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P R O C E E D I N G S

(11:06 a.m.)

MS. DAPOLITO: Okay. Then let's go ahead and get started. Did you have any welcoming remarks?

CHAIRPERSON URBA: Yes, I guess I would just like to thank everyone for taking time out in their schedules to be together with us this morning to go over these site visits, and if you want to go right into the roll call and conflicts of interest, that would be great.

MS. DAPOLITO: Okay. That's what I'll do then.

I'm going to read the conflict of interest statement with the hopes that we'll get another couple of members on board by then.

If you are not talking and could put it on mute, that would be great.

The Food and Drug Administration convenes today's meeting of this Cellular Tissue and Gene Therapies Advisory Committee under the authority of the Federal Advisory Committee Act of 1972. With the exception of the industry representative, all members of the committee are special government employees and are subject to the federal conflict of interest laws and regulations.

The following information on the status of this Advisory Committee's compliance with federal conflict of interest laws, including, but not limited to, 18 USC Subsection 208 and 21 USC Subsection 355(n)(4), is provided to participants of today's meeting and to the public. FDA determined that members of this Advisory Committee are in compliance with federal ethics and conflict of interest laws, including, but not limited to, 18 USC Section 208 and 21 USC Section 355(n)(4).

Under 18 USC 208, applicable to all government agencies and 21 USC 355(n)(4) applicable to certain FDA committees, Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for a particular individual's services outweighs his or her financial conflict of interest -- that's Section 208 -- and where participation is necessary to afford essential expertise, Section 355.

Today's agenda includes a review and discussion of the intramural research programs in the Gene Transfer and Immunogenicity Branch, Office of Cellular Tissue and Gene Therapies, Center for Biologics Evaluation and Research, and in the laboratories of immunology and chemistry and the laboratory of cell biology in the Divisions of Therapeutic Proteins and Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research.

Based on the agenda, it was determined that the committee discussion presents on actual or appearance of a conflict of interest for today's meeting.

Dr. Gunter serves as the industry representative acting on behalf of all related industry and is employed by Hospira, Incorporated.

Industry representatives are not special government employees and do not vote. This conflict of interest statement will be available for review at the registration table.

We would like to remind members that if the discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement, and their exclusion will be noted for the record.

FDA encourages all other participants to advise the Committee of any financial relationships that you may have with the firms that could be affected by the committee discussions.

Thank you.

So what I'll do is I'll call the roll for the record of the Committee and then we'll introduce the FDA participants, and we will go on to the presentations. I think the members have their slides. They can follow along, and I would remind the presenters to please indicate when you're changing slides for those on the phone.

I'll start by calling roll. Dr. Urba.

CHAIRPERSON URBA: Here.

MS. DAPOLITO: Dr. Calos. Dr. Calos.

PARTICIPANT: She may have her mute on.

MS. DAPOLITO: I know she was here.

DR. CALOS: Oh, wait. Can you hear me?

MS. DAPOLITO: Yes.

DR. CALOS: Okay.

MS. DAPOLITO: Okay. Dr. Chamberlain.

DR. CHAMBERLAIN: Present.

MS. DAPOLITO: All right. Dr. Tomford.

(No response.)

MS. DAPOLITO: Not yet. Dr. Gerson, have you joined us yet? Not yet.

Dr. Guilak.

DR. GUILAK: Here.

MS. DAPOLITO: All right. Dr. Allen.

DR. ALLEN: Present.

MS. DAPOLITO: Dr. Taylor.

DR. TAYLOR: Here.

MS. DAPOLITO: Dr. Kwak.

DR. KWAK: Present.

MS. DAPOLITO: Dr. Chappell. Dr. Chappell, are you there still?

DR. CHAPPELL: Yes.

MS. DAPOLITO: Okay, and Dr. Woo.

DR. WOO: I'm here.

MS. DAPOLITO: All right. Thank you very much.

We'd like to go around the table here on site. On site we do have FDA speakers. We have some audience, and we have a transcriber and a video. We are being videotaped, too, for those on the phone to let you know who we have here.

And we'd like to go around the table now and introduce the FDA participants, and I'll start with Dr. Witten.

DR. WITTEN: Celia Witten, Officer Director of OCTGT.

DR. BLOOM: Eda Bloom, Branch Chief, General Transfer and Immunogenicity Branch, DCGT, OCTGT.

DR. ROSENBERG: Amy Rosenberg, Director, Division of Therapeutic Proteins.

MS. DAPOLITO: Do you want to introduce your lab staff, Amy?

DR. ROSENBERG: They can go ahead.

DR. MAX: Ed Max, DTP.

DR. BERNSTEIN: Ralph Bernstein, DTP.

DR. BEAUCAGE: Serge Beaucage, DPT.

DR. NORCROSS: Mike Norcross, DTP.

DR. WANG: Jinhai Wang, DTP.

DR. CLOUSE: Kathleen Clouse, Director, Division of Monoclonal Antibodies, and Dr. David Frucht will be calling in about 12:10. He was called out of town on an urgent family matter.

DR. SHORES: Elizabeth Shores, Deputy Director of OBP.

DR. KOZLOWSKI: Steve Kozlowski, Director of OBP.

DR. EPSTEIN: Suzanne Epstein, OC Director of Research at OCTGT.

DR. PURI: Raj Puri, Division Director of Division of Gene Therapy, and I have staff here, GTIB. They can introduce themselves.

Carolyn.

DR. WILSON: Carolyn Wilson, GTIB and DCGT.

DR. ARGAW. Takele Argaw, GTIB.

DR. BYRNES: Andrew Byrnes, GTIB.

DR. MARKOVITZ: Nancy Markovitz, GTIB.

MS. DAPOLITO: Okay, all right. Thank you.

Okay. Did someone just join us?

DR. GERSON: Hello.

MS. DAPOLITO: Dr. Gerson?

DR. GERSON: I'm here.

MS. DAPOLITO: Thank you. We just did a roll call and introduced the FDA.

DR. PURI: And Dr. Carbone is on the phone.

MS. DAPOLITO: Yes, and Dr. Carbone is on the phone.

Dr. Carbone, are you ready for your slide presentation?

DR. CARBONE: Certainly am.

MS. DAPOLITO: Okay. We're going to start with Dr. Carbone then.

DR. CARBONE: I'll start with Slide l. We can skip that because that's just my name. What I'd like to talk about is just the Division of CBER today and a little bit about the site visit process, a little bit about critical path, and I'll be brief.

I'm with some people who weren't here for my presentation to the site visit community. I'll just review the highlights with the Committee.

Basically, if you look at the second slide which has the division, the real important points there are two. One is the fact that we actually facilitate development and approval and for all products for the American public, and that we consider international and global health and the public health a real primary goal for this center.

Next slide.

And when I say "biologics," I mean the complex biologics. Of course the OP people have a biologics portfolio as well.

The next slide is a small, brief chart showing the orientation, and the only thing I want to point out here is that there are four offices that participated in the research enterprise, which is a major part of the facilitation effort, and that's the Office of Biostatistics and Epidemiology, Office of Blood Research and Review, Office of Vaccines Research and Review, and this office, the Office of Cellular Tissue and Gene Therapy.

They also have a wonderful engagement in our research management process from the Office of Compliance and Biological Qualities, although they currently do not do research.

The next slide which is Slide 4, just gives you a brief overview of the concept of scientific research in the evaluation process. We all know scientific research from the point of view of product development, both the early discovery phases in the development through clinical trial research.

However, there is an evaluation science which is important, and one of the areas of focus for the FDA and which overall has been somewhat neglected in the massive investment in biotechnology and other kinds of biologics discovery for products.

And so part of our goal is to develop the scientific pools and information we need to regulate on a scientific basis because once we're outside the scientific basis, it becomes the philosophical discussion, and that's where a lot of the problems arise both in the inabilities to predict outcomes in a scientific manner and also disputes regard certain safety issues, et cetera.

The more we know about how to evaluate our products appropriately, the better.

The next slide, Slide 5, just shows that the critical path, which is a portion of the FDA research that applies directly in facilitating the biologics product development, really happens early in the process and involvement in design and discovery is actually quite important. We would like to have particularly the tools to predict clinical efficacy and safety issues actually in the preclinical phase. So that kind of evaluation process in science is extremely important.

Obviously clinical development and improvement in clinical trial development phase is important, but we would prefer products not fail in that stage, in late Phase 3 clinical development. It is a very expensive way to fail. We would like to have better predictors early in the process, and biologics both in OPD and in CBER have led the way in terms of early and frequent interactions with sponsors which are often academia, small biotech, et cetera, because the early interventions often have a huge impact in key products being successful products going downstream.

Next slide, six.

Bottom line is people ask. The first thing I'm ever asked is, "Oh, does FDA do research?"

The second thing that comes out is, "Oh, why does FDA do research?"

And one of the things we'd like to explain is that there are reasons that FDA science is so definitely value added to the process, and that includes the fact that innovators who are people who typically understand product development well; they understand science and have areas of scientific expertise, but they're working for specific products typically in a proprietary setting, and they're discovering their assays, their standards, their methods are not shared with others.

CBER scientists are also one of the few groups that are expert not only in scientific disciplines but in the biological product development. They also have the opportunity to see success and failures and missed opportunities across the board, and therefore, their scientific input and scientific assessments and scientific activities in terms of research and have broad impact in the field and help all products in a particular category to move ahead.

The science, of course, needs to be communicated to be valuable, and CBER guidance documents, other public communications, publications and peer review of the science so that it can be either repeated and others in the scientific community agree with the findings or it can be disputed. It's very important, and so guidance and other documents based on good science makes for better predictive critical path.

And finally, CBER can actually play a convening and coordinating role a disinterested, if you will, from a financial point of view or a non-conflicting party that helps coordinate sponsors and gets scientific questions answered that are going to help cross product category.

Next slide, Slide 7.

I wanted to point out that the CBER researchers that were reviewed here are fairly unique, and OBP and CBER are the two groups that routinely have researchers doing a standard regulatory review. And I've looked at them on this slide, but it's really too much, and this includes both actual being on site in sections, being there as part of experts when our experts go on section, as well as writing guidances, reviewing R&D, et cetera.

So they are fully integrated in the part of the process. In fact, it has always been my belief that CBER researchers, research regulators, in general, identify clear issues that need resolving better because they're actually involved in the regulatory process and see the challenges at the table, if you will.

The next slide is a culture issue that I have tried to promote, which is the discussion that often follows the FDA dose research discussion with "oh, well, I see. NIH does the basic research and you do the applied research."

The bottom line at CBER is one that's mission relevant. It's the research output and how it is applicable to support the complex biological products. It is not whether it is basic. It is not whether it's applied. That really doesn't matter. It's whether it's applicable, and sometimes some of the most major improvements and assistance that CBER scientists have given have been in the basic biochemical arenas.

So we really approach and utilize all kinds of science. The key is how it relates to the product development and approval.

The next slide is basically one slide that summarizes years of work with a variety of research and regulatory science and the quality office, and that includes a curricular pattern where every year the pattern is to review the regulatory and public health portfolio and analyze the regulatory portfolio based on scientific issues and challenges.

We, of course, track very carefully INDs, BLAs based on titles, base on sponsors, but what's done here is to identify the key scientific issues and challenges within those regulatory processes and to formulate a report from in the office.

And that was submitted this year. Research priorities are then developed because once you identify the key scientific challenges, you have to identify those that can be resolved without resources that need urgent resolution, and if you will, maybe then focus on either low hanging fruit where we can have an impact or major public health issues that are so significant that we must work on them.

The offices sends them and provides the center with their research plan and budget which is formulated, and we're currently in that process now for '07 because we're just initiating this formal initiative, and this year we're, if you will, beta testing the process.

But in '06 they submitted research plans and budget. We developed a form that we liked, and it was very informative, and now the process is being repeated. Next year we have the process more on target with timing because it will be the final product in research management.

And then we have, of course, the scientific program review both for performance as well as prioritization and future scientific quality and their plans, and then an annual report is required, and that also is currently in the works.

And then with the Advisory Committee, the first presentation will be involving the response to the office site visit and a discussion of this process for that office, and that will be coming up for OCTGT. The goal here is to have public input responses and to make the planning process and the prioritization process back-and-forth and allow, of course, public input for interested parties.

Next slide is Slide 10.

Basically there are two kinds of things we do here. We either create regulatory pathways where there are few or none, and that's particularly applicable to this office, or in some cases where there is, quote, historical regulatory pathways, such as in vaccines, which oddly enough are really some of our oldest and most established products. We have to improve and update with 21^st century science those regulatory pathways.

As you can see, our portfolio tends to and always has tended to focus on safety, and we do product quality as an issue and product efficacy, but safety is key, particularly because our products are either fairly novel or they're products like vaccines that are administered to healthy people, and therefore, the safety bar is quite high.

Next slide.

Slide 11, I will let you read to yourself, but we also developed this as part of the research management initiative, Guide Principles for Science at CBER, and you will note words like "collaborative," "crosscutting," "multi-disciplinary." Our staff really lead the chase in terms of having that total scientist, the renaissance scientist who really is quite broad in their expertise and quite forward thinking, and yet collaboration is key because science in this world these days is an international and certainly multi-institutional effort, and I'll leave you to read those yourself.

Today, just for a little bit of site visit definitions, I want to sort of give you some CBERese, if you will. Today we have senior investigators, staff scientists that may be already converted staff presenting under review. A converted staff is tenured and, therefore, they're evaluated either for promotion to a higher GS level, for example, or for simple progress.

We have asked the Committee to comment both on their previous performance and on their future plans.

Then we have another category which is being reviewed, which is service fellows, which are considered non-permanent. If you're a non-tenured STEs we have two versions of those. One is the staff fellow or visiting associate, who is evaluated from conversion to staff scientist or support scientist, and let me just say as an aside not necessarily because that individual could not be an independent investigator, but because of financial or budgetary reasons, administrative needs it has been determined that there is not a need for a second independent program in this area.

And so these scientists form part of a team working under a principal investigator and contribute tremendously to the effort, but sometimes the staff scientist designation is clearly an administrative designation because we have very talented staff.

Senior science staff fellows and visiting scientists are also temporary, not permanent MPEs, and those when they come in are considered senior investigator track, and so they're evaluated for conversion to senior investigator and all the things that go with that, including independence, ability to run an independent program, et cetera.

The next slide, 13.

Basically the site visit team is now viewed as the Roman Coliseum, and appropriately what they help us out with is to identify staff that are on track and help as experts in their field given suggestions for improvement. They identify staff that are not on the right track. They help us with prescriptive advice to get the staff on track, which we appreciate.

And so with the non-permanent staff, the fellows, if you will, service fellows, we like to get them reviewed mid-cycle and then once at the end of their seven-year track so that in the mid-cycle review they have a chance to change direction, change course and take the advice of the site visit in order to improve their programs if it's needed.

Next slide is 14.

The site visit report is what we're talking about today. Basically at the end of the review of the team, the oral summaries presented to the research management, and there's an opportunity for discussion and clarification.

A draft report has been written. It has been distributed to the Advisory Committee. The final report is here today to be discussed, and the final approval by the Advisory Committee, and then that report becomes a major document that is used for the promotion or conversion of staff.

And on the next slide you'll see, Slide 15, that that report which is in red, the Advisory Committee approved report at Slide 15 is part of a package that goes forward to the promotions or conversions committee, and that includes other elements, such as curriculum vitae, bibliography, the nominating memorandum from the advisors of that individual. Locations are submitted, words of recommendation. Again, other outside scientific reviews are sought, and that entire package is reviewed by the promotions and evaluation committee, which contains both research and regulatory scientific staff because an entire scientific and regulatory performance review is performed in parallel. Then that committee makes a recommendation. The center director will ultimately decide on the outcome.

The final slide.

I just want to say thank you very much for all of your time and energy and help in this and every site visit that is performed by the Advisory Committee and the site visits because we greatly appreciate it. We would like to recognize the FDA, along with OBPs who participate in this process as having one of the most rigorous and high quality scientific evaluation processes in the FDA.

I just want to thank you and take any questions if you have any.

CHAIRPERSON URBA: Well, thank you, Dr. Carbone.

We left some time after Dr. Witten and Dr. Bloom's presentation for questions. So unless there's some burning question from a Committee member, I would suggest we go on to Dr. Witten's presentation.

DR. CARBONE: Super.

DR. WITTEN: Okay. Thank you.

This is Dr. Witten. Do you have the slides? I'm assuming everyone has the slides in front of them. That's true?

CHAIRPERSON URBA: Yes.

MS. DAPOLITO: That is why you say "change slide."

DR. WITTEN: All right, good. All right. So the topics I'm going to cover -- this is on Slide 2 -- are the mission and organizational structure of research in our office, the Office of Cell Tissue and Gene Therapy; the regulatory scope of our work; and then some highlights of what our research actually covers.

Next slide.

So the mission in OCTGT is to facilitate development of approval and access to safe and effective medical products. Our products are quite innovative. So some of the research that we do is a very cutting edge, not necessarily on the products, but on research on test methods of other tools that might be needed in product evaluation and development.

Next slide.

This slide gives the structure of the office, our office, and as you can see, there's three divisions that actually do regulatory work, and one of those divisions that does lab and other research, that is the Division of Cellular and Gene Therapies. Dr. Puri is the Division Director of that division.

Next slide.

And here on this slide is a scheme describing the organization of that division. So we are today talking about the Gene Transfer and Immunogenicity Branch, which is depicted in this slide.

Next slide.

Okay. So I mentioned that products regulated by our office are quite cutting edge and also diverse. Here is a general overview of the types of products we regulate: cell therapy, gene therapy, tumor vaccines, and immunotherapy, tissue based product, xenotransplantation products, and these aren't mutually exclusive categories. That is, some of the vaccines might also be considered cell and gene therapy, and certainly some of the cell therapies would be considered xenotransplantation products. So it's more of an overview of the technology of our products rather than specific product categories.

Next slide.

On this slide I've listed the regulatory portfolio and activities, and as you can see, we're a very active office in terms of the research that's here. There's over 1,100 active INDs, IDEs, and master files. These are active, meaning there's a number of amendments for these that we have to look at because they're ongoing studies.

There's one licensed product, but there's a number of products that are in Phase 3 or in discussion about Phase 3, and these are some of the regulatory activities that we participate in.

Next slide.

We're relatively small, but our reach is large as I've indicated in the previous slides about the scope of our work. So much of our both regulatory and really our research work, too, is done with partnerships.

And I've listed here some of the types of groups that we partner with, the National Toxicology Program and other organizations, NIH and CDC. We have some specific initiatives with these different agencies, in particularly with NCI. We have a lot of interactions.

We've listed the IOTF Program, but there's others. We had a workshop this year on cancer vaccines that was conducted within NCI. We have a lot of interactions with NIH. The Stem Cell Task Force is only one example.

We have an MOU with MINDS. There are not all of these listed, but it just gives you a flavor of some of the kinds of outreach and interactions we do, and certainly there are international partnerships, ICH and WHO, but as you can imagine, there's a lot of interest in the field, and we do have a fair amount of discussion with our regulatory counterparts and other areas.

Next slide.

Here I've just listed specifically. I have on an earlier slide that we participated in guidance document development. I have in this slide an update and from when. It is the significant guidance documents from this calendar year. You can see that they're fairly significant: a knee cartilage tissue engineering guidance document and one that we worked on together with cancer drugs; the finalization on clinical trial endpoints for cancer drugs and biologics. We also regulate human tissue and finalize the eligibility determination guidance document, which is certainly very important in enhancing tissue safety, and also the core blood guidance document that was discussed at a meeting that was conducted earlier this calendar year was issued indirect this year.

Next slide.

I'm not going to cover the roles and work of the researcher reviewers again sine Kathy Carbone has already gone through it, but I will just echo what she said in that there's a unique role of the researcher reviewers, and both components of their work here are important and are recognized both in terms of the research and the regulatory component, and I think they are very intimately tied together.

Next slide.

So this list of contributions in the research area and the regulatory area, specifically for the branch that we're going to be discussing today since the 2003 site visit, and I know that Dr. Bloom, following me, is going to go into more detail about what her branch does, but you can get the idea from this that not only does the office overall participate in IND review guidance document, regulatory work and active research, but in particular, this branch has been extremely active in all of these areas that I have mentioned.

Next slide. Okay.

So I think also Dr. Carbone did discuss what is the goal of research at FDA or at CBER, and the goal is to stay ahead of the curve as these products and technologies evolve.

So, in particular, in our field we look at the research that's going to address the regulatory needs of tomorrow. We have a good idea of what the anticipated products are based on our regulatory work, and we use that knowledge to feed into some of the objectives of our research program.

Next slide.

So that we do systematically look periodically internally, as Dr. Carbone did mention. There is a system across, you know, CBER to look at what are the critical path issues in these products, and our research is different from what sponsors do. The sponsors will study individual products and have proprietary results, whereas we look at studies relevant to product classes.

So, for example, if a sponsor wants to do toxicology testing of his or her particular product in an area where test methods don't really exist, they have a double challenge where they're developing the test methodology and of developing their product, and then that test methodology is done by them and relevant to what they do. So we try to encourage development of cross-cutting tools, such as test methods, for example, that can be used by anybody and where there could be a greater understanding of these tools, you know, as they are used across the field. People have a greater understanding of what the results mean.

Next slide.

I've listed on this slide our current research areas. This is across the office, and Dr. Bloom will be focusing specifically on the research in that branch.

Next slide.

I just want to mention reference materials are certainly an important part of our research. It's not basic science research in a way developing reference materials, but it's along the lines that I mentioned of assisting the evolution of standardized test methodologies.

Last slide.

And so lastly, I just want to thank everyone for participating in our review program. It's very important to us to make sure that we, you know, are reviewed and that we make sure that we're evolving in both a relevant way regulatorily and that our science continues to be of high quality and we get input from outside as is needed in all scientific endeavors.

And now I'll turn it over to Dr. Bloom.

DR. BLOOM: Thank you.

I'm going to speak with you this morning about the Gene Transfer and Immunogenicity Branch site visit that happened on March 2nd and summarize for you some of the information that was presented at that site visit.

The investigators at the site visit include myself, Dr. Andrew Byrnes, Dr. Suzanne Epstein, Dr. Nancy Markovitz, Dr. Carolyn Wilson, and Dr. Takele Argaw.

I would like to say that while my presentation will focus on the research of this group, I may refer to one of Dr. Witten's slides on the regulatory activities, and you can see that we have a quite substantial role in regulating INDs and the licensed supplements.

Our particular branch regulates samples of all of the types of products that are received in the Division of Cellular and Gene Therapies, including gene therapies, cellular therapies, xenotransplantation products, tumor vaccines and basically the whole nine yards.

So, in general, problems in development of cell and gene therapy products include -- I'm sorry. I'm on the second slide now -- include that there are a lack of preclinical models to predict performance of gene and cellular therapy products in vivo.

There is a potential for transmission of infectious agents to the patient and even beyond, especially for certain xenotransplantation products and certain gene therapy factors. So not all of the products pose this kind of risk, but many of them do.

And, in fact, some of these products were often intended for lengthy or even permanent residents in the recipient, which raises the risk level.

The complications of the product or --excuse me -- manufacture of the products are quite complicated, and the structure of these products are, as you can well appreciate, very, very difficult to describe and quantitate.

So the challenges for the Gene Transfer and Immunogenicity Branch, in particular, include on the next slide now product safety, which is affected by virus containing products. For example, unintended replicating viruses in viral vectors and in xenotransplantation products and other products pose risks not only to the immediate patient receiving these products, but also beyond the patient, and that's an issue of safety.

Some of our products contain intentionally replicating viruses. Generally these are intended to be attenuated or selected in their replication properties, for example, Herpes simplex viruses.

Viral vectors themselves also carry inherent risks, such as toxicity, tumorigenicity and off-target effects. Immunogenicity of these products impacts both safety and efficacy. Immune responses to viruses and transgene products, xenotransplantation and cell therapy products can severely compromise the efficacy, as well as harming, potentially, the recipient.

In addition, many of the products that we regulate rely on immunologic activity for their mode of action, such as tumor vaccines or immunotherapy, documented immunotherapy products.

The Gene Transfer and Immunogenicity Branch now in the next slide addresses these challenges through critical path research. We use multiple viral systems, and we use a flexible system to address immunogenicity in the function of many OCTGT products.

We believe that the predictability in the clinic of these products comes from understanding the fate and effect in vivo from the role of structure and function in product safety and from interaction of these products with the immune system.

Slide 5 is just to tell you that I am about to discuss with you the individual products that were presented at the site visit on March 2nd.

(Pause in proceedings to respond to cell phone interruption.)

DR. BLOOM: So I'm going to do