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FDA s George Mills on Digital Imaging s Future in the Agency

To understand the role that George Mills plays in how medical imaging will be used as a drug approval tool by the FDA, look at the agenda for the Drug Information Association meeting on imaging to be held in Betheda, Md., May 5-6. Mills is giving a keynote presentation and leading two other sessions of the workshop.

After FDA acting deputy director Janet Woodcock singled out imaging as one of the agency's top priority for development last week, (see related article) BioCommerce Week spoke to Mills to learn how the agency sees the future of the digital medical imaging toolkit in its approval processes.

Did Dr. Woodcock's speech last week signal any kind of acceleration of emphasis on imaging by the FDA?

I would not necessarily say a change in emphasis. I think it is more an acknowledgement that the area of imaging, as related to drug development, has increasingly come into focus over the past several years.

There are two [FDA] documents that are important in imaging. Last June, we put our medical imaging guidance document out, which outlines the criteria we have in looking at the safety and efficacy of new imaging agents. That is fresh and we spent a lot of time in the development of that and feel quite positive that it will be an excellent platform in going forward in imaging development from the drugs and biologics side. It doesn't directly address issues for the devices themselves. For that, we look at our sister agency, the Center for Devices and the sentinel paper of the Critical Path.

In the Critical Path document, imaging was discussed in perhaps two paragraphs.

Imaging is one element in that critical path and it's certainly one of the platform pieces. We have enough momentum in enough areas now to be able to say that, Yes,' we can look at imaging as positive and constructive enough to move drug development along safely, and we think in a well-constructed and improved pace.

We have very much seen this now related to the incorporation of imaging with therapeutics. For example, the Bexxar and Zevelin experience emphasizing the use of imaging to look at the marker, the CD20 antigen, in assessing the evaluation of safety for a go/no-go decision on the therapeutic. That same type of emphasis is now being shown in an exploratory IND draft guidance that is coming forth now where we are looking at imaging to assess the targeting of tumors and non-tumor areas, as well as being able to look at the distribution of the drug or biologic within the body to assess for both safety and potential efficacy.

The guidance you mentioned and the Critical Path seem to represent different approaches to imaging.

In terms of the Critical Path and then the exploratory IND process, you are seeing two complementary — but not identical — paths.

First, the Critical Path is to improve the turnaround of the development cycle process. We are trying to enable industry to better utilize the IND process, and to allow drugs and biologics to be approved safely, but more rapidly. To that end, when we are looking to the Critical Path, we are looking for facilitations. One of the facilitations that may be of value and available to us is looking at imaging surrogate end points, which may, over time, allow us to look at drug-development and safety at the same time.

One of the areas that we tend to focus on right now is oncology. But there are other areas where imaging end points have been shown to be very valuable. Our experience in the rheumatoid arthritis drugs has shown us that we can effectively use imaging to demonstrate the effects of these drugs, and do it over a long span of time. We have actually been reassessing the response evaluations in rheumatoid arthritis over a five-year period in a follow-up to the original approvals. That has given us a lot of experience and understanding of imaging end-point development in this area and seeing if we can now further apply that to, in one push, get these products through the system in a very safe and effective way. But, at the same time, allow us to monitor for evidence of long-term improvement of care for patients. We have been effective in the rheumatoid arthritis area and we feel that we can take that experience, along with what we have seen in the biologics and oncology area, and blend those together to help improve the overall drug development.

On the exploratory IND side, I like to use the analogy that what we are doing is approving the on-ramp in drug development — that is, going from the preclinical, where we talk about Phase 0, to Phase I, the initial experience. Here what we are enabling is the ability to assess promising from not-so-promising drugs and biologics in their initial introduction into human trials. This area may well have a long-term improvement in drug development.

So what you are talking about is today's imaging technology — PET, CT, MRI?

The here-and-now is PET. And certainly, FDG [fluorodeoxyglucose] is the most popular and broadest based [tool]. There are others that are investigational, and some that are essentially able to help us better assess these early development drugs at Phase 1 from Phase 0. We expect that as we gain experience and really refine our regulatory review of these imaging technologies, we can enhance drug development, not only in Phase I, but going into Phase II and Phase III. We will gain great experience in the initial development and in the long term. I think that is where a lot of the success story is going to be with imaging — to help as we develop our experience with a drug or a biologic from Phase I going forward, so we have an enhanced experience with that product.

Have the tool makers failed in their ability to produce instruments?

Oh no, not at all. They have been very successful. From our standpoint, what we are looking at now is how to improve the precision, the reproducibility of those imaging techniques across our clinical trials. Part of our development process now has to be taking those excellent imaging techniques, which many times are done slightly differently across multiple medical centers, and provide a more systematic process for building a review data set that can strengthen the review process for the drug or biologics.

Does the Critical Path help industry have a target to shoot for in molecular imaging?

Molecular imaging is here in various small center experiences; and it's here in development. But it is not here in terms of being a systematic approach across multiple centers that allows us to take molecular imaging that has been qualified in a way that the industry and the drug-development groups are concerned, and that can be applied systematically. Right now, that is part of the process. Imaging is a tremendous opportunity to take and advance drug development, and, at the same time, advance imaging techniques. To keep that in a systematic approach is part of the enriching process we are going to have to do over the next several years.

Can you be more specific about that time frame?

I think that for a good systematic approach we are looking at a development cycle of three to five years. I don't mean that we will be doing it five years from now — we are going to participate now. Let's try to see if in five years we can have all of these working systematically, and let's hope we can do it in three.

Is the FDA's process amenable to dealing with all these technologies?

I see many of these [imaging] approaches having to get positioned to do a procedure in a way that can be brought forward to get established in the community. It's an exciting time for many of those [technologies] and I see that positioning as something that will occur well within that window of time. Once that imaging technique is accepted within a community, then it next has to be incorporated into the drug development community. What we are inevitably doing right now is looking at developmental imaging techniques at the same time that we are looking at putting [imaging] into various clinical trials to see if we can assess various drug development steps. We may be in an exciting time where modalities may get themselves established — and incorporated — almost in a parallel fashion. Don't expect an end-to-end structure. Medical imaging is part of the [FDA's] new oncology office and development plan, and it's there to closely parallel the development of imaging in many avenues.

A lot of the development we have seen is in the biologics area, where we have seen very specific antigens, such as CD20 antigen, within the body now, and then target those, and approach them diagnostically from imaging as well therapeutically, and do that from one approval process. That is an exciting moment when you look at that, from the standpoint of all of us who will one day need some sort of therapeutic or diagnostic intervention.

Is there any sort of guidance being considered for this?

Not from within the agency. A lot of processes have to be cloaked because it is proprietary development. So, we can't come out and talk about new modalities. They don't want us touting their development.

What are the risks of this imaging?

Certainly, No. 1, whenever you go inside the body with any type of contrast agent or other agent, there will be some safety issue involved. We know that even just applying an X-ray has some minimal risk level, but we decide that the benefit is far greater than those risks when we let one go forward. Now with the old standard iodine contrast agents, we know we had some associated risks with allergy, kidney disease, or liver disease. All of those represent a certain amount of risks. For the new ones, we will do the clinical trials for safety and efficacy.

Contrast agents and the idea of combining in vivo and in vitro information largely drove the General Electric acquisition of Amersham last year. Is the agency prepared to deal with that type of convergence?

We are encouraging and receptive. We will work with the industry to understand and develop in those areas. It's a growth experience, an opportunity for both industry and the agency.

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