 renal insufficiency for example.

25 But I wouldn\'t necessarily think they

> 88 1 would need to return to the treatment center to do

2 that. So, one would need to have in a protocol

3 physician examination, perhaps laboratory studies

4 and if you want samples, have samples sent but not

5 require them to return to the treatment center.

6 DR. SALOMON: If we want to have a break

7 this morning before lunch, this would be a logical

8 time to take a ten-minute break and then come back.

9 I think that would be good, just in terms of

10 everyone having a chance to break for a second and

11 come back. So, ten minutes.

12 \[Brief recess\]

13 DR. SALOMON: Thanks, everybody for coming

14 back to the table. You never know with these

15 breaks how long they will take; I always have this

16 fantasy that they will be ten minutes. So, I

17 thought we would try and see how much we can get

18 done between now and 12:30. That is an hour, and

19 then break for lunch.

20 So, just trying to restart where we left

21 off, it seems like one big step to take right now

22 would be to come back again to one of the primary

23 questions, and that is can we \-- you know, option

24 one, there are no gene transfer protocols today

25 that the committee believes should be exempt from

> 89 1 long-term follow-up as has been defined.

2 Option two, there are some possible gene

3 transfer clinical trials that should be exempt and

4 we are not trying to define exactly what that

5 should be yet. Can we deal with that because

6 depending on whether we agree with option one,

7 there are none that are exempt, then we can just

8 agree on that and move forward? Then I would like

9 to come back to sort out finally this tier thing.

10 DR. RAO: I think it is more like option

11 two, that there are some trials where there

12 shouldn\'t be necessarily an absolute long-term

13 reporting requirement.

14 DR. MULLIGAN: I vote option one, that

15 there are none that shouldn\'t have long-term

16 follow-up. By long-term we mean longer than one

17 year. Is that what we are talking about?

18 DR. SALOMON: Yes.

19 DR. CHAMPLIN: I voiced earlier that I

20 wanted to be reassured that both the manufacturing

21 as well as the concept was consistent with the

22 goals of option one and that there was truly no

23 potential for long-term toxicity, so I think the

24 onus is on the sponsor to demonstrate that.

25 Perhaps if you think that there are some that would

> 90 1 meet those criteria, you know, you could describe

2 those types of studies that would meet those

3 criteria.

4 MS. LAWTON: I would just like to comment

5 that as far as, you know, if it is decided that

6 everything needs long-term follow-up, that is fine

7 but we also need to look at where is the highest

8 risk that we want to try and collect information

9 and understand, and the practicality of all of this

10 is a huge issue and I don\'t want us spending a lot

11 of time trying to collect long-term follow-up on

12 those very low risk things and, therefore, not

13 getting the information in the high risk areas

14 where we really want to focus. So, that is the

15 only comment I would make.

16 DR. SALOMON: Any comment on that to try

17 to give us what your sense of the public would be?

18 MS. KNOWLES: Well, I wrote something down

19 here earlier this morning during our discussion,

20 and this is probably something that is not going to

21 be taken very well but it sounds like in some

22 senses FDA needs to redefine research protocols to

23 include long-term follow-up at the front end of

24 those protocols so that it is part and parcel of

25 the research protocols. The sponsors know about it

> 91 1 up front and there is no discussion. It just

2 happens.

3 DR. SALOMON: Well, I think that is

4 definitely the premise of all of this, that we

5 would define a type of long-term follow-up that

6 would be applied, and would be up front, and would

7 be applied to all protocols to the extent that

8 those criteria \--

9 MS. KNOWLES: Excuse me, I am not talking

10 about just gene therapy. That is why I say it is

11 probably not going to be well received, but I think

12 it is something that should maybe considered at

13 some point in time.

14 DR. SALOMON: Well, I think everyone would

15 realize that it is beyond the purview of this

16 committee to comment on any other committee\'s area

17 or any other FDA activity, but I certainly think

18 that that is now on the record.

19 Dr. Patterson, I don\'t want to put you on

20 the spot but you have a very important role here in

21 terms of not only your expertise in the area but

22 your liaison with the recombinant DNA advisory

23 committee. Can you give us some sense of where the

24 RAC is on this?

25 DR. PATTERSON: Well, I think since the

> 92 1 inception of this field the NIH and the RAC, in

2 concert with the FDA, has underscored the

3 importance of long-term follow-up. I think as an

4 agency, its mission is to advance knowledge in

5 order to promote good health and it is incumbent on

6 us to try to get information that is pertinent to

7 the safety and progress of this field.

8 I think I have said before each of the

9 other times the committee has discussed this topic

10 that I think that the FDA is to be commended for

11 the steps it has taken so far in trying to outline

12 a paradigm for long-term follow-up, as has this

13 committee. I want to stress that we think that

14 there needs to be a broader consultation process

15 before the final lines and characteristics of this

16 framework are put in place. That consultation

17 should include I think not only patient advocacy

18 groups and communities, but it should also include

19 people and agencies, such as the CDC, with

20 expertise in surveillance studies and long-term

21 follow-up so that twenty years from now we have

22 data that is both scientifically valid and

23 statistically useful, and is as least burdensome in

24 the collection process as possible. So I would

25 hope that this is a very important pivotal first

> 93 1 step to a longer-term process.

2 I also realize, in reading the briefing

3 materials, that there is mention, particularly for

4 the autoimmune diseases, about the possibility of

5 having some of these conditions become reportable

6 diseases. That is a process that involves the CDC.

7 That is a longer-term process. I know that

8 colleagues at the FDA recognize this.

9 I also think, in addition to the tier

10 approach we may want to think about a phased

11 approach to long-term follow-up. What is the

12 short-term fix to long-term follow-up? What can do

13 we do right now? What can we put in place now

14 versus in the longer-term? What regulations may be

15 needed? What changes in the local and state health

16 departments for reporting diseases are needed?

17 That is a longer-term issue that is going to

18 require a much wider dialogue than what is

19 happening here, important as it is, in this room.

20 DR. SALOMON: Thank you. I certainly

21 think I can speak for the committee in saying that

22 we would very much welcome additional discussions

23 outside this committee. I think as you have had to

24 come back three times to this committee to get us

25 to this point reflects the fact that I don\'t think

> 94 1 anyone here feels that the complexity of this

2 issue, and its impact on so many different groups

3 with so many different kinds of interests, can be

4 adequately reflected by anything we accomplish

5 today or, you know, in the last two meetings. So,

6 I agree. Do I speak for everyone? I think we

7 would love additional consultations, and I think

8 that is implicit in any advice we give today.

9 DR. CHAMPLIN: To say the obvious again,

10 long-term follow-up is easy to say but it is very,

11 very, very hard to do, and it is very hard to get

12 information. It is hard to get information that is

13 interpretable. Just thinking about, you know, if

14 you have a questionnaire and somebody says, \"I have

15 kidney problems\" and sends that back to you. How

16 do you score that? Do you call them? What sorts

17 of things do you do to sort that out, glomerular

18 nephritis, bladder infection? So, you are going to

19 get just reams of data that are going to be very

20 difficult to interpret, and this is really going to

21 require enormous resources in personnel, in time

22 and computer systems and effort to sort it through

23 probably for very little gain in the end. We hope,

24 in fact, there are going to be few, if any,

25 long-term adverse events and it is just an enormous

> 95 1 undertaking to try to be sure of that.

2 MS. LAWTON: I was just going to comment

3 that that is assuming you can find those patients.

4 DR. SALOMON: So, trying to move this

5 forward, what I have heard so far this morning is

6 \-- trying to seek kind of minimum consensus here \--

7 everybody agrees that not all vectors are created

8 equal and that we all agree with the basic concept

9 that there is an array of relative risks for long

10 term. But having said that, I also sense that

11 rigidifying that in a tiered system is something we

12 are probably not really comfortable with.

13 I think to move this field forward, I

14 think what Amy suggested for the first phase would

15 be that we have so far agreed with the concept that

16 long-term follow-up beyond one year after the last

17 dose of the gene transfer vector is appropriate.

18 That is an important start.

19 Secondly, I think there is a general sense

20 today that probably all gene transfer vector

21 clinical protocol patients should be followed long

22 term. I am not going to tell you that that is

23 fifteen or twenty years yet. We will get to that

24 in a minute, but there ought to be some tracking of

25 those patients, albeit all of us are concerned

> 96 1 about what that will entail, and we feel that is a

2 reflection of concerns from regulatory agencies,

3 Congress and the public.

4 Perhaps if one agrees then that all should

5 be tracked, in the future we can use that data and

6 come back to this so that this is, as Dr. Siegel

7 instructed us at the beginning, only our best

8 advice for today and not necessarily for all future

9 time, that we could agree that the tier system per

10 se doesn\'t add anything and it would be just

11 rigidified interactions. If everyone has to have

12 some form of long-term follow-up, then we can

13 basically not try and stick to specific vectors

14 without repudiating the basic concept that there

15 are going to be relative risks that will increase

16 with certain kinds of trials and that that should

17 be dealt with on a trial by trial basis. Can we

18 have some discussion of that? Can we get there?

19 Have we gotten that far?

20 MS. LAWTON: Can I just ask a question?

21 Then, if we agree that we need long-term follow-up,

22 are we willing to have a discussion around what we

23 think is a minimal of the data that we need to

24 collect, and then that the additional things is

25 what is out for further discussion?

> 97 1 DR. SALOMON: I think that is critical.

2 So, what I would suggest that I can be comfortable

3 with \-- again, this is just to start the discussion

4 \-- is affirming that we need long-term follow-up;

5 creating a framework that is generic enough to

6 cross all different kinds of trials that come

7 forward that would satisfy, in phase one, what I

8 think are critical issues. One is I just can\'t see

9 burdening this field with such a financial

10 involvement based on just this sort of major thing

11 \-- everybody needs follow-up \-- that it just

12 decreases the ability to do gene therapy and move

13 this field forward because that is the last thing

14 this field needs right now. But, at the same time,

15 we need to be respectful of the fact that there are

16 a lot of unknowns in this new technology and do

17 that as well.

18 So, I am thinking that what we could deal

19 with in the next half hour or forty-five minutes is

20 what this committee feels would be the phase one,

21 what everyone should get, and then if you want to

22 do, you know, brain biopsies yearly on a specific

23 trial that is between you and the sponsor on that

24 trial and that didn\'t come from this committee.

25 DR. SIEGEL: I guess I would also like, in

> 98 1 light of Alison Lawton\'s question and some that we

2 have, rather than accept \-- you made a comment that

3 while the tier system sort of becomes irrelevant

4 everyone needs follow-up, but her comment was, and

5 our approach and thinking has been that even if

6 everyone needs follow-up attention ought to be

7 focused on those areas of greater concern, which

8 could lead to systems where there was either more

9 frequent or extensive data collection based on

10 certain factors, or whatever, and I would like to,

11 you know, keep that on the table for discussion as

12 to the merits of that sort of approach.

13 DR. SALOMON: I guess what I am trying to

14 get at, and I am just testing the water in a way,

15 but what I am trying to get at is affirm that the

16 principle of long-term follow-up is there; affirm a

17 framework for long-term follow-up that we feel

18 could be applied to anyone in the gene transfer

19 protocol, with the implicit advice to the FDA that

20 the protocol details should then be left between

21 the sponsor and the FDA staff. Then, we could

22 finish by discussing more generally principles for

23 that long-term follow-up, which we already have and

24 I think there has been tremendous progress. So,

25 that could be the last thing we do. You know, if

> 99 1 you want to do details, here they are. But that

2 way at least I think the committee could get to a

3 point where we move the field forward. We affirm,

4 we gave a general concept, we didn\'t kill the field

5 \-- not to be too dramatic but I am just really

6 scared of that. So, we could be practical, move

7 the field forward and also give you good advice.

8 That is what I am hoping.

9 DR. MULLIGAN: One thing is that we are

10 not getting rid of the tier system but, I mean, we

11 have spent a year talking about the tier system and

12 I think that the concepts and principles are very

13 sensible. So, it is a question of whether to

14 incorporate the tier system organizationally into

15 the formal long-term follow-up. So, I think we do

16 agree; there is some consensus about what diseases,

17 what applications require more or less and I think

18 we are saying we don\'t want to stick that into the

19 formal long-term follow-up because of all the

20 issues we have discussed over the last hour or two.

21 But I think that all of those principles are very

22 reasonable and there probably is a consensus, or we

23 could get at some point to a consensus on the tier

24 principles. We probably did that several months

25 ago.

> 100 1 DR. SIEGEL: Right. The tiers came out in

2 the November discussion to try to incorporate those

3 principles. What you are saying is you endorse the

4 principles but it is hard to be too highly

5 prospective and specific about exactly how to use

6 them. I understand that. I made the case for why

7 there is a lot of advantage to trying to be

8 prospective and give guidance on how they are used.

9 But I hear what you are saying.

10 DR. MULLING: But the other message,

11 certainly my message is that I think there ought to

12 be a very deliberate incorporation of some of these

13 principles into the actual product review. That is

14 the other part of this, a kind of a different way

15 of thinking, that those things that are most of

16 most concern to people that are bringing up issues,

17 taking samples for the first five years \-- you

18 know, we maybe ought to be thinking a little

19 differently about those.

20 DR. SIEGEL: Just to clarify further in

21 terms of the way you set the goals for the end of

22 today, surely, basically it is feasible but I

23 question setting them too low, and there is some

24 consensus there needs to be longer follow-up

25 because where are we in the process? That is, I

> 101 1 said before we are all in agreement that we need \--

2 I agree, by the way, with everything Amy said \--

3 further consultation about the best information and

4 about who to collect it and how to collect it, and

5 funding, and whatever, and yet there appears to be,

6 unless I am wrong, a strong consensus on this panel

7 that the right thing to do with the protocols that

8 we receive next week at the FDA is not what we have

9 been doing, which is if it is a retrovirus, there

10 is five-year specimen collection and long-term

11 follow-up, and if it is not a retrovirus, one year

12 and then you are done.

13 So, while I don\'t disagree that other

14 areas need to be put forward, I am suggesting that

15 we come to a point in time where it would appear,

16 based on this advice of this committee and

17 assessment of the situation, that one of the steps

18 of the process, and one that we are moving toward,

19 is to request that sponsors commit to more

20 extensive long-term follow-up for a broader class

21 of vectors. And, I think you already said it is

22 kind of the sense of the committee that there is be

23 general support for that. But we also need

24 whatever we can get in terms of practical input in

25 terms of what the nature of that would be.

> 102 1 While recognizing that it is not final, it

2 is also the case that the easiest time to work

3 these things out often is as the research is

4 beginning, as people are funding the research and

5 planning the research and thinking through the

6 research. It is much harder, if not impossible, to

7 go back to a study that was started ten years ago

8 and say, huh, you know, you really needed a

9 twenty-year follow-up, so even though you haven\'t

10 done anything for the last five years it is time to

11 reopen the study and find those patients and ask

12 them all these questions. So, we don\'t want to be

13 twenty years from now not having gotten started.

14 DR. SALOMON: And, I think what we are

15 trying to say is what is it in this phase one that

16 this committee would agree with you doing next week

17 when you get such-and-such and I want to try and

18 get there. Then we can stop and discuss in general

19 principles of long-term follow-up that would be

20 advice but not, you know, a specific guidance to

21 you in the sense of how the committee thinks you

22 should do things next week, and that might be

23 setting up a framework for consultations with other

24 groups that I think all of us accept as a

25 principle.

> 103 1 DR. MULLIGAN: You know, there is a

2 sensitivity about your existing retrovirus

3 long-term follow-up requirement. I mean, I hate to

4 take on another thing for us, but it seems like you

5 raised that in that there is an inconsistency. In

6 a way we are tacitly rescinding \-- you could

7 interpret that we are rescinding the need to do

8 this stuff that is now in force. Is that something

9 you want us to address?

10 DR. SIEGEL: Well, one of the reasons we

11 came here in November was the growing awareness

12 that we had advice that it was important to collect

13 certain types of information. We were asking for

14 that information and it wasn\'t being collected.

15 Okay? So, I personally, and I think many others of

16 us, didn\'t just want to sit on that, you know, that

17 the whole world thinks that we are getting

18 archiving specimens. And, one of the questions I

19 asked the committee was, well, given that we are

20 not collecting this information in the current

21 infrastructure of a higher incidence, does that

22 mean that we are asking (a), for the wrong thing,

23 (b), we should collect the best we can or, (c)

24 should we put all the research on hold because the

25 fact that we can\'t collect it makes it too unsafe

> 104 1 to conduct the research?

2 The answer I got, at least as I understood

3 it, was that while there has continued to be some

4 level of confusion \-- not confusion, I don\'t mean

5 that, some level of lack of consensus about exactly

6 what is the best thing to do, there was no strongly

7 held belief that the appropriate approach is to

8 stop the research until we can work up the

9 mechanisms to gather the data right.

10 Now, we have had some discussion about

11 those mechanisms here and the relative value of

12 having simple postcards and whatever, and focusing

13 and whatever, and those were useful. We have had

14 other discussions. I think as Amy points out, CDC,

15 other groups that have expertise to bear on that.

16 And, also some of the issues that we got into

17 discussing are infrastructural issues. You know,

18 there should be an organization that does this or

19 something like that. And, I think that sort of

20 advice is useful but I think we are feeling also a

21 need \-- you know, was it Amy who said short-term

22 solutions and long-term follow-up \-- those are the

23 sorts of things that you are going to build

24 organizations, structures, governmental or not,

25 cohorts, whatever, that need to be under discussion

> 105 1 and, indeed, are under discussion. But, at the

2 same time, we need to know what are we doing

3 tomorrow? Should we stop all the research until it

4 exists, or should we ask them to commit knowing

5 that they will do their best but that their best

6 may have some significant holes in it?

7 DR. SALOMON: We are going to try and do

8 that. So, what I think we should talk about now is

9 what do we, today, phase one, agree should be done

10 for gene therapy long-term follow-up \-- some of the

11 details now. What do we feel is the phase one, the

12 first cut? Then we will go on to talk about what

13 we could see being done as part of the consultation

14 with others interested in this area in phase two

15 and three. What do you, guys, think? Phase one?

16 What is the bottom line?

17 DR. CHAMPLIN: What I have sort of been

18 wrestling with is I think we all agree with sort of

19 detailed follow-up for the first year is

20 non-controversial. We have sort of signed off on

21 that. Then a survey for some extended period of

22 time of late, unexpected consequences. I guess

23 what I am sort of wrestling with is the middle

24 ground, what is now listed as the five years of

25 annual physical examinations and review. And, that

> 106 1 is sort of protocol specific I think in terms of

2 the vector involved and what data is needed to

3 analyze that vector. If you are expecting

4 long-term expression, of course, you want to

5 measure is it being expressed, etc.

6 But in terms of toxicity assessment, I

7 would probably try to simplify that to not

8 necessarily requiring a person to come back to the

9 treatment center and the sponsor assessing the

10 toxicities in those patients during that five-year

11 period by interactions with the patient directly

12 and with their local physician, and then getting

13 whatever samples are necessary for the study

14 protocol itself. But it becomes increasingly hard

15 to get people to truly come back to the treatment

16 center, if it is a long distance patient, beyond

17 the first year, and it is asking for missing data

18 and problems in executing the protocol if you

19 require that.

20 DR. SALOMON: One principle that maybe we

21 could agree on is that there should be a database

22 in which all patients who have been in a gene

23 transfer protocol are identified, that details of

24 the protocol are identified, that the vector, the

25 promoter, etc., etc., the purpose, the initial

> 107 1 patient data, the response \-- all these different

2 things, that this should be in the database; that

3 the integrity of that database should be assured,

4 should be easily searchable so that if ten years

5 from now or twenty years from now any question is

6 raised in public or in the halls of the CDC, or

7 whatever, all this information is immediately

8 available and you can instantly say how many people

9 got this and this vector, for what disease, etc.,

10 and why, and what were the details of the protocol.

11 Can we start with that one principle?

12 DR. SIEGEL: Right, and I think we are

13 pretty comfortable that that is well on its way to

14 happening. NIH and FDA have put substantial

15 efforts into that.

16 DR. SALOMON: Now, the second principle \--

17 does everyone on the committee agree? We all agree

18 with that? I mean, we have covered that before.

19 The second principle would be what is the

20 sponsor? Would that be an individual investigator

21 on an NIH grant, or a biotechnology company, or

22 some mix thereof? What is the responsibility of

23 the sponsor to this first principle, the database,

24 the integrity of the database? My feeling would be

25 it is the sponsor\'s job to make sure that all this

> 108 1 detail is in this database. It is not the

2 sponsor\'s job to be the database but it is to

3 submit the data requested by the database holder,

4 and whether you, guys, do that within the FDA, the

5 NIH, I know the RAC has done some work on that. It

6 is fantastic. Or, whether in the end you contract

7 \-- I don\'t think that is this committee\'s issue

8 right now. But it is the sponsor\'s. Do we agree

9 that it is the sponsor\'s duty to obtain and provide

10 the integrity of that data?

11 MS. LAWTON: One comment I would add to

12 that is if this is for the purpose of tracking

13 patients, you also have to look at how frequently

14 do you want the sponsors to keep that information

15 up to date.

16 DR. SALOMON: Right. That is good.

17 DR. CHAMPLIN: So, there are precedents

18 for these kinds of organizations. For example,

19 there is the international bone marrow transplant

20 registry that collects transplant outcome data on

21 patients. Basically it is operated under contract

22 from the NIH. Similar to what you envision, they

23 then develop case report forms; they have annual

24 reports on all the patients that are submitted.

25 This would seem to be a sort of parallel function

> 109 1 that we are describing here.

2 DR. SALOMON: Yes, there is also UNOS.

3 There is the end-stage renal disease database.

4 There is the AIDS vaccine trial. So, I think a

5 principle here would be that these should be

6 web-based from the sponsor\'s point of view. They

7 should all be available at web-based data entry

8 sites so that would facilitate data entry.

9 MS. LAWTON: I guess I wouldn\'t get into

10 that level of detail here. I think we should be

11 saying there should be a registry. Sponsors are

12 responsible and there should be a way of updating

13 it. But we shouldn\'t start recommending whether it

14 should be web-based, whether it is held at NIH,

15 FDA, whatever.

16 DR. SALOMON: I agree. We are not telling

17 where it is going to be. I am okay with stopping

18 there. I was just trying to get a sense that it

19 didn\'t get ridiculous, you know, that we had to

20 have carrier pigeons. I mean, there has to be some

21 limit. I think a principle here is that it has to

22 be technologically made in such a way that it is

23 not an onerous burden on the sponsor. I shouldn\'t

24 give any more detail now. I agree.

25 DR. SIEGEL: I would like to say that I

> 110 1 would like to really focus in that regard on what

2 information to collect. For example, there are

3 issues that we are trying to address right now that

4 relate to securing the privacy of the information.

5 DR. SALOMON: I agree. Mahendra, you had

6 a comment?

7 DR. RAO: You already addressed it. I was

8 going to say the two points we should only make

9 about the database is that all the information from

10 the sponsor should be in the same format because it

11 is all going to be kept in one place. The other

12 thing is, from what we have discussed before, there

13 will be levels of information depending on the

14 category of trials that you have. So, it is not

15 that all information is going to be identical on

16 all the samples that you have. Right? You are

17 going to have patients on a trial where you might

18 have just a simple questionnaire. Right? Or,

19 others where you might have additional data.

20 DR. SIEGEL: Yes, just so that you all can

21 feel somewhat comforted by this, there have been

22 ongoing efforts that have included broad

23 consultations with groups such as UNOS, and bone

24 marrow transplantation, and other people who work

25 in this area that have also had input from our

> 111 1 efforts, people at NIH, FDA and CDC working on gene

2 therapy or working on xenotransplantation where

3 some of these issues arise. And, a lot of efforts

4 to date have gone into defining what are the data

5 fields and the databases, which would determine, of

6 course, partly what information you collect; how

7 should that be defined; how we classify vectors;

8 how do we classify events; how do we track sites,

9 patients, physicians or whatever in the database.

10 And, how do we build systems that will allow

11 analysis for that. Where we are trying to get at

12 this point though in a sense, at least from the

13 perspective at least of long-term data, is what

14 efforts need to be made to get the data to populate

15 those systems so that we can analyze. That is

16 right, Dr. Rao, we anticipate that it wouldn\'t

17 necessarily be the same.

18 DR. SALOMON: So, picking up on where Dr.

19 Rao left off, I guess where I was going \-- I got a

20 little bit off detail when we were talking about

21 the web base \-- I guess the principle I would like

22 to see if we agree on \-- and this was an issue that

23 we got into some discussion with the leadership of

24 the American Society of Gene Therapy at the meeting

25 in Seattle a few months ago, and that is, we really

> 112 1 think that efforts have to be made by the federal

2 agencies to harmonize this information. I know

3 you, guys, have heard this message and are doing

4 your best to do that, but I think as a principle

5 from this committee, unless again my colleagues

6 want to disagree, it is very important that there

7 not be twenty different data reporting requests

8 from twenty different federal agency groups. I

9 think one of the things you should hear from us is

10 that we would hold you responsible for harmonizing

11 some of this information the very, very best that

12 you can. Is there any discussion on that?

13 DR. PATTERSON: I would just like to

14 request time at a future meeting to go over with

15 you some changes, some significant changes to the

16 NIH guidelines and reporting requirements that I

17 think they will speak directly to the issues. We

18 heard very clearly the call from investigators and

19 industry that you wanted wherever feasible or

20 possible one set of federal requirements, and we

21 are harmonizing our definitions, time lines and

22 scope of reporting to parallel those that the FDA

23 has set forth in 21 CFR.

24 In addition, we have a number of

25 initiatives under way that I think this committee

> 113 1 could make important contributions to, a series of

2 ongoing safety symposia on the database for setting

3 up a gene transfer data safety assessment, and we

4 will be working closely with colleagues at FDA to

5 help prepare reports for that. Just whenever you

6 have time on your agenda, I would like to maybe

7 give you a more detailed update on those efforts

8 that we have heard and paid attention to.

9 DR. SALOMON: That is excellent. We are

10 on a roll here. I don\'t know how long it is going

11 to last. So, the next step would be getting a

12 little bit closer to what would be the generic

13 detail then. What do we advise now needs to be

14 done for this first phase?

15 DR. SIEGEL: Maybe to help focus more, I

16 will ask a more specific question although, again,

17 all comments and all aspects are welcome, and that

18 is how long? I think you pointed out at some point

19 in time we thought we should be following people

20 for the rest of their lives. At this point, to

21 summarize what we have proposed in analyzing risks,

22 at least on the basis \-- and we don\'t know for gene

23 therapy of course, but on the basis of other

24 treatment, the nature of the disease, the nature of

25 virus-induced disease, and the nature of genetic

> 114 1 mutation-induced disease, I think our summary,

2 looking at malignancy and neurologic disorders and

3 perhaps those that might take the longest time, we

4 would still see much of what we were looking for in

5 ten years, and most of what we were looking for in

6 fifteen years, and a very large proportion of what

7 we were looking for over twenty years of follow-up,

8 and I don\'t know that we have a good feeling for

9 the additional costs or even additional yields as

10 you go to ten, fifteen, twenty or longer periods of

11 follow-up. But we put on the table time ranges

12 between fifteen to twenty year range as a standard

13 amount to do this sort of follow-up, and it would

14 be interesting and useful to get feedback on that.

15 DR. SALOMON: Okay. So, we can look at

16 time frames. I think that is a great place to

17 start. Five years? Ten years? Fifteen and

18 twenty? I think what I would like to return to

19 when we are done is a second principle that is

20 connected, and that would be do we think it would

21 be more intense in the first year, five years

22 versus ten years? But let\'s get to that in a

23 minute.

24 How about comments from the group about

25 phase one, all patients on a gene transfer vector

> 115 1 clinical protocol, what time frame are we going to

2 look at data for?

3 DR. MULLIGAN: I think one issue has to do

4 with trying to not dissociate that question from

5 what it is. What is the data collection? It is

6 sort of ridiculous to talk about that and then have

7 to spend another hour or two rationalizing it. So,

8 I mean, I would almost do it in reverse. You know,

9 if you are talking about ten years, fifteen years,

10 twenty years is there a significant difference in

11 the amount of information you will add based on the

12 kind of system that you put in place? If it is an

13 automatic e-mail that goes to people, you know,

14 something like that. I think that is going to end

15 up dictating where we are going to cut down because

16 I still look at this as a pretty raw database that

17 we will have, and I do look at it as changing over

18 time. Ten years, you know, from now another group

19 here may have to rehash this whole thing.

20 But at this point, I would be interested

21 to hear what people think about ten years or twenty

22 years in terms of getting info, and if you have an

23 attrition rate between ten and twenty years, do you

24 care? That is, are you still getting the info?

25 Then, you know, almost base a decision on that. I

> 116 1 would be most interested to hear what people think

2 would be the manner of data collection. You know,

3 what would be the actual kinds of questions,

4 questionnaire, how would you get it to people? I

5 think if you don\'t understand how you get it to

6 people, then we can\'t really give a sense of how

7 long to keep it.

8 DR. SALOMON: Fair enough. Comments?

9 DR. HIGH: I would just say that looking

10 at the field in general, to me, it is more useful

11 to collect a minimal amount of data between five

12 and twenty years than to collect a great deal of

13 data between one and five years. I think that for

14 what we need the amount of information is really

15 minimal. I think we could just have, as you said,

16 a one-page questionnaire or even a postcard. You

17 want to know causes of death, development of new

18 medical conditions, that sort of very minimal

19 information, and it could go first as a

20 questionnaire to the patient and if it fails to

21 elicit something, you know, the sponsor could

22 follow-up with the treating physician.

23 DR. CHAMPLIN: I would think after about

24 five years you are going to be dealing with very

25 rare events and you are really concerned about

> 117 1 malignancy as the number one thing, possibly

2 neurologic disorders. So, you could have three

3 questions on the card, basically, did you develop

4 cancer? Then, some more general, did you develop a

5 major medical problem? And, pretty much leave it

6 at that. Whereas, during the first five years you

7 are going to try to screen more comprehensively for

8 the acute and the intermediate toxicity.

9 DR. SALOMON: The only thing I would add

10 is we actually have a little bit of a framework

11 here that I think is useful, and that is, you know,

12 did you develop any kind of cancer? If so, what

13 kind? Did you develop any sort of autoimmune

14 disease? If so, what kind? Did you develop any

15 neurologic disease? Just basically following the

16 patterns that we have come to because I think there

17 is a lot of very reasonable, scientifically based

18 work there that I think was very nicely reviewed

19 for us this morning by Philippe and Steven.

20 DR. MULLIGAN: From a database point of

21 view, going back to that tier system, not to throw

22 that away, you could, indeed, organize a database

23 somewhat along the lines of the tiers so that you

24 would at least know that you may be most interested

25 in getting to the database that deals with that

> 118 1 class of patients.

2 DR. SALOMON: Sure. I mean, I personally

3 don\'t see that as being a big advantage but that is

4 a detail. To me, what is going to be most

5 interesting I think down the line would be vector

6 classes, promoter types and the nature of the gene

7 construct that has been delivered and, of course,

8 its interaction with the disease. That is going to

9 be the most interesting thing.

10 I think the weakest part of the long-term

11 data is going to be this whole issue that was,

12 again, nicely described this morning, and that is

13 you are going to give it to a disease population

14 and the population that has that disease and that

15 didn\'t get the gene vectors is really the only one

16 that is going to make any sort of sense. Then, the

17 reality of defining disease groups is going to be

18 extremely fallible, and that is going to reduce the

19 quality of the data and make the interpretations

20 much, much more limited, I am afraid. Even when

21 you do something, as we will discuss on Friday I

22 guess, but even something as simple as defining

23 heart failure in an AIDS patient, or define a

24 specific type of leukemia \-- it is going to be very

25 difficult.

> 119 1 So, I think if we can go with reasonable

2 kind of data so that we could say twenty years from

3 now that we saw 200 cases of thyroid cancer and we

4 can trace it back to this group of patients, and

5 that all relates to a certain class of vector or it

6 relates to any class of vector in anyone you use

7 the CMV promoter, or something like that, I think

8 that would be incredible kind of data. It is

9 probably the strongest data that will come out from

10 long-term follow-up.

11 DR. GAYLOR: Obviously, follow-up is not

12 new. There are a lot of studies on a number of

13 drugs particularly with follow-up on chemotherapy

14 trials, for example. These people will tell you

15 the worst thing to do is to mail out a

16 questionnaire. It is much better to have a nurse

17 conduct a telephone interview. A well-conducted

18 follow-up on a hundred people may tell you a lot

19 more than mailing out questionnaires and getting

20 ten, twenty, thirty percent response, especially

21 years down the road.

22 So, I would encourage FDA, CBER in this

23 case, to really look into what has been done in

24 other long-term follow-up and consider sampling

25 rather than just trying to follow up a hundred

> 120 1 percent of the people. I can\'t sit here today and

2 tell you what you need to do, but one advantage is,

3 if you are looking for rare events, you don\'t need

4 a large sample. You don\'t need tens of thousands

5 of people. Three rare events can be statistically

6 significant. A hundred people can tell you if you

7 are getting an incidence of five to ten percent.

8 Epidemiologists tend to look at relative

9 risk but if you look at just the absolute risk,

10 what is the chance that your population has a five

11 percent or ten percent incidence of some adverse

12 effect, that is not that difficult to pick up from

13 a relatively small sample. It wouldn\'t be a

14 terribly big burden, I don\'t think, for a sponsor

15 to follow a hundred people carefully, and two or

16 three years down the line maybe you can go to fifty

17 people, or maybe decide you have to go to two

18 hundred people. But, of course, you sort of want

19 to tell the sponsor up front what is expected, and

20 you sort of hate to say, well three years from now

21 we may decide to go to a thousand people for

22 follow-up and you have been doing a hundred. So,

23 that would be a little tough to deal with, but I

24 would certainly recommend sampling rather than

25 trying to do a hundred percent follow-up.

> 121 1 DR. SALOMON: The problem I see with

2 sampling is that you are treating this gene therapy

3 as this population and then you are going to sample

4 within it, which makes sense until you realize that

5 that is really not the population. The population

6 is all these little groups, each one getting

7 different vectors, and different genes, and

8 different diseases. So, I think that sampling is

9 not likely to be as powerful as it is conceptually

10 when you have a unifying disease process and a

11 unifying treatment.

12 DR. GAYLOR: Sampling would work for

13 following up in a clinical trial group \--

14 DR. SALOMON: If it was big enough.

15 DR. GAYLOR: If it was big enough and if

16 it is only fifty people, you would probably follow

17 all fifty of them.

18 DR. HIGH: I would just second that. I

19 mean, there are 4000 patients on 400 trials

20 approximately. So, to try to sample in that

21 setting is not meaningful.

22 DR. SIEGEL: Maybe within the next few

23 years we are going to be seeing large, multi-center

24 Phase III trials.

25 DR. SALOMON: Right, and I think then Dr.

> 122 1 Gaylor\'s point would be that perhaps at that time,

2 in negotiation with the sponsor, detailed follow-up

3 might be done on a sample and that would be great

4 to reduce the onus of a twenty-year follow-up.

5 DR. SIEGEL: One thing I have reflected on

6 relates also to the concept about long-term

7 follow-up and a comment or two in areas outside of

8 gene therapy is that one of the issues here \-- if

9 somebody starts a trial of a new experimental

10 product, often a few years later it is either

11 approved or it is dead \-- the product is dead, and

12 the long-term follow-up of the patients, depending

13 on the nature of the product, may be important to

14 the patient\'s safety. But if the product is not

15 going anywhere it is not critically important to

16 the understanding of the product. So, often we

17 face these issues at the time of product approval

18 when it is going to much larger numbers and it is

19 going to be around for a while, and we can work out

20 with a company about what is necessary to find out

21 even longer term than three or four years they have

22 already been studying it about long-term effects.

23 But the premise we are working from in

24 gene therapy is that if we are dealing with 400 and

25 4000, whatever those numbers are, the information

> 123 1 on one product, as long as we are talking about,

2 you know, vector specific rather than highly

3 protocol specific risks, the information on one

4 product is relevant to all products and we have

5 kind of an obligation to look at it all together,

6 and that is why we are talking about databases or

7 studies. Even if you do a study today, even if

8 that product doesn\'t work or you find a somewhat

9 better vector, the long-term follow-up of those

10 patients is important not only for their welfare

11 but for understanding the study risks of gene

12 therapy. That is one of the reasons we are

13 specifically focused on this issue in this field.

14 DR. SALOMON: Yes, I think another

15 scientific argument is just to look at the Donahue

16 report where the rhesus monkeys got the lymphoma.

17 Now, nobody would do a retroviral vector trial

18 designed like that where they have homologous

19 sequences and a packaging vector that allowed for

20 the RCR. Obviously, we have learned our lesson.

21 Obviously, we don\'t design vectors like that. We

22 are way past that. So, you could argue that that

23 is a dead issue but it is so important because it

24 explains why, like on Friday when we look at vector

25 issues that were brought up with the RAC about

> 124 1 possible recombination, about how many plasmids

2 they had divided there, packaging sequences, and so

3 on. So, I think that it is valuable even if we

4 discover a complication in a retroviral vector or

5 another kind of vector product that we all realize,

6 God, we would never do that again. It still

7 defines the field.

8 DR. SIEGEL: I don\'t want to go too far

9 down the lane of being philosophical, but one of

10 the things that we noted that was particularly

11 difficult in this field as it got started with

12 preclinical studies, and it is still the case to

13 some extent, is we would ask, say, French Anderson

14 who was doing some of the first experiments, we

15 would ask for a two-year animal study to look at

16 some of the longer term concerns. Invariably, at

17 least for the first few years of therapy, and it

18 may still be the case, by the time you got a

19 two-year animal study on the safety of a vector

20 there were other generations of vector that on

21 paper just look like they would be safer. They had

22 been engineered to have less risks. So, now you

23 start that one in a two-year study, at the end of

24 which you have something better to go with.

25 So, it is a reasonably good guess and it

> 125 1 is something to bear in the back of the mind

2 because I think it is relevant that when we get

3 this twenty-year safety data it is going to be on

4 products that we are not interested in using

5 because even if it is an effective approach to a

6 given disease, we are going to believe that we have

7 developed testing and manufacturing and genetic and

8 molecular mechanisms to make a better product. So,

9 we are working on the presumption that there are

10 certain general principles that we may elicit about

11 what the risks are. It may not be quantitatively

12 true that the risk is exactly the same, but if it

13 turns out, as you say, that a CMV promoter is

14 associated with a certain disease, that that

15 general principle will not apply quantitatively to

16 any given specific product would be extremely

17 important to elucidate.

18 MS. LAWTON: Jay, can I just comment on

19 that because I assume we are not just going to

20 collect this and look at it in twenty years \--

21 DR. SIEGEL: Oh, of course.

22 MS. LAWTON: \-- we are going to look at it

23 on a routine basis. So, hopefully, you would

24 gather other information along the way that may

25 lead to making decisions about not wanting to use a

> 126 1 particular vector anymore, or maybe even, you know,

2 that is recognized and at that point you say you

3 don\'t need to continue with long-term follow-up for

4 twenty years because nobody is going to use this

5 vector anymore. I mean, those are the types of

6 decisions you can make along the way; it is not

7 just at the twenty-year time point.

8 DR. SIEGEL: No, that is right. I guess I

9 hadn\'t specifically thought through that if a type

10 of vector isn\'t used it doesn\'t need to be

11 followed. But, as I alluded to earlier, there

12 might well be a case where even a single patient

13 report, whether at year two, five, eight or twenty,

14 if it is associated with appropriate biological

15 data may raise enough of a concern that, as long as

16 we get that report in, it will be enough of a

17 signal to tell us that we have a problem.

18 Absolutely. We would anticipate, based on our

19 analyses, that even for malignancies most of the

20 signals are going to come in the first five or ten

21 years.

22 DR. MULLIGAN: On the philosophical part,

23 one of the things that I always used to tease

24 French about is when he would get up and talk about

25 his eight monkey years of safety testing was that

> 127 1 that only proved that if you didn\'t have gene

2 transfer it is perfectly safe. I think it is very

3 relevant here because over the time period, you

4 know, you will be getting data, safety data, where

5 there is a learning curve on the gene transfer

6 efficiency. So, the same clinical trials using the

7 same vectors, as you get more efficient,

8 undoubtedly bad things or more bad things will

9 happen. I predict that that will be the most

10 significant aspect of the long-term follow-up, that

11 as the learning curve, not so much technically on

12 the actual vectors but, you know, how you

13 manipulate the cells to get them infected, and that

14 is something that somehow we are going to have to

15 work into all this. I think there is going to be

16 an amazing difference when people begin to get

17 fifty percent stem cells infected in bone marrow

18 transplants, as opposed to 0.001 percent.

19 DR. SIEGEL: So, while we have heard some

20 advice that once we know something is safe we may

21 have less oversight in that area, as often happens,

22 you are suggesting that as technology evolves, more

23 efficient and effective technologies may also raise

24 new safety concerns that aren\'t addressed.

25 DR. SALOMON: Right, which is a good

> 128 1 argument why we need to get something going now,

2 and we owe that to everyone. We owe that to

3 history, if nothing else, to document what is going

4 on, and to realize the cyclical nature of science.

5 You know, a lot of things come back around. I

6 mean, the vector that we throw our or the promoter

7 that we throw out today could be the key thing

8 tomorrow when some new disease comes along that we

9 didn\'t anticipate.

10 So, how about the referring physicians? I

11 mean, we have talked about postcards to the

12 patients. Maybe on a yearly basis, once a year, at

13 the same time should we match it to the referring

14 physicians and also, of course, try and keep track

15 of not only where the patient is but whom the

16 patient is seeing as the doctor at the time,

17 realizing that has definitely, you know, holes in

18 it?

19 DR. CHAMPLIN: Particularly during the

20 first five years of follow-up, I would say that the

21 sponsor working with the patient and the referring

22 physician would be mainly collecting information.

23 As you get further and further away, again,

24 patients move, they get new doctors and that is,

25 again, much more chaotic.

> 129 1 DR. SALOMON: I was just thinking that

2 getting a postcard back from a patient saying they

3 developed, you know, an autoimmune disease and then

4 getting a postcard back on the same patient from

5 the doctor saying, yes, the patient has scleroderma

6 would mean a lot to me, as opposed to this patient

7 is whacked \-- you know, has no idea what is going

8 on and has decided they have some unknown

9 autoimmune disease.

10 DR. SIEGEL: I am trying to think this

11 through from a pragmatic point of view. I think

12 Dr. Champlin pointed out very well that the reality

13 is that people will have moved out of town and

14 after a year, not withstanding Dr. Bishop\'s

15 comments, that perhaps the investigator knows what

16 best to ask and the likelihood is much better, or

17 even samples if it is done by a referring

18 physician.

19 In terms of what a sponsor can and should

20 commit to in a protocol, I would think that that

21 would require making the referring physician a

22 co-investigator on the protocol and getting

23 appropriate paperwork. I am not sure how else \--

24 do you want to comment about that? Can a sponsor

25 just call up a referring physician, if not an

> 130 1 investigator, and say we need you; please contact

2 your patient and get this information?

3 MS. LAWTON: It is a good point. I was

4 shaking my head when you said trying to make the

5 patient, physician a co-investigator. That would

6 just be a nightmare and, obviously, there is no way

7 that you can go that route to track that. I don\'t

8 know whether you could do something along the lines

9 of the patient and the informed consent, that they

10 have a responsibility to inform their physicians,

11 whether that goes on their medical record, or

12 something, when they change physicians so that you

13 are able to contact a physician. I don\'t know.

14 Is there no experience out there of these

15 types of long-term follow-ups? For the most part,

16 we have only ever only contacted patients and then

17 you could maybe ask for informed consent from the

18 patient to contact their physician to get more

19 information. That would seem the obvious route to

20 go, to be honest.

21 DR. SIEGEL: Right, I wasn\'t sure you were

22 shaking your head because you disagreed or because

23 you were concerned. Because I am concerned and

24 that is why I threw it out there. Just from a

25 practical point of view, usually we deal with

> 131 1 contact through the sponsors, investigators and

2 patients. There may be precedents for other

3 approaches. To the extent I am aware of them, if

4 significant amount of the follow-up involve

5 follow-up by the local physician, that is in some

6 cases written into the protocol and they are made

7 co-investigators. But I certainly recognize that

8 that is not something that is easily or lightly

9 done from an organizational point of view. That is

10 why I just rolled that out there. Whether there

11 are other legal ethical ways, you know, consistent

12 with principles of informed consent, and all of

13 that, are things that we can explore but I am not

14 sure I am in a position that I want to comment on

15 what the possibilities are at this point of time.

16 DR. SALOMON: I brought it up for that

17 kind of a point. In practice, at least in southern

18 California where I work, you can\'t get referring

19 physician data without a signed permission from the

20 patient. I think the conservative view of that is

21 that that shouldn\'t be a blanket either so that

22 every year one would probably have to update that

23 because I think to say, \"sign here and, if for the

24 next twenty years, you are okay, you need to get

25 data from your referring physician.\" I don\'t think

> 132 1 that would be legal. Assuming consent and they are

2 going ahead and trying to reassure referring

3 physicians that for the next ten years I am going

4 to send you a postcard, and the patients have

5 consented \-- just assume that unless you hear

6 otherwise from the patient or me. I don\'t think

7 that is going to work.

8 So, I think we have to agree that the

9 referring physician, despite the important

10 corroborative data that a physician could provide,

11 would probably have to be brought in, in a second

12 loop. In other words, the subset of patients who

13 have autoimmune disease, if it suddenly rises above

14 some trigger point in the review of the database,

15 you would now contact that subset of patients and

16 request confirmation of the results of the skin

17 biopsies, the autoimmune antibodies or whatever the

18 specifics were. Is everyone kind of comfortable

19 with that?

20 DR. CHAMPLIN: So, in reality this is

21 going to be the rule and not the exception.

22 Long-term follow-up, meaning that the patients got

23 home; they go to their local doctor and don\'t come

24 back, you know, a thousand miles to the treatment

25 center.

> 133 1 DR. SALOMON: If that is true, do we agree

2 that this should be done once a year? We still

3 haven\'t quite said ten years, fifteen years or

4 twenty years yet, but we are going along this line.

5 DR. CHAMPLIN: I would hope that once the

6 registry is formed that they can get into the

7 nitty-gritty of what data needs to be collected

8 once a year, and I also agree with Dr. High that

9 the data that you collect on year two should be

10 very different than the data you collect on year

11 nineteen or even ten, and that you want more

12 comprehensive, broad-based data early and as you

13 get further out, you know, far more generally

14 focused information that we are going to discuss.

15 And, I would probably argue for more detail maybe

16 for the five-year period and a very limited data

17 set after that time. But I think this really is

18 going to be a job of organization and we hope that

19 we will get people involved and excited as a sort

20 of an intellectual pursuit to try and identify

21 problems that are going to exist in these patients.

22 MS. TICE: You were asking for an example,

23 and Schering-Plough \[not at microphone;

24 inaudible\]\... the protocol usually has data that is

25 detailed over three months and analysis \[not at

> 134 1 microphone; inaudible\] \... but this is all protocol

2 based now, and the first year is very detailed,

3 every three months CT and \[not at microphone;

4 inaudible\] \... then every six months unless it is

5 triggered \[not at microphone; inaudible\]. Now, for

6 long term we are doing a yearly fax back to the

7 referring physician, and the referring physicians

8 \[not at microphone; inaudible\] \... then there is a

9 communication to that referring physician \[not at

10 microphone; inaudible\] \... and we ask them four

11 basic questions, autoimmune disease, cancers,

12 hematologic and neurologic, and that is where the

13 doctor can put in the right diagnosis. A patient

14 cannot tell you if they have had the appropriate

15 diagnosis. They can\'t do that. So, we have been

16 doing a fax back and if there is a \"yes\" then we

17 treat it as an expedited report and tell the FDA

18 that something is going on there. Then the FDA can

19 follow-up with the site if they want to get more

20 detail. \[Not at microphone; inaudible\].

21 DR. SALOMON: So, what you are saying is

22 that your strategy built in your protocol has been

23 dealing with the referring physicians, not with the

24 patients. None of these go to the patients.

25 MS. TICE: None of these go to the

> 135 1 patient. They get faxed back to the site.

2 DR. SALOMON: So, how did you deal with

3 the question that just circled here regarding the

4 legality of a referring physician providing

5 privileged medical information on the patient?

6 MS. TICE: When you sign on, I mean the

7 protocol is signed by your investigator; the

8 investigator has agreed to follow what you stated

9 in the protocol.

10 DR. SALOMON: But that is the

11 investigator; it is not the referring physician.

12 MS. TICE: Okay, that is a good point.

13 There may be some type of setup between how that

14 person got referred to a site. I don\'t know the

15 relationship between that referring to the site.

16 Typically, our patients are local. They don\'t

17 travel thousands of miles.

18 DR. SALOMON: Right. Just so that we are

19 clear on what you are doing, you are sending your

20 CFR clinical \--

21 MS. TICE: We are sending the clinical

22 form.

23 DR. SALOMON: But you are sending it to

24 your investigators, not to what we are calling

25 referring physicians.

> 136 1 MS. TICE: Right, but typically our

2 investigator is the treating physician.

3 DR. SALOMON: And, you are not really

4 concerned with how that investigator gets the

5 information as long as you get your response form

6 back.

7 MS. TICE: Yes, after they are finished

8 all their routine CT scans and what is required in

9 the protocol, then maybe it is a phone call, maybe

10 they come in for their yearly checkup but we ask

11 the investigator to answer these forms.

12 DR. SALOMON: Right. That is very useful.

13 Thank you. I think the critical point here in

14 trying to come up with some practical suggestions

15 is going back to your principal investigators is

16 relatively straightforward. Thinking about twenty

17 years of going routinely to referring physicians

18 out in the community to which your patients have

19 dispersed and maybe changed three times as they

20 change their health plans \-- I don\'t know what is

21 going on in the rest of the country but in southern

22 California it is like changing your tie to change

23 your health plan. You know, that is the part that

24 I don\'t think is going to work, at least not under

25 the current situation we have with information

> 137 1 rights, etc.

2 MS. TICE: You are saying that they are

3 changing four or five different times, moving from

4 Nebraska to New York. We cannot, as a sponsor,

5 track patients down like that. I mean, we give up.

6 DR. SALOMON: But as a sponsor you are not

7 even trying to track the patients. Right? What

8 you are doing is you have an investigator at

9 institution XYZ \-- it is easy for you, you send it

10 to that guy and he either comes back with it or

11 tells you, \"I\'m sorry, I lost contact with the

12 patient,\" and you are done.

13 MS. TICE: \[Not at microphone; inaudible\].

14 DR. SALOMON: Make sure you identify

15 yourself.

16 MR. REYNOLDS: Tom Reynolds, Targeted

17 Genetics. I want to echo the sentiment. We

18 typically, for confidentiality reasons, don\'t know

19 who our patients are. We have heard numbers

20 assigned by our investigators, and typically every

21 year we provide them with a list of all the

22 patients that they have had who have responded in

23 the prior year. Then they try to contact the

24 patient, usually by phone or by clinic visit, and

25 do the long-term follow-up and report back to us.

> 138 1 One thing that I think is going to be a

2 big issue for this over the long haul with that

3 kind of approach is that we know a lot of

4 investigators move from site to site to site. The

5 institutions to which they belong are not really

6 funded to do that kind of work. Once that

7 investigator-patient contact is broken it is not

8 clear how that can be reinstituted, whether we need

9 to sign on a new investigational from that site, or

10 now that the guy has hopped from site A to B to C,

11 we have to contact there and trail them back.

12 Usually there has been a fair amount of attrition.

13 DR. SALOMON: Okay. So far yearly

14 questionnaires to patients. Referring physicians

15 are left out of the loop in the first go around but

16 in targeted patient groups referring physicians

17 would be fair game, but it would have to be under

18 appropriate, at that time legal allowance for

19 disclosure of privileged information between a

20 patient and a physician. That is probably about as

21 far as I can see us going, except that we have to

22 give you a time frame now. But I don\'t think you

23 have heard us say that they need physical exams. I

24 don\'t think you have heard us say that you need to

25 be archiving materials.

> 139 1 DR. SIEGEL: I guess I am not sure what I

2 heard in that regard, but if that is correct I

3 would like to hear some further discussion of that

4 point, if we are asking for too much in the

5 retroviral area in general in terms of archiving.

6 I think we have laid forward a philosophy for why

7 we thought it might be useful to have those

8 specimens.

9 DR. SALOMON: Yes, that is why I brought

10 it up, Jay, so we could have some discussion. I

11 guess the principle I am trying to hone to is that

12 this is what the committee is comfortable telling

13 you for all gene transfer vector protocols, not

14 trying to exclude you in individual cases,

15 individual protocols, from demanding anything else

16 on top of it. It is just that this committee is

17 sending this message \--

18 DR. SIEGEL: No, I understand. I am

19 simply saying that at the present time for all

20 retroviral protocols we are asking, although not

21 necessarily receiving, and maybe we should stop

22 asking for it or maybe we have pointed out reasons

23 that we might want, in retrospect, when we have

24 safety concerns and be able to look back at some

25 serologies, viremia, other issues. On the other

> 140 1 hand, one might make the case that if you have

2 samples out to one year on that, that is going to

3 cover most of what you want to know, and five years

4 is not going to happen anyhow and we should stop

5 asking for it. But I would like to hear a little

6 more before assuming that there is a consensus of

7 the committee, a little more discussion about that

8 situation.

9 DR. SALOMON: Fair enough. Go ahead.

10 DR. MULLIGAN: I would say that I would

11 rescind the blanket archiving of samples. I think

12 you can definitely think of different applications

13 where there would be different reasons for having

14 or not having them. So, coming back to the tier

15 system, you know, if you are doing transduction of

16 tumor cells, irradiated tumor cells with a

17 retroviral vector, I think the need for archiving

18 is completely different than doing bone marrow

19 infections with a retroviral vector during bone

20 marrow transplantation. So, simply put, I would

21 say that having archived samples for retrovirus

22 probably, at this point, doesn\'t make sense. It

23 probably did make sense but I think we are much

24 more sophisticated in classifying different

25 applications.

> 141 1 Then, I would say you do it on a case by

2 case, and I would argue that there would definitely

3 be, in the case of retrovirus vectors, certain

4 cases where you would want to ask them to do that.

5 DR. CHAMPLIN: In terms of the physical

6 exam, it is very rare that an asymptomatic patient

7 has a striking finding that just pops up in a

8 physical examination. So, again I would call for

9 toxicities based on a global assessment, however

10 you make it, working with the referring physician

11 or directly with the patient. But the actual

12 physical exam part is usually not informative.

13 DR. SALOMON: With respect to the physical

14 exam, if I could get my head around the idea that

15 it is easy to do, I would argue that in the context

16 of getting an expert to sit down with a patient at

17 some point or points post closure of the protocol

18 would be one of the most ideal ways of saying, \"oh

19 my gosh, you do have glomerular nephritis.\"

20 DR. CHAMPLIN: So, it is the history that

21 you take from a patient is much more information

22 than anything else, and the actual examination part

23 is not or it just complements your analysis of

24 their symptoms. So, much of this can be done on

25 the telephone or working with referring physicians,

> 142 1 again, to make life more realistic for the people

2 in the treatment center.

3 DR. GAYLOR: Something more than an annual

4 postcard has to be done. You get two major biases

5 with postcards. You get the people with the

6 disease or perceived disease \-- \"yeah, I\'ve got

7 something because maybe I can sue somebody.\" So,

8 you get that bias. The worse bias is those people

9 that died due to gene therapy perhaps, you don\'t

10 hear from. So, there has to be some kind of

11 quality control beyond an annual postcard. I will

12 go back to my sample again. If you have half a

13 dozen on the important vectors, maybe half a dozen

14 categories of vectors and you make sure that

15 somehow you sample at least thirty people in each

16 vector category and do some more extensive

17 follow-up on one or two hundred people perhaps.

18 DR. SALOMON: I think that is an excellent

19 point. And that probably deserves a minute of

20 consideration by the committee, and that is what do

21 we feel comfortable with as a guideline to sponsors

22 for how they should pursue the quality of this

23 sampling protocol? I mean, the lightest obligation

24 is every year you will send out a postcard or a

25 form to every patient that you put on this

> 143 1 protocol, and that is it, to going as far as saying

2 not only will you do that, but you will follow

3 through with the ones you didn\'t get back, and even

4 those that have a problem you will contact or make

5 a good faith attempt to contact their referring

6 physician. So, maybe can we get some discussion of

7 that from the committee? Again, there is a lot at

8 stake here because what we demand out ten, fifteen

9 years of sponsors is going to reverberate through

10 this whole system.

11 DR. SIEGEL: I would like to say in that

12 regard that in the setting of clinical trials where

13 people try, whether a cancer or an MI trial, to get

14 half year, one year, two year, five year follow-up,

15 there is a broad spectrum from simply sending a

16 questionnaire to sending a questionnaire and

17 multiple reminder cards, followed up by phone

18 calls, and also by having patients give, at the

19 start of a trial, the name and number of a reliable

20 contact who will know where they are if you are not

21 at this address and phone number. And, we see a

22 huge spectrum from people being able to follow over

23 99 percent of patients out to at least half a year,

24 a year or two years, and also incentives, you know,

25 send in the card and you get a free dinner or

> 144 1 something.

2 \[Laughter\]

3 I am not sure we are necessarily in a

4 position to require that but I do think it is an

5 issue. We are all facing the fact that it is one

6 thing to say, you know, attempt to get information;

7 it is another thing to actually get the

8 information, and there are efforts and there are

9 real efforts.

10 DR. GAYLOR: As far as death is concerned,

11 the FDA can check the death registry.

12 DR. SIEGEL: We don\'t have patient lists.

13 DR. GAYLOR: Oh, that is right, you don\'t

14 have that. So, it has to go back to the

15 investigator.

16 DR. MULLIGAN: I propose that we may not

17 be the right people to figure out how many

18 postcards and so forth. So, the message that is

19 key is there needs to be thinking about how to make

20 sure that the word gets out to the people. I think

21 our message is that it has to be simple.

22 DR. SIEGEL: Can I follow-up with that

23 question of simplicity because I have heard both

24 the comment that we should focus efforts in the

25 areas we have been talking about, but also the

> 145 1 comment that we should not lose track of other

2 areas. So, the general issues of collecting

3 information \-- have you had any medical problems or

4 perhaps any hospitalizations or causes of death \--

5 certainly, one can see that getting more

6 information that could be useful. On the other

7 hand, it has implications regarding the simplicity,

8 as pointed out, if somebody says, \"yeah, I\'m having

9 kidney problems\" and what is the next step? And,

10 the other issue, of course, is even if it is more

11 specific and you start with a low index of

12 suspicion about it, what do you do with it in an

13 uncontrolled case report? So, now it is, you know,

14 twenty years later and you say ten percent of the

15 people developed heart attacks. Where do you go

16 with that? Whereas, if ten percent of the people

17 develop a chromocytoma, you know you have

18 something. So, I guess I am a little uncertain as

19 to whether we want to be only focused or whether we

20 think there is a value to creating broad data

21 tracking for all major health events or lethal

22 events, or the like.

23 DR. HIGH: Well, one relatively simple way

24 to get that is to just put on the postcard

25 something like \"what medications are you on?\" I

> 146 1 mean, it may give you an indication about diagnoses

2 that the patient may not know otherwise.

3 DR. SALOMON: Yes, I agree with that. You

4 could also certainly put in a question of \"have you

5 been hospitalized in the last year? If so, why?\"

6 MS. LAWTON: Maybe an easier way of doing

7 this is to actually have the sponsors make sure

8 they regularly contact the patients and ask who

9 their current treating physician is, and then have

10 the sponsors follow-up directly with the physicians

11 because then you can ask some of those questions

12 and actually get reasonable information back.

13 DR. SALOMON: I think that kind of follows

14 what PhARMA does. You know, I am trying to walk

15 the fine line here is NIH, principle investigator

16 sponsored research where you get a five-year grant,

17 and we are talking suddenly about \-- we haven\'t

18 define the time yet but, you know, ten- and

19 twenty-year follow-up, and anything that comes out

20 of this committee, I am hoping, is consonant with

21 not putting the onus or knocking all these guys out

22 of the field, including myself.

23 It is 12:50. I was thinking a minute or

24 two ago, well, if we just push on we will be done

25 and then go to lunch, but I don\'t think that is

> 147 1 going to quite happen. I don\'t think we are going

2 to satisfy some of the broader final phase two to

3 three kind of questions that I think, very

4 properly, Dr. Siegel and the staff wants to

5 address. So, unless there is something we really

6 have to say right this second, I thought maybe we

7 would break for lunch and come back at 1:30, a

8 little less than 45 minutes for lunch. Is that

9 enough? It is not exactly gourmet dining here, and

10 we will try and finish it up. Is that okay?

11 \[Whereupon, at 12:40 p.m., the committee

12 was recessed for lunch, to reconvene at 1:45 p.m.\]

> 148 1 A F T E R N O O N P R O C E E D I N G S

2 DR. SALOMON: Welcome back, everybody, to

3 the afternoon session here. Where we were at was

4 kind of working step by step through what it was we

5 could specifically request of a sponsor, and the

6 premise was that when we kind of got as far as we

7 could in defining that we would go back and revisit

8 the very specific question of five-, ten-,

9 fifteen-year follow-up in that context.

10 Just so that we are all on the same page,

11 so to speak, what we have agreed so far is that

12 there should be a database that has all patients

13 that have been involved in a gene transfer clinical

14 protocol, that that database should be maintained

15 by one of the regulatory agencies, presumably the

16 FDA or the NIH but really that is not the

17 committee\'s concern today, but that we do agree,

18 all of us, that there should be such a database and

19 it should be monitored. We are not trying to tell

20 you whether it should be monitored weekly, monthly

21 or yearly. That is, again, a detail that we expect

22 the agencies to work out and we don\'t feel that is

23 the purview of the committee.

24 We agree that the sponsors should be,

25 however, absolutely responsible for providing that

> 149 1 data set agreed upon to the registry, wherever that

2 registry is, and for whatever period of time we end

3 up deciding.

4 We agreed that at the moment the most

5 comfortable position we have is that all gene

6 vector protocol patients should be followed long

7 term within the guidelines of what we are going to

8 spend the rest of the time talking about.

9 As far as long-term follow-up went, we

10 intellectually accepted the discipline that there

11 were more risky vectors, more risky inserts, more

12 risky diseases and less risky vectors, diseases and

13 inserts but that as a principle for long-term

14 follow-up, if we accepted the fact that everyone

15 would get long-term follow-up and we could be

16 comfortable defining sort of the generic baseline

17 long-term follow-up, that additional, more intense

18 follow-ups that would be specified by appropriate

19 scientific reasoning for specific vectors, specific

20 diseases, specific construct or any combination

21 thereof would be between the sponsor and the FDA

22 staff.

23 So, pursuing that, we talked about the

24 fact that long-term follow-up would focus on the

25 patient and instrument of contact, whether that be

> 150 1 a postcard or a phone call \-- I don\'t think we

2 really specified that at this point, not to the

3 referring physician as a routine \-- we are getting

4 pretty close to where we were just before lunch.

5 Oh, and that questions would include, but

6 not be absolutely limited to, the four major

7 categories, neurologic disease, malignancy,

8 autoimmune disease and hematologic disease. And,

9 additionally, that we would request information of

10 hospitalizations and medications as, again, a clue

11 to potentially other complications that might have

12 occurred during the interim, and the general

13 concept we all agreed on was if there was a new

14 medical problem, unexpected medical problem that

15 should be reported regardless of whether it fit

16 into any rigid criteria we set. For hematologic

17 disease and a whole bunch of patients with heart

18 attacks, we definitely weren\'t excluding the

19 importance of reporting that.

20 So, I think that brings us up to when we

21 went to lunch. Does everyone agree?

22 MS. LAWTON: Sorry, I just wanted to try

23 something as far as the comment about direct

24 contact with patients. One thing I should say for

25 most of the corporate-sponsored clinical trials is

> 151 1 that that would have to be through the

2 investigator, obviously, because we wouldn\'t

3 necessary have direct access to patient

4 information. So, that is just for the record.

5 DR. SALOMON: So, somewhere here we had

6 better decide we have gone as far as we are going

7 to go in specifying it, and then we can get back to

8 the years. Right? So, let\'s pursue that. Does

9 anyone on the committee want to go any further in

10 terms of yearly contact at this point? Do we need

11 to go further than that today?

12 DR. CHAMPLIN: So, you are talking about

13 after the first year?

14 DR. SALOMON: Right.

15 DR. CHAMPLIN: There would be sort of a

16 minimum of yearly contact. It sounds good.

17 DR. SALOMON: Again, the premise is that

18 we are not excluding the FDA staff and the sponsor

19 from agreeing to any additional follow-up. It is

20 just that this is what we considered the baseline

21 for everybody at this time. Dr. Siegel

22 specifically wanted us to be real clear about the

23 fact that we were drawing a line there and not at

24 physical exams. So, we need to make a specific

25 comment on that, and archiving of specimens.

> 152 1 DR. SIEGEL: First I want to say that I

2 think you summarized well much of what was said.

3 Most of the points you made seemed to be consensus.

4 There are one or two things that were put in the

5 category of advice of individuals but haven\'t

6 really been discussed from the point of consensus

7 \-- medication records, hospitalization and so

8 forth.

9 DR. SALOMON: Let\'s go through that.

10 Hospitalizations, does everyone agree or disagree

11 that we should capture hospitalizations? I think

12 we should, and I think medications is easy. It is

13 certainly something I have done many times in the

14 past. I do agree with Dr. High that that very

15 useful. You know, all of a sudden they are on

16 hypertensive medication or gout medication, or an

17 anti-inflammatory shows up or Imuran or Celcep

18 those are very valuable.

19 DR. SIEGEL: So, as clues to specific

20 diagnoses, you are not necessarily suggesting we

21 create a database of all the medications that

22 everybody is on, but asking about medications is a

23 way \-- because if somebody is taking some

24 chemotherapy or immunosuppressive that could

25 trigger \--

> 153 1 DR. SALOMON: Right. I mean, in the

2 example of a patient who might have chronic fatigue

3 syndrome it would be hard to diagnose that. So,

4 you have to be really, really cautious about it.

5 But if suddenly a patient shows up on any kind of

6 steroids and azathioprine and they tell you they

7 have an autoimmune disease, I would be willing to

8 believe them.

9 DR. CHAMPLIN: Part of this is sort of a

10 method as opposed to the form that you send in at

11 the end. I am not sure I would want to list all

12 the patient\'s medications but, certainly, as you

13 would be talking to the patient and asking him what

14 has been going on in the last year since your last

15 survey, you would ask them about important

16 illnesses and drugs that they are on, etc. But,

17 actually, the information that would be submitted,

18 I would actually try to make it in a more

19 abbreviated, focused kind of fashion.

20 DR. SIEGEL: Well, I heard a number of

21 comments that sending in postcards may not be

22 either efficient enough accurate enough as opposed

23 to contacts. Also, Alison Lawton\'s comment pointed

24 out that it is not just the sponsor and the

25 treating physician and the patient, there is also

> 154 1 the investigator and if there is probably some

2 practical way this is going to be carried out,

3 carried out meaningfully, as your comment would

4 reflect, you would want somebody with some

5 technical background getting some specific

6 information.

7 DR. SALOMON: We are getting close to

8 where my concerns start to rise, and that is, if we

9 go down the path of we have to have absolutely one

10 hundred percent data on a hundred patients, there

11 are ways to do that but I don\'t feel that is a

12 appropriate. That is my position. I don\'t feel

13 that is appropriate at this time in the field. I

14 think it would have a chilling effect on the field

15 that wouldn\'t be justified to date by any of the

16 complications so far found. You know, the idea

17 that we need to report is fine, but are we talking

18 \-- I am okay with a survey instrument approach. If

19 Dr. Champlin is saying he doesn\'t agree with the

20 survey instrument approach and that there has to be

21 a nurse practitioner or a physician, then that has

22 to be discussed.

23 DR. CHAMPLIN: I guess my concern is that

24 the survey is likely to provide such fuzzy

25 information that it won\'t really be useful. But

> 155 1 the more practical thing is to have somebody

2 calling and interviewing patients in a very

3 abbreviated format. One of the real problems with

4 all these kinds of things is that an organization

5 forms and now they want data, and then next year

6 they want more data and they want even more data,

7 and you get new questions and you get excited about

8 collecting the data and before you know it you have

9 a book that you have to submit each year on every

10 patient. So, the postcard idea is something that

11 appeals to all of us but realistically it needs to

12 be like a one-page kind of form and beyond that it

13 really does become onerous.

14 DR. SALOMON: I certainly agree that a

15 postcard may not be quite the right image I wanted,

16 but a single page format.

17 DR. CHAMPLIN: I also made a comment

18 earlier that, needless to say, you know, dead

19 patients don\'t return the postcard and so there has

20 to be some other mechanism to contact people to try

21 to really ferret out if there is anything serious

22 going on.

23 DR. SALOMON: So, would you go on with

24 saying that there should be certainly a good faith

25 effort on the part of the sponsor to account for a

> 156 1 hundred percent of patients enrolled?

2 DR. CHAMPLIN: Yes. The other issue is we

3 are sort of looking at a couple of different

4 issues. There is the sort of generic long-term

5 side effects issue that can be handled to some

6 extent with a sampling where you wouldn\'t

7 necessarily need to have hundred percent compliance

8 in terms of data reporting to at least have

9 meaningful information. On the other hand, you do

10 want to have early data on an individual product.

11 So, to try and look is there an issue of CMV

12 promoters, you know, it wouldn\'t be necessary to

13 have a hundred percent in all gene therapy trials

14 and twenty-year follow-up to address that issue.

15 So, a good faith effort wouldn\'t necessary need to

16 include a hundred percent of patients in terms of

17 the ultimate delivery of the data.

18 DR. SALOMON: I think what I have heard

19 from a number of people, not just today but also

20 today, from sponsors, the comments from

21 Schering-Plough and from Doug Jolly and his

22 experience at Chiron, is that if we do this and we

23 do a good faith effort, we are not going to get a

24 hundred percent compliance. It is definitely not a

25 true sampling strategy because it is not random,

> 157 1 but it is probably what we have to be realistic

2 about getting, and it will be valuable but it might

3 not be invaluable.

4 So, we are at the point here where I think

5 we have defined about as much as I think we can

6 define and be responsible at this point, with no

7 commitment from the NIH or Congress or FDA to fund

8 this sort of thing.

9 DR. SIEGEL: You said you were going to

10 get back to the issue of whether it is twenty

11 years.

12 DR. SALOMON: Yes, I thought the premise

13 we went through this was define what it is and we

14 will talk about time. So, I just want to make sure

15 that the committee feels like we are done with that

16 process, and also that you and staff feel that we

17 have addressed it in detail.

18 DR. SIEGEL: Then the other issue that I

19 am not sure is still on the table or whether we

20 have heard all the comments we are going to from

21 this group, is whether there is general guidance

22 about if and when, and how often or whether

23 archiving of specimens \-- we have heard about the

24 difficulty after a year. We have heard about

25 people in general coming back to the study site

> 158 1 after a year, for example, and, indeed, we know the

2 difficulties we would have in archiving stuff. But

3 from a scientific perspective, if the thinking is

4 that this is not one of the more critical pieces,

5 and I think I heard just a general comment from Dr.

6 High that she would be more worried about getting

7 general information or focused information after

8 twenty years than a lot of detailed information

9 over that three to five year period, or one to five

10 year period.

11 So, we are now faced I think with one of

12 the questions we are going to need to decide in the

13 future for retroviruses, where current guidance

14 asks for this sort of information and other areas

15 where it doesn\'t is, is this not only unrealistic

16 but not all that critical or not worth trying for,

17 and we need to look for other ways to do that?

18 DR. SALOMON: The way I am thinking right,

19 and again the group can modify this, but the way I

20 was thinking about it is finishing this cycle of

21 what we think is a phase one where all gene

22 transfer vector patients should give you this data.

23 Then, when we are done with that, signed off, we

24 are clear and done, then we could stop and say, now

25 let\'s go to the general advice, and relax and not

> 159 1 feel like we are burdening the field with

2 everything we say, and talk to you about sampling

3 issues and retroviral vectors. Are we okay with

4 that?

5 I think right now all of us on the

6 committee feel a heavy pressure to be very clear

7 and specific about what we feel is practical and

8 responsible for a developing field to address, you

9 know, all the constituencies \-- regulatory

10 agencies, the public, the patients and our ability

11 to do investigator-sponsored research. That is

12 what we are trying to do now. All right, fifteen,

13 five, ten years, twenty years, life? What? A

14 resounding silence here! Dr. Rao?

15 DR. RAO: Since nobody was willing to give

16 a number, I thought I would start the discussion at

17 least by saying it seems that fifteen years maybe a

18 reasonable number to consider.

19 DR. SALOMON: I personally would second

20 that. I think twenty years is just an additional

21 five years with an extremely small yield but really

22 expensive; and ten years, I think there would be

23 enough examples of people saying, gee, a lot of

24 stuff happens at twelve and fifteen. Why did you

25 stop? Fifteen kind of crosses those both off.

> 160 1 DR. MULLIGAN: I think so too, for no good

2 reasons.

3 \[Laughter\]

4 DR. CHAMPLIN: The signal to noise ratio

5 becomes untenable as you get further and further

6 out. So, I think a happy medium is fifteen years.

7 MS. KNOWLES: That is a long period of

8 time, I think it is probably appropriate.

9 MS. LAWTON: Yes, I think fifteen years is

10 a reasonable period as well.

11 DR. SALOMON: So, I think you have

12 consensus on that issue as well. I think we are

13 done with this portion. We could try, if you want

14 to do more for five years or for one year, and all

15 that, but I think that this is good enough.

16 Fifteen years of follow-up. Everybody can be

17 followed up. It is all going to go into the

18 database. It will give you big things like cancers

19 and autoimmune diseases and unexpected

20 hospitalizations or unusual drug occurrences. I

21 think for a first phase, again without really any

22 reassurance from anyone that they are going to fund

23 this, I think that is pretty good.

24 DR. BISHOP: Certainly, I think fifteen

25 years will capture all the examples that we put

> 161 1 into the briefing document for all the four

2 clinical areas that we have. So, it certainly

3 would be encompassing from this perspective at

4 least in the discussions that we have had.

5 DR. CHAMPLIN: I don\'t want to burst the

6 bubble but, you know, there is an example of the

7 later malignancies but I still think it is going to

8 be a small frequency and it is going to be a lot

9 more work than it is worth to ferret out these very

10 late cases. So, this becomes sort of a reasonable

11 compromise of resources for the return that you

12 will get on those resources.

13 DR. SIEGEL: Are there examples of later

14 malignancies that don\'t occur earlier than fifteen

15 years?

16 DR. CHAMPLIN: I was thinking of the

17 radiation-induced solid tumors that peak around

18 twenty or twenty-five years after the exposure.

19 They probably begin at some earlier point but their

20 peak incidence is quite late. Leukemias and

21 lymphomas are much earlier. That is the only

22 example I can think of now.

23 DR. BISHOP: Testicular also, we came up

24 with references at twenty-five years.

25 DR. SALOMON: I think I would speak for

> 162 1 the rest of us, just again from the gestalt of

2 talking today and at previous times, that in a case

3 where the NIH or Congress stepped up and said we

4 are going to create a registry; we are going to

5 really take responsibility for this sort of

6 follow-up, I am not sure that this committee would

7 object to indefinite follow-up under those

8 circumstances but that is given a different

9 practical set than we are faced with today.

10 DR. CHAMPLIN: The mechanisms, as we

11 talked about outside of the meeting over lunch,

12 often in these registries is payment for case

13 report forms to cover the cost of actually doing

14 the follow-ups and providing the information. So,

15 that is the unfunded mandate that is sort of

16 implicit in our recommendation. Right now there

17 isn\'t a mechanism to really fund long-term

18 follow-up. So, such an organization needs to be

19 created with a mechanism to pay the people doing

20 the work to collect the data.

21 MS. LAWTON: I am going to state the

22 obvious again, and I know it was said earlier but I

23 still want to say obviously we are saying fifteen

24 years now. Fifteen years is a long time in the

25 life of gene therapy and what we are going to

> 163 1 learn, and I think we do need to make sure that we

2 have that regular review of the data that is in

3 that database, what it means, what we have learned

4 about the field, and we adjust our expectations of

5 what is needed.

6 DR. SALOMON: I also think that we have a

7 consensus that the message should be very clear to

8 FDA that a big concern for this committee is the

9 fact that investigator-sponsored research with the

10 NIH is three or five years, and we realize that in

11 agreeing to a fifteen-year follow-up we are doing

12 so as responsible physicians, scientists,

13 employers, members of the community but that it is

14 implicit in our recommendation that the FDA stand

15 ready to work with all the involved bodies,

16 including NIH, general Congress, to obtain a better

17 a solution in which funding is specifically put

18 aside for these sort of mandates of long-term

19 follow-up. It is the public that wants this; it is

20 the Congress that wants this; and it is very

21 appropriate for us to be very clear about saying

22 that we have done our job today, and we are putting

23 the onus back on government and regulation and

24 Congress to come through with that sort of a

25 funding process for us.

> 164 1 DR. SIEGEL: Let me reiterate what I have

2 said before to reassure you in that regard, we

3 recognize that that is just one of several

4 practical questions that need to be addressed.

5 Impediments for getting this done, from a pragmatic

6 point of view of where the resources come from, and

7 also some of the points that we have discussed of

8 how you could do it, how to pose questions by the

9 investigator, the sponsor, whatever, that needs to

10 be addressed. And, those issues are under

11 discussion and I hope will continue to be

12 addressed.

13 There is a chicken and the egg situation

14 here, where it is somewhat difficult to decide on

15 mechanisms, funding and infrastructure to address a

16 problem, to collect data without deciding what data

17 you need. It is somewhat difficult to decide what

18 data to get without knowing what the mechanisms are

19 and what is possible.

20 So, we are going to come back from this

21 committee with a recommendation to collect data for

22 fifteen years, fully aware that NIH investigators

23 are on a five-year cycle and we do not see as a

24 solution to a problem to simply ask everyone to

25 say, well, we are going to make a good faith effort

> 165 1 knowing full well those efforts are going to fail.

2 So, we see this as a step to a complex problem

3 whose solution is multifactorial and involves many

4 parties, but I think is an important step that

5 needs to be taken.

6 DR. SALOMON: I think, again, for the

7 committee, we have agreed that to take this step

8 forward was necessary, and we have gone as far as

9 we feel comfortable doing in the absence of this

10 sort of funding assurance. I hope that even though

11 it will get out, well, they demanded fifteen years

12 follow-up, I hope that it will always be with an

13 intelligent look at what we are demanding for

14 fifteen years.

15 So, that is settled, guys. Now can we

16 relax and answer some of these larger questions as

17 a discussion and not making the whole field

18 responsible for our decisions? What Dr. Siegel

19 wanted us to address would be specimen archiving,

20 for example, and why don\'t we talk about retroviral

21 and lentiviral vector systems specifically and more

22 generically? How about comments on that?

23 DR. CHAMPLIN: I think even with

24 retrovirus it is complicated. I don\'t want to

25 dredge up another albatross from the past but the

> 166 1 PA317 issues are relevant to this I think because

2 there is that question of the need to look for

3 replication competent virus depending on what

4 system you have, and I think we will actually get

5 into that over the next couple of days too. So,

6 putting that aside, I think that archiving

7 retroviral or related products is important and

8 will become more important when there is better

9 gene transfer. Whether you are going to be looking

10 for abnormal blood counts \-- I don\'t know. Bone

11 marrow transplantations would be a context where I

12 think it is going to be important. Whether other

13 in vivo applications of lentivirus vectors will be,

14 I am not so sure. But I would just leave it that I

15 would look at that as a very individualized case by

16 case. So, the precise vector they have and we have

17 some outline of the different issues with the

18 retrovirus vector production systems; and the

19 length of persistence anticipated of course. So,

20 again, I think that having archival samples from a

21 vaccine or something where you are just going to

22 end up with dead cells, I don\'t think that is

23 important.

24 But I do, I think this will be more and

25 more important. I think that the risks of

> 167 1 retrovirus insertion and lentivirus insertion will

2 probably raise their ugly heads at some point as we

3 get more and more efficient, and it won\'t be

4 replication competent virus but it may be

5 integration, activating something or repressing

6 something that will cause the cells to misbehave.

7 DR. SALOMON: I also agree. As a

8 principle, I think it is very reasonable for two

9 things. One would be appropriate specimen

10 collection at several key points in the follow-up

11 of the trial. I don\'t want to go to whether that

12 is one year or two months, but at least several

13 time points afterwards going out to at least the

14 first, third, fourth or fifth year afterwards. I

15 think in general, as you say, as we get more

16 efficient gene delivery we should increase rather

17 than decrease our concerns.

18 I think we should also be careful that for

19 each trial we should specify \-- we shouldn\'t be

20 just random; we should be very specific.

21 Peripheral blood collections are very appropriate

22 in, let\'s say, ex vivo T-cell or hematopoietic stem

23 cell involvement but I think it is absolutely

24 useless in maybe something you are injecting into

25 the liver or into the thyroid gland. I think at

> 168 1 times the simplicity of getting plasma and

2 peripheral blood T-cells has overcome our good

3 sense about their value. I think a good example of

4 that has been xenotransplantations where, if you do

5 an islet cell transplant and all they do is follow

6 plasma, and are amazed that they put some cells in

7 the brain and they didn\'t have any exposure in the

8 peripheral blood and, therefore, the procedure was

9 safe. I mean, how anyone can do that with a

10 straight face is beyond me but that even gets

11 published. So, I think we have to be very clear

12 about what is appropriate here. In some cases it

13 is very appropriate. So it shouldn\'t be just

14 random.

15 The second thing, I think it should be

16 mandated that if somebody develops an acute

17 complication like a T-cell lymphoma or a tumor,

18 that a really good effort be made \-- it isn\'t

19 always possible, but a really good effort be made

20 to get tissue from that lesion, and that should be

21 specified in the protocol approval, whether that be

22 bone marrow or a leukopheresis unit, or whatever,

23 in the appropriate disease.

24 Another question that came up would be

25 seeking evidence for replication, retrovirus,

> 169 1 replication competent lentivirus in terms of

2 long-term follow-up. How far should we go with

3 that?

4 DR. MULLIGAN: I think there the issue is

5 much more complicated because everyone has their

6 best system and everyone thinks their system is

7 safer than the next person\'s, and there are clearly

8 differences. But the measurement of those

9 differences is often tough or impossible. But I

10 think certainly some of the things that are out

11 there that are being talked about would be

12 candidates for looking at it, continuing to look

13 for replication competent virus. Alternatively,

14 there are systems out there where I think it is

15 probably not necessary at this point.

16 DR. CHAMPLIN: If you didn\'t see any RCR

17 within the first five years, is there a reason to

18 look as routinely beyond that point in a stable

19 individual?

20 DR. SALOMON: I would think if you didn\'t

21 see RCR in the first six months there would be no

22 reason to look.

23 DR. MULLIGAN: Yes, I would say probably

24 the best indicator of the need to look for it might

25 be whether you have a certain level of gene

> 170 1 transfer, vector gene transfer too. That is, if

2 you see nothing initially, probably nothing got

3 transferred, helper or vector.

4 DR. RAO: It just really does seem to boil

5 down to the fact that archiving seems to be

6 specific for the protocol that you are going to be

7 using, and the sample that you collect and the

8 frequency at which you collect it will all depend

9 on the protocol. I think the point that Dr.

10 Salomon made is critical, that once you have

11 indication of an adverse reaction, then you should

12 have a clear-but set of samples that you need to

13 collect or archive for that particular problem

14 because that will give you a clue as to what might

15 be happening. So, that should be clear-cut in the

16 guideline. Even that would depend on the kind of

17 problem you have because if it is a malignancy

18 then, you know, you collect a certain set of

19 sample; if it is another, you take a different

20 sample.

21 DR. SALOMON: I think we certainly are not

22 objecting or trying to suggest you go in a

23 different direction with respect to your current

24 thinking about approaching follow-up in a

25 retroviral or lentiviral vector, that specimen

> 171 1 archiving is an appropriate request.

2 DR. CHAMPLIN: But for a limited period of

3 time.

4 DR. SIEGEL: We will, of course, be

5 discussing lentivirus in more detail.

6 DR. SALOMON: Just in terms of generically

7 for the retrovirus. I think that we all agree \-- I

8 mean, whether it is a year or six months but I

9 don\'t think you need a five-year specimen to look

10 for replication competent retrovirus. That is all

11 that we were trying to say, unless someone comes

12 down with an acute lesion of some sort. Then you

13 have to stop and start again.

14 How about things like bringing patients

15 back for physical exams with the principal

16 investigator? That was an issue that we left out

17 of the details. Do we agree that there would be a

18 need? I am just trying to address things that Dr.

19 Siegel brought up earlier. Would everyone agree

20 that there would be circumstances for a period of

21 time, early to late, relatively late, that this

22 would be appropriate, to demand that the sponsor to

23 have hands-on contact with a patient?

24 DR. CHAMPLIN: During the first year I

25 think is what I think we had talked about this

> 172 1 morning, it is appropriate, but beyond the first

2 year you want to collect toxicity information,

3 however you can get it, either directly from the

4 patient or working with the referring physicians.

5 But I don\'t think you necessarily need to have the

6 person return physically to the center.

7 DR. SALOMON: Dr. High?

8 DR. HIGH: I was just going to say I agree

9 with that, and I agree with the point that Dr.

10 Champlin made earlier. It is really unusual for

11 the sorts of complications that we are talking

12 about to be picked up on a physical exam with an

13 asymptomatic patient. The patient is going to be

14 presenting in some other setting.

15 DR. SALOMON: One thing that came up was

16 the concept that there should be sort of a national

17 ID that, if you were in a gene therapy trial you

18 should have a little card that says, \"I was in this

19 gene therapy trial\" and maybe a number to contact.

20 If you entered an emergency room for a complication

21 you would sort of produce this, have it on your

22 wrist, or something. Does anyone have any comment

23 about that?

24 MS. LAWTON: I am not sure what that will

25 do other than scare the patient so that nobody will

> 173 1 enter a gene therapy clinical trials.

2 DR. SALOMON: I think we are done unless

3 there is anything else that you, guys, want to put

4 on the table here.

5 DR. SIEGEL: Well, thank you very much. I

6 think obviously as we anticipated, we don\'t have

7 solutions to all the questions but I think we have

8 a lot of very useful advice. We really appreciate

9 the efforts.

10 DR. SALOMON: Any last comments from the

11 committee? And from the audience?

12 MS. TICE: I just have a question. How

13 are you going to determine relatedness fifteen

14 years down the line and you only gave one dose?

15 Fifteen years is an awfully long time and you are

16 going to go back and try to determine relatedness.

17 I think you have to think about this.

18 DR. SALOMON: I think, in Dr. Patterson\'s

19 words, there are experts. We have one at the

20 table, Dr. Gaylor, who is really trained to figure

21 out what are statistically appropriate connections

22 to be made with data from patient groups. I don\'t

23 think that the committee\'s expertise is there. We

24 encourage that as part of the consultation process

25 with the different agencies and with the rest of

> 174 1 our community to establish that kind of detail, but

2 we do agree that it is fair. I am sure there is an

3 incidence of cancer, and autoimmune disease, and

4 hematologic and neurologic diseases out there, and

5 there are all kinds of sampling errors that we have

6 already articulated, and we absolutely agree with

7 that I think, and we will defer to other experts.

8 Dr. Gaylor, do you agree?

9 DR. GAYLOR: Yes.

10 DR. SALOMON: I thank everybody for today

11 for a good job and all your attention and input,

12 and I will see you here tomorrow at 8:00.

13 \[Whereupon, the proceedings were recessed

14 at 2:30 p.m., to be reconvened Thursday, October

15 25, 2001 at 8:00 a.m.\]

16 - - -