Food Safety Counterterrorism Initiatives

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This is what i described as federal stone soup. When we started about ten years ago in the area of gene therapies, gene therapy was then really quite new, and as the INDs were being submitted, every single one we put on clinical hold because they didn't have such things as, oh, like their clinical plan was, how they manufactured the virus and the vectors, simple things that we decided that we could teach each one of the sponsors and go through on an individual basis: "Well, here's your IND, these are all the questions you have to need."

But we think it's a far better way to actually first teach our own reviewers what do they need to look for. We'll be starting to release a series of what we call 'reviewer templates,' which are for our internal use, but will be for public dissemination and discussion. With these templates, these are all the things that we've learned over the last 11 years about what to look for, being put down in a document. We have our reviewers look at this, look to see whether or not they're in the submission. There are links to all the regulations, to the ICH guidelines, to our current policies and practices. They're updated as we go along.

And by the way, we feel that within three to six months we can take a naive reviewer, and that reviewer can then generate about a 15-20 page review that's comprehensive. It's not excessive. We can identify the immediate issues to be developed at the IND stage, and will obviously be a good template for how we create the pathway for these and other kinds of products.

We are thinking, as a matter of fact, that these templates are so useful to use, we know that industry is going to be very interested in looking at these, so they know what kind of questions we're going to be asking. And these are not simple questions. This is not a fact of "Oh follow this and you'll get an IND and an approval." Some of these you're to have to spend perhaps literally millions of dollars to build the technology to address the question, but if that's what it takes to get something on the market, we already know industry is not looking for the easy path. And academia is not looking for the easy path. You're looking for the path that will give you products that will be patient-centered and that will lasting and can be developed for the future.

In terms of partnerships and federal stone soup, speaking of Jesse Gelsinger's death in late 1999, the NIH had a very large three-day meeting about it, and one of the recommendations is "create a reference material standard for adenovirus, so we can compare our cross-trials." We have trials for cancer. We have trials for genetic diseases. We have trials that are just marking studies. A whole variety of things. But the infectivity one trial may use is different from another, is different from another, is different from another. This is an old concept of "create the standards so people at least can include that in their development, and we can now complete does 10-to-the-7th infectious units in the cancer trial equal 10-to-the-7th infectious units in the gene therapy trials for ornithine transcarbamylase.

With an interruption from 9-11, about two years ago, we put together a proposal. It was handled by the Williamsburg Bioprocessing Foundation. We set up a system which is quite remarkable. We actually called for bids for portions of what needed to be done, and the idea was you can bid for producing GMP quality material. You would bid for being one or more of the testing facilities to do the standardization for infectivity. You can bid for the testing for infectious disease and adventitious agent. Now the other part of it is "and you will volunteer everything for that." This is all pro bono.

We estimate that the material cost for this very large effort was something on the order of $750,000. However, the man hours that were involved from at least 40 different institutions--both large, small, academic centers, was clearly somewhere in the low to probably high millions of just man effort. An absolute prime example of what we should term federal stone soup: we provide the framework, we provide the ball park. You know, "Build the park and I know you will come."

We are also working with the NIH Stem Cell Task Force. This has just been initiated by Dr. Zirhoni, and that goal of that particular task force is "Well, you know they have all cell lines available, but there really haven't been very many applications for that. So the task force is to identify what are the impediments and they want to make sure FDA is there so that they can make sure that the studies that are being done will contribute to their present and future needs for any future cell therapies that use stem cells.

And finally to get to the concept of a patient-centered therapy. This is not individualized therapy. This is not taking pharmacogenomic measurements and trying to exclude patients based on a particular phenotype or genotype. This is really trying to say that "What if you turn the whole pharmaceutical development process on its head? That is, when you do a large clinical trial at Amgen, as an example, although you are looking for a patient population, you identify that up front, by and large it's "If you take this, it will work." Of course, it doesn't fit any one person exactly well, but for the average, for the bulk done during a clinical trial, it works not too badly.

We think we--everyone, you all--can do better. This is where the patient defines the therapy. The patient walks in the door, may need a knee replacement, needs a new mechanical device, and at the same time has psoriasis with another treatment. And so forth and so on. This means that we're turning everything upside down. We're talking about market share, because everybody needs to play in this. The large pharmaceutical manufacturers absolutely must be a part of this. It is only they who have the large capacity to produce the reagents, to produce the cytokines, to produce the monoclonal antibodies, that are necessary for patient-centered therapies.

So it's a share, it's a niche. It is not dominance for the market. The delivery is obviously evolving. If we're going to do a gene therapy, where do you go for that? Can you go anywhere in the country? The answer is 'no.' Somewhat facetiously I give the example of "We need thinking like, well, you can go anywhere in the world and get a McDonald's hamburger, and you may not like it very much, but you know it's going to be same. You know it's going to not cause you food poisoning." Whereas Jack-n-the-Box, they couldn't even do that very basic thing of quality control.

So there are opportunities for delivery for the infrastructure that needs to be built. A part of it is we also need to get the first patient therapy approved. Obviously, financing product developments are evolving. But most of all, I'd like to propose that for this process, the patients who are out there, who have missed the opportunities of biotechnology are the ones to drive this process. It doesn't matter how pure the insulin is, if you are a brittle diabetic, you still feel lousy, you still are not controlled. You may die from your diabetes, and not necessarily from the diabetes. Very often these patients just pass out right while they're driving a car. My stepfather almost did the same thing, as a brittle diabetic.

Now, do we have any examples. We think we have at one prototype example of a patient-centered therapy. There is a syndrome called "X-Link Severe Combined Immunodeficiency Syndrome." X-Link because it's on the X-chromosome. The popular term is "bubble baby syndrome." This is a lack of a gamma C chain, which is a part of what makes up receptors for cytokines. This particular gamma C--actually without having it you loose five different cytokine receptors, and so you have essentially no T-cell function. You have relatively normal relatively normal but not adequate B-cell function. There is a death within the first year of life if it's untreated, from severe recurrent infections.

If you could get a full HLA identical transplant, usually from the sib, you can get greater than a 90 percent survival. Unfortunately only about 20 percent of the time do you have such a person available. Haplo-identical transplant becomes the second level of transplantation. It still carries between a 50 to 30 percent mortality rate. And in both of those cases, the reconstitution that you see is adequate; that is, you can survive, you can do pretty well. But we don't know about the long-term survival very much. The oldest is now 19. And usually the patients at the minimum need monthly or quarterly infusions of gammaglobulin because their B-cells, while somewhat normal, really are not adequate for typical antibody responses.

Now, it's not without its own hazard. In France, nine of 11 children showed evidence of immune reconstitution following gene therapy. Just late this August, actually right at Labor Day, one successfully treated child out of the nine that were treated in France developed a leukemia-like syndrome.

We had a quickly constitutive BRMAC meeting, or Biologics Response Modifier Advisory meeting, on October 10, 2002, and in a way it was really quite remarkable. Because as science put it, "What do you do when you have when you have a successful treatment and the risk is really unknown but it's there?" The significant findings was that in fact, the gene insertion by gene therapy that led to the therapeutic effect also caused the leukemia-like disease. As Stu Orkin put it, more succinctly, if you see an animal with four legs and it has stripes, you call it a zebra. If you see a child with leukemia and it's got a gene therapy and a retrovirus has inserted in an oncogene associated with leukemia, you tend to call it leukemia. So the clear risk at an unknown frequency is that the same therapeutic event can cause a disease. The child has been treated, however, not in complete remission, but is still surviving at this time. Obviously we are looking at it very closely.

Because of this potential superior immune reconstitution, these kids actually do well for both their T-cells and their B-cells. And ironically this one young child actually developed chicken pox and was able to withstand that and actually to throw off the chicken pox somewhere probably after the malignant event occurred. But clearly immune function restoration is quite large in these individuals.

We are going to make sure that the trials that will start in the United States--we have two for X-SCID, will have all this information available. There will be new test requirements for looking for clonal expansion, and within any child that is treated, and a whole bunch of other things that are related to that.

We will also be going back and making sure all the informed consent process for all retroviral gene therapies are done. And that is a process, in fact Dr. Cynthia Rask is right in the middle of heading that project up.

Let me just illustrate to you what we're talking about here. It's very simple to say, "Well, we had a gene therapy and we got a cure." Here we're talking about exactly what was done in France and what will be done in the United States in several trials, trying to replicate that experience. The end product is on the right-hand side the CD34 putative stem cells--probably not the stem cell, but within that population are the primordial stem cells--that is now expressing the normal gamma C receptor. That is the product, per se. You notice that the Office of Cellular Tissue and Gene Therapies does not have the word, "product" in it, because this product, we lose count. You start with cord blood, you pass it over an FDA-regulated column that has FDA-regulated antibodies into a dish that's FDA-regulated because it's a flask. You take a murine retroviral vector, which is an FDA-regulated product, into a fibronectin, oh that's another FDA-regulated product flask, to do your transduction, in which you add three or four growth factors that by themselves have yet to show clinical benefit to patients, but in combination are critically important for the ability of the retroviral vector to actually transduce those cells and lead to a therapeutic effect.

With apologies to Dr. Davis, three out of the four are now at Amgen. Stem cell factor Flit 3 ligan [ph], and IL-3. The pegylated MDF is a different product. Just to divert just a little bit, there are issues in terms that are still available because Amgen owns the intellectual property for three out of these four. And clearly they do want to make sure that their products can be used and developed, but they don't want to lose the intellectual advantage, nor do they want to be in a position where if something goes wrong, they get blamed for that.

Well, we're working with Amgen and with the National Cancer Institute to work out an arrangement whereby in fact we can start to address those kinds of things. The issue right where is that as an entity, this particular patient-centered therapy, it is unlikely that any pharmaceutical company wants to do the whole thing. On the other hand, clearly if we start thinking about market niche, if we have stem cell factor that is clinical GMP quality, from a licensed manufacturer, why would we prefer that over getting something repackaged by Sigma? And that's part of the issue of where we are going, part of the types of issues that we will be facing.

I put this in a little bit of a tabular form, here, to just say there are about five different areas, each of which overlap because, for example, we have devices, but the devices have monoclonal antibodies. We're looking for surface markers. Some of those devices have extracellular matrix whose regulatory status, per se, may be a little bit confused, but in this context, are part of that whole cellular therapy.

Specified products, or these recombinant products, stem cell factor Flit-3 ligan--in no way does the fact that they're used in small quantities in an ex-vivo situation mitigate the fact that they need to be in their own right as safe and as pure as possible. We feel that the pharmaceutical biotech industry is a place where that can be done on a reasonable basis, and must be done. The quality of each part of the products that go into the final therapy here, we cannot compromise on the quality. And that quality simply comes from the coordinated review, the coordinated review of the science, the coordinated review of the research reviewers, that can make that happen.

If you look at all this, and I am not going to spend a lot in terms of what the proposed transfer of products will do, but let me put it to you in a very practical way. It is a little bit daunting, and I was much more comfortable just a few weeks ago to launch a new office that actually is smaller than most divisions at FDA. Because I knew I had the support of OTRR. I had the support of the Center Director. We could do this, we could work it out.

Transfer of the scientists, of the products, of the expertise, no matter how you cut it--some will be lost, some will want to go, very likely not too many. Some will leave. Some will go to other centers. Some will enter private industry because we train the very best. Our folks can go out any time they want, and they know it, but they don't want to. They want to do the right thing, which is this.

We need that expertise for the medical review. We need that expertise for the products. I need to know for sure that a CD34 monocloncal antibody actually has undergone the same type of review that we have for a therapeutic monoclonal antibody. And you know what? Sometimes that slips through the crack. And you know what? If it's not within our Center, it's going to be extraordinarily hard to necessarily figure out where it's going to be don. In our Center, we are a product-oriented center, so in one sense we try to package the whole review of the product, the clinical Pharm/Tox review, the compliance, and everything else. Although they are in different offices, we are one center that does it. If it goes instead to a medical indication, so Flit-3 Ligan may go to several different divisions because of the medical indication, it will be impossible to adequately address the issues for a therapy, a patient-centered therapy such as this.
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