Center for Drug Evaluation and Research




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Agenda Item: Open Public Hearing

We now have the first of several open public hearing speakers that we will have during the next two days. During this session because we want to ensure fairness to all, we will have timed presentations. Our first guest is Larry Sassich from Public Citizen, who will make a presentation to the committee and he will have ten minutes.

Larry, welcome.

MR. SASSICH: Thank you very much.

I am Larry Sassich, a pharmacist with Public Citizen's Health Research Group in Washington, D.C.

Public Citizen strongly urges that the Food and Drug Administration's Pharmacy Compounding Advisory Committee consider the following four important issues: The nominated bulk drug substances appearing in the FDA's January 7th, 1999 proposed rules as substances that may be used in pharmacy compounding should be reviewed by appropriate agencies -- divisions in a manner similar to the drugs that will be discussed today and tomorrow and then be discussed by the Pharmacy Compounding Advisory Committee before this rule is finalized.

I would like to commend the Derm and Dental Products Advisory Committee on their rigorous review of what is known about these three sensitizers that was presented this morning. Even though some members of the committee might not feel that rigorous science is necessary, I think the public does and I think the reviews that were done this morning will make excellent newsletter articles for our consumer news letter that goes out to about 130,000 people.

My second point is five of the above mentioned 20 bulk drug substances are currently ingredients in commercially available products and, thus, should not be included on the list of substances that may be used in compounding. These are ferric sulfate, ferric sulfate hydrate -- and I think the FDA considers this as one compound -- phenindamine tartrate, phenyltoloxamine and taurine.

The third point, there should be clarification of the reasons for including currently marketed nutritional substances on the list. Three of the above mentioned substances are currently sold as nutritional supplements. These are choline bitartrate, glutamine and taurine. Taurine is also an ingredient in an FDA approved product as mentioned above.

Choline bitartrate is advertised heavily on the Internet as a brain stimulant. Glutamine as the -- will be the successor to creatine for body buildings and taurine, if I remember, is sold as to normalize the pH in the central nervous system. Ads for these products appeared on pharmacy Web sites on the Internet.

My last point and the most important, I think, is the use of abuse of pharmacy compounding. We feel that there is evidence for the abuse of pharmacy compounding. The nomination of DDMPS, a chelating agent, and piracetam, a brain booster, on the list of substances that may be used in pharmacy compounding are clear examples of this abuse.

The suspect use of DMPS is discussed in Public Citizen's comments submitted to the docket regarding the list of bulk drug substances that may be used in compounding. Examples of how piracetam is being promoted and what use it is being promoted and sold for are given below.

In considering the bulk drug substances that may be used in pharmacy compounding, it was the FDA's expectation that "fraudulent or quack remedies will be less likely to be included on the list because the practice of compounding such drugs is not expected to be sufficiently prevalent or longstanding."

Unfortunately, the misuse of pharmacy compounding for exploitation of the public may contribute to a significant segment of pharmacy compounding.

There is a an unprincipled symbiotic relationship between some compounding pharmacists and exploitative practitioners of complementary/alternative medicine movement, each requiring and using the other for their own economic well-being.

The Web sites for the International Academy of Compounding Pharmacists and the Professional Compounding Centers of America link to the Web site of the American College for Advancement in Medicine or ACAM in Laguna Hills, California, an organization that claims on its Web site to be "dedicated to educating physicians on the latest findings and emerging procedures in complementary/alternative medicine, with special emphasis on preventive/nutritional medicine."

ACAM has been involved with the promotion of chelation therapy that involves the intravenous injection of EDTA, approved by the FDA for the treatment of heavy metal intoxication. We have been informed that an action is pending between ACAM and the FTC over charges that ACAM made unsubstantiated and false advertising claims that non-surgical EDTA chelation therapy is effective in treating atherosclerosis and that this has been proven by scientific studies.

Two weeks ago, the editor of Public Citizen's Health Letter, a newsletter for consumers, received a complementary copy of the March/April 1999 issue of the International Journal of Pharmaceutical Compounding, a publication, as Dr. Loyd Allen mentioned -- he is the editor-in-chief of this particular publication and a member of this committee.

He was also listed as a consultant to Professional Compounding Centers of America in August in 1998, though, this announcement no longer appears on the PCCA Web site.

The International Journal of Pharmaceutical Compounding was delivered to our editor bundled with print and promotional materials from Smart Publications of Petaluma, California, an organization that proudly announces on its Web site, "We're the people who created the classic, international best seller, Smart Drugs & Nutrients, pioneering the concept of cognitive-enhancing substances.

A cover letter draws attention to an enclosed press release entitled "Natural Testosterone: Good for Your Heart." This is a chapter in a recently released book entitled Maximize Your Vitality and Potency: For Men Over 40, published by Smart Publications, a book that "covers natural testosterone and other supplements to reverse the effects of aging."

The cover letter goes on to say, "Also enclosed is a recent copy of the International Journal of Pharmaceutical Compounding in which the 'Heart Health' chapter is excerpted. What's the connection? Natural hormones must be custom prepared by compounding pharmacists because they are not available from drug manufacturers."

The cover letter also invites our editor to "Please consider reviewing our new book or writing a story on these topics." The press release announcing the book says in part, and it is very similar to the above statement, "The key chapter on heart health from this book has been excerpted in the current issue of the International Journal of Pharmaceutical Compounding. What's the connection? Natural hormones, like natural testosterone, are available from compounding pharmacies represented by this journal."

At the end of the "Heart Health" chapter published in the journal is the following advertisement. Maximize Your Vitality and Potency can be purchased direct from Smart Publications. Wholesale pricing is available for pharmacies wishing to resell the book to customers (a good way to educate about the value of natural hormones.).

Also in the materials received by our editor was a newsletter entitled Smart Publications Update, apparently written for distribution to the general public. The newsletter advertises products, such as deprenyl citrate drops, piracetam liquid and triple natural estrogen cream as anti-aging products. On page 6 of this newsletter an article appears entitled "The Top Smart Drugs & Nutrients." Mentioned in this article is piracetam, a bulk drug substance nominated by compounding pharmacists. The article describes piracetam as "an intelligence booster and CNS stimulant with no known toxicity or addictive properties. Piracetam has been described by many people as a drug that 'wakes up your brain.'"

Piracetam has never been approved for use in this country and there is no legitimate medical use for this drug that we could find.

In some Third World countries, it is promoted for the treatment of memory loss, in others for lack of concentration and in still others for intellectual deterioration. In India and Thailand, piracetam products are promoted for the treatment of mental retardation or learning problems in children. In Malaysia, Singapore, the Middle East, Mexico and Colombia, they are recommended for the treatment of alcoholism or alcohol addiction.

Two boxed advertisements appear on page 4 of the newsletter in close proximity to each other in the same style and with the same color highlighting. These ads are reproduced below without color.

Briefly, the first ad, "How to Find a Compounding Pharmacy." The easiest way to locate a compounding pharmacy is to contact the Professional Compounding Centers of American, Inc. or the International Academy of Compounding Pharmacists. They can be contacted as follows -- and their phone numbers are given and then parenthetically you can also ask these organizations for a referral to a physician near you.

The second adjacent ad is "How to Find a Knowledgeable and Understanding Physician." The quickest and most efficient way is to visit a medical doctor or osteopath, who is a member of the International College of Advanced Longevity Medicine or the American College for Advancement of Medicine. All members of these professional organizations are skilled and knowledgeable in the prescription and use of natural hormones and other alternative compounds.

These two advertisements show the completion of a treacherous triad between compounding pharmacists, complementary/alternative medicine practitioners and an unwitting public. Public Citizen strongly believes that the FDA and the members of the Pharmacy Compounding Advisory Committee must consider that some of the nominated bulk drug substances you will be discussing have no legitimate medical use and will be compounded by some pharmacists to exploit the public while making exploitation appear as a noble cause.

Thank you very much for your attention.

DR. JUHL: Thank you.

We will, of course, take your comments into the suggestion hopper for future meetings of this committee.

Agenda Item: Discussion and Vote on Dermatological Products

We now will move back to a discussion and vote on the product compounds that we have discussed in the morning. Let me ask if there are general comments before I suggest a way of proceeding.

Carmen.

MR. CATIZONE: Mr. Chair, I have two points of clarification I had raised earlier. The first, I would ask representatives of the FDA to respond to, please. That is the question of if this committee recommends that a product not be included on the list of substances to be compounded and the FDA approves that recommendation, does that exclude that product entirely from practitioners and prescribers and patients or does it allow that product to be used to a more controlled system, such as the IND process?

DR. DeLAP: I think we are not interested in withholding products from people that may benefit from them. So, I would like to put that out first.

I think there are different mechanisms that people can access products. This is one mechanism we have discussed a little bit about the IND mechanism. And I think if there are products that people need to have access to, but it is your sense that you would like to see them accessed with a little more involvement of the FDA under the IND process, you certainly could give us that message.

I don't think you have to simply say "yes" or "no," this product should or should not be available because I don't think that is -- I don't see that as being what the discussion is about today. I think really it is should it be available under this mechanism and if you feel strongly that it should be available, but you think we should work on perhaps a different mechanism, then that is a message you can give us, too.

MR. CATIZONE: Mr. Chair, with that answer then, a question to the committee in terms of what is our responsibility. If we agree and accept the fact that by not placing a substance on the list, that we are not excluding the availability of that product to physicians, prescribers and patients with a demonstrated need for that substance. It is not our responsibility, as somebody mentioned earlier to decide what the availability of those products should be, based upon the criteria, which the FDA has established.

So that if we place the substance on the list of substances that can be compounded, we are saying that that product is perfectly safe for any practitioners, duly licensed or registered to compound that product to use in any situation, including based upon information that was presented to us this morning to allow patients to home treat and titrate themselves with those medications or are we saying to ourselves we need to distinguish between products that are ultimately or perfectly safe and those products, which the FDA has produced data that indicate there is a concern and problem with safety and, therefore, we should allow those products to be available through a mechanism that addresses and manages those safety issues so that the public and practitioners involved in the compounding of these substances are safe and protected from the concerns, which have been noted and published.

DR. JUHL: Well, with the exception of using the words "perfectly safe," which I don't think any -- is used any time at the FDA or elsewhere, I think that is the sense of the issue.

David.

DR. LIEBMAN: Piggybacking on Carmen's question, you have said that there is a mechanism whereby an IND can be obtained, give me a sense of the time frame. If I were to apply for an IND or if M.D. Anderson would apply for an IND today for one of these drugs, give me a time frame as to when they would have it such that it would be available and they could then dispense the product or the medication.

DR. DeLAP: Well, that is -- it varies to some degree, based on what the need appears to be in the particular situation. If it is a situation where there is an individual patient, who greatly needs to have a product and they need it today or tomorrow, then we do have mechanisms for that, for approving an IND and approving availability literally within a day in those situations.

The more standard approach is if we are getting a protocol in that deals with the treatment of potentially a large number of patients and it is a new IND, then under our regulations, we have 30 days to review that and respond. Again, that is more for the situation where there is a research program that is being submitted with a protocol that we are reviewing and providing comments on. And, again, the timetable there is for us to respond within 30 days.

DR. LIEBMAN: Let me see if I heard you correctly then. If we were to put these on the non-acceptable list -- and Dr. McBurney has patients or Dr. Rosenberg has patients and they want to use either one or both of these drugs, they could put an application to your offices and within 30 days, they would have approval?

DR. DeLAP: Well, 30 days is the review time for an IND. The great majority of INDs are accepted within the first 30 day cycle. There are some that come in with some significant problems in the proposals that need to be worked through and there is a little back and forth that may take a little longer. But the great majority are finished within that first 30 day period and people can go ahead and start using the product and treating patients.

DR. LIEBMAN: One last question. Dr. McBurney has to put in an IND. Dr. Rosenberg has to put in an IND. Every physician who treats alopecia would then have to put in an IND if they wanted to continue using one or more of the products that we talked about this morning. I need a sense of clarification. I don't know the process.

DR. DeLAP: I think we would want to work with people to see if there was -- what was the most efficient way of dealing with this. If in fact there are a large number of individual physicians, who would want to be able to use these products under an IND mechanism, our preference would be to work with people to find some umbrella mechanism such that not each individual person would have to go through the IND process, but there would be some centralized mechanism such that people could participate in a consortium, as it were, and individually have access to the product without having to go through the IND process individually.

DR. LIEBMAN: One last question. For the two physicians involved, does that sound reasonable to you?

DR. MC BURNEY: I have a couple of questions just to follow up on what you said. If it is decided not to include it on the bulk list and that is upheld by the FDA, the decision of the committee here, then it is my understanding that immediately it will no longer be available to legally compound. Am I correct on that?

MS. AXELRAD: I would say once we -- once November 21st, 1999 comes, because we have this one year grace period, once we published the final rule and we pass that November 21st, 1999 date and assuming it is no longer under consideration, then strictly speaking it shouldn't be used for compounding.

DR. MC BURNEY: With that in mind then, all of the patients who are using it or who potentially would be using it by then. For each patient we would have to submit an individual IND. Am I correct on that?

MS. AXELRAD: No.

DR. MC BURNEY: As a physician, if I am, say, treating 10 patients that way, what would be my recourse of action as a practitioner?

DR. DeLAP: I don't think we would envision people submitting INDs for individual patients. I think that we would envision people submitting INDs for their entire group of patients in their practice. Again, I would prefer that we could come to some way of having further organizations, such that people collaborate in this process and have mutually agreed upon programs, such that, in fact, we could have one IND that would cover multiple physicians and practices.

DR. MC BURNEY: My experience as an individual in practice, having applied for individual INDs for thalidomide before that was approved and so forth. We did it on an individual patient basis and the turnaround time I will say from the FDA was very prompt and they were very good about it and within 30 days I had my approval and so forth.

But even doing those, it takes about five hours of time to get everything together with the review -- you know, the hospital review board and everything else and to get the pharmacy and everything set up, the pharmaceutical company. With these products, would we be held to a more intensive -- not having seen the forms that would have to be filled out, for, say, to treat ten patients with it, would it be a more extensive form? Are you going to, you know -- I am trying to get a feel for how complex it would be, I guess, is my question.

DR. DeLAP: Well, we have, really just one set of forms for INDs. You know, whether it is an individual patient or a group of patients or a major, you know, multi-center protocol, it is basically the same kind of paperwork involved in an IND process.

I think the thalidomide, of course, had some special issues and I think that we were trying to be attentive to some of the special concerns with thalidomide. So, you might have experienced a little more paperwork with that in some respects.

DR. MC BURNEY: So, actually, you would say that it would be less for -- if I wanted to do ten patients, I could do it as a group and not need individual patient data?

DR. DeLAP: That is my expectation. And, again, I think we have an interest here, too, that we don't want to go through a lot of paperwork from multiple investigators about a lot of individual patients. So, we really try and work with people to do this as efficiently as possible. Again, I think, thalidomide raised some special issues and we spent a lot more resources internally on that and ended up collecting a lot more paperwork from people externally than we might have otherwise done.

DR. MC BURNEY: Can I ask you one other question? Would the FDA consider giving, say, a blanket one to something like the National Alopecia Areata Foundation and have physicians go through them in an approved source of getting the medicine if that organization was willing to oversee that.

DR. DeLAP: I think we would be comfortable with some kind of overarching organization like that, managing an IND if they want to take it on. I don't want to say that the paperwork is trivial because it is not. There is some paperwork involved, but it is a lot more efficient to have kind of an overarching organization with a lot of participating physicians than to have everyone going through it individually.

Obviously, we have a great vested interest in getting done what needs to get done, but getting it done with the least amount of paper that we have to look at, too. So, we are not interested in having things happen that would require more paper.

DR. JUHL: I think, unlike term papers, there is an advantage that the INDs all be the same. That has the opportunity to maximize the public benefit. I mean, that would be one of the purposes. So, it wouldn't be necessary or even desirable for individual physicians to ad hoc write their own IND. It would be useful to use the same kind of information.

DR. ROSENBERG: Thank you for letting me come back, but someone asked a question. As someone who has written INDs, they are not trivial. That would be one thing. And as someone -- and when they get it, the Agency, they get a level of review, which is not superficial. So that my reaction would be to use the IND route as a means for us to continue what we are now doing, which is treating patients, because we think it is all right, would not be right. That is not what the INDs are for. It would be -- it is not fair to the IND process, which is much too important for that.

Very few physicians will fill these out. Those that do, they don't want to read them. I think individual physician's IND kind of behavior would be wrong on -- for several reasons. I haven't thought long enough. I am sure I could come up with more reasons but I think these are two good ones. I think it would be just not the -- INDs should be treated with more respect than that, both coming and going.

The second thing is, you know, what is an IND really trying to tell you. Is this drug safe and effective? And in terms of safety, how is it going to come up with safety? I mean, the doctor has no idea what company supplied the chemical. He doesn't know how it has been analyzed. He doesn't know anything. So, when the doctor writes an IND, we are not going to know anything. If we wanted to talk about having an organization sponsor something, I think we could talk about it.

If we wanted to go back to the point I tried to make before was if we are talking about safety and efficacy, I think -- I did not prepare myself -- I must say, I did not understand the nature of this meeting precisely, that I would need to, you know, bring in all the efficacy data, as if I were bringing the drug before -- as a drug sponsor. I was speaking of the interest of the practicing physicians and I think did that fairly, but I think if you said let's have somebody who really wants to be a sponsor of this come in and present the case for it, I think the Alopecia Areata Foundation -- I can't speak for them, but I think it would be something they would certainly consider doing.

I believe with all my heart that this group or any other reasonable group would say the stuff seems safe enough and I think the people around this table and both the Agency and within the pharmacy review experts could tell us about the safety, in theory at least. In terms of experience with safety, I think there is no -- the whole question of Phase 4 study is, of course, an enormous one. Whether you would want a registry or not, I don't think so. I am repeating myself.

Thank you.

DR. JUHL: Loyd, other questions of clarification before we begin the discussion formally?

DR. ALLEN: Yes. For the presenters this morning, if the IND/NDA approach is used, the source of the product, as it is now for your standard INDs that comes from a manufacturer or single source, you know, maybe three lot, single source type product, if we look at a compounded product, would this be limited to coming from a single source, at which point it would then become a manufactured item or would it come from pharmacists throughout the U.S. that were participating in these studies? Would they be working from the same formulation or just how would this all work down at the bottom line level? Because we are almost moving it from a compound to a manufactured product.

DR. JUHL: Want me to offer an opinion on that? I believe the IND asks you to specify your method of manufacture, with a small "m." And I think to whatever level the group who was sponsoring or individual was sponsoring wanted to delineate that, it could be useful. And it may mean that they would say that the bulk compound should have a model certificate of analysis of whatever the most precise one is that we have and then that would allow multiple sources, as long as they met that standard with a similar certificate of analysis.

And then any pharmacist, who was operating under that IND would be obligated to follow the manufacturing process that is specified, whatever it is. So, I think there is a great deal of flexibility in that, but it would allow the setting of standards and perhaps ameliorate some of the concerns that we have over the impurities and their possible contribution either to ineffectiveness or side effects.

DR. ALLEN: I was primarily referring to formulation instead of the source of the raw drug material.

DR. JUHL: And how it could be compounded could be specified.

DR. DeLAP: I think that is exactly how I would envision it. You would have some way of saying what your expectations are regarding the bulk substance and then you would also describe in the program what are the acceptable range of practices, as far as compounding it, to make the final product.

MR. TRISSEL: Yes. There are examples of products that have gone through the Agency that way. 2CDA, when we first had it at Anderson, we had to compound it under a set of instructions from a sponsor. But they had no product at that point. In fact, the first three or four batches had to be compounded before they finally had a product to test. That product, I believe, now is commercially on the market. So, there is an example of how it progressed. There is a mechanism for specifying or allowing compounding pharmacists to do that through the Agency and the IND process.

One question I would like to ask about the three compounds that we have been discussing have been generally classed together, but one of our speakers, Dr. Rosenberg, seemed to make a differentiation between DNCB and the other two products. I was wondering if our other dermatologists would care to agree or disagree that there is a difference between DNCB and its safety and toxicity versus the other two in clinical use.

DR. MC BURNEY: I think what has happened is that when the Ames test data was made -- was widespread knowledge, was made available to everyone, everyone backed away from it clinically as a general group. As David has mentioned, there are people in his area that are still using it, but I think as a group they backed away from it and not because there was data about problems with its safety, but because of the fear that there could be potential danger and move to the other two products, either the squaric acid or the DPCP.

In more recent years, I think people are using more of that than the DNCB and that is -- I don't have any hard numbers on that, Larry, but that is just my impression in talking with people, who do this kind of therapy.

But there are still very good clinicians in medical centers, who are using DNCB, not frequently but for very difficult cases.

DR. JUHL: David.

DR. LIEBMAN: I am sorry. As a practicing clinician who compounds, if an organization has an IND, clarify for me what that means to me at the compounding level. Can one of my physicians write for it because there is an IND somewhere out there? Do I need special permission to make it? Does he need to be a member of that association? Do I need to get it from a particular source? Lots of questions. And I need to know what that means to me as a practitioner.

There is one thing -- let me just say when M.D. Anderson is doing it, it is all in one building. That is kind of easier. If you have got 50 or a hundred or 200 or 500 pharmacists around the country, who are going to be impacted by it, but individually, give me a sense of how we are going to be impacted, what this means to me at the patient level.

DR. JOHNSON: Well, both of these, both the physician and the pharmacist need to be tied to the IND in some way.

DR. LIEBMAN: Does that not create an automatic nightmare? Do you send a list around and say how many compounding pharmacists in the country would like to be tied and if I want to be tied, if I don't want to be tied now and a year from now, one of my docs says, David, can you do so and so, where does that place me?

DR. JUHL: I think the tie goes through the physician.

DR. LIEBMAN: Does the physician have to be a member of the National Association of Alopecia Treaters, blah, blah, blah? I hear lots of -- I don't mean to be a pain. Okay? I am a practitioner. I need to know exactly what this means to me, to my doctors and to my patients and I need for you all to understand clearly that whatever -- you know, in your wisdom you decide this is the best way to go, that is fine and I will have to live with it, but I need to know that you know that when you vote for something or when you agree to something, these are the ramifications and I am at the patient level. I am at the doctor level. I am at the patient level. I am at the compounding level. So, I am going to be impacted very clearly by whatever decisions the committee makes, whatever recommendations you do to the FDA.

DR. DeLAP: I think the way it is usually done would be to have a list of the participating physicians on the IND and then those would be the people that are empowered to write the prescriptions and add the patients to the program. I am not sure -- you were describing your M.D. Anderson experience. I mean, ordinarily, I think, the people that the physician works with professionally don't really need to be specified to the level of detail, as long as you have someone that is identified as being the responsible person at that site.

Again, often times it is just the physician who is actually writing the prescription and administering the treatment. So, we don't ask for information on who all might be involved in preparing the product for the administration, for example.

DR. JUHL: The only responsibility would be to the pharmacist, who was preparing it, would follow it according to the manufacturing process.

DR. DeLAP: We would expect people would be appropriately licensed and follow their usual, you know, good practices, but we don't ask for that kind of information ordinarily.

MR. LIEBMAN: My last comment and I will let you go. If the Alopecia Society does this, what does that do to Dr. Buddy Cohen at Johns Hopkins, if he is not a member? Ergo, he can't participate? If I don't get asked, do I want to be one of the participating pharmacists? A year from now, what happens?

What I am hearing is you are about to create a nightmare. If you want to go with saying, oh, we will vote it off the list but we will do an IND, when you start looking at the mechanics of it, it is a monstrosity. I think the voters need to think about that. It is one thing to do it in an enclosed institution. There is something very different about doing it to a physician group nationwide and a pharmacist -- 50,000 pharmacists, pharmacies nationwide.

I envision lots of problems.

DR. DeLAP: I think there are definitely tradeoffs and I think you have eliminated some of the issues very clearly. I don't think anyone would have a monopoly on this kind of thing. I mean, if there was an AA sponsored program that served as an umbrella for many physicians across the country to do this with minimal personal paperwork, that wouldn't mean that someone at Johns Hopkins couldn't say, well, I want to be on this and then if for whatever reason they couldn't just get added to the AA sponsored program, they could -- you know, they could file their own protocol and do it if they wanted to.

So, there is no law that says that if there is one umbrella organization that is doing it that nobody else can. I agree with you that there are some very real logistic questions that come up and I think I would say that it is not our interest anymore than it is yours to have it be onerous or impractical. We do have to do the best we can to manage those issues. There is a little time, as Jane was saying before this actually takes effect anyway, but not a lot and we have to do the best we can to get things organized so that it wouldn't be -- wouldn't disrupt people's lives too much.

The only other thing I would add is, obviously, the compounding list is a living document. It is not set in stone and if it was decided later on that the public health advantage was to just put one or two of these compounds on, even if they hadn't been put on originally because it was just not working otherwise, you know, we could always revisit the issue, too.

MR. TRISSEL: To address your concern at many sites, it was M.D. Anderson, but it was also a number of other hospitals that were participating in this early phase study of 2CDA. So, we had different pharmacies and different physicians from different institutions all listed on the same IND. The pharmacies were not cited by individuals. The IND just said that the product would be made according to the set of instructions in the institutional pharmacy. That is about as far as it went. To add physicians was a matter of adding a name to a list, along with their C.V. to show appropriate credentials, if you want to add an investigator to that list.

DR. LIEBMAN: That is easy to do at an institution. Independently, it is hard. I know you don't mean to make it difficult and I know you are not trying to exclude anybody and I know that we don't set it up in terms of, well, we can do it but nobody else can do it and we are going to exclude everybody else, so our members have control over it.

Forgive me. It gets worse and worse as I listen. It just gets more and more difficult, more and more complicated and the ones who are going to suffer are the patients. That is my real concern is patients are not going to be able to get what they need and physicians are not going to be able to treat their patients.

DR. JUHL: Who are prescribers in your experience for this? Are they primarily dermatologists? I would expect so.

DR. LIEBMAN: They are all dermatologists. One is a dermatologist, who teaches at Johns Hopkins in the medical school. Another one is a community dermatologist, who teaches at the University of Maryland. There are other practitioners, who have --

DR. JUHL: I think there is no denying that it will offer an extra level of bureaucracy, but I think you are going far off the edge of the fence on how bad it is going to be.

DR. LIEBMAN: I would love to be wrong on that issue.

DR. JUHL: Let's assume that it is dermatologists and they need to be part of this process. It would be a simple matter, as Larry said, of them submitting their C.V. to whatever organization this is and being listed on the IND. That would take care of the physician. From your perspective, all you would need to know is that the physician is on the IND and what the protocol for preparation is. I can see that being widely distributed to all compounding pharmacists all over the country.

DR. LIEBMAN: And to all dermatologists across the country to let them know that if they choose to use this, they need to have their name -- because I think if we do that, that needs to be a condition.

DR. JOHNSON: Well, absolutely, absolutely.

DR. LIEBMAN: Okay. If you can work it out, I think it is great. You know, I am not opposed to it, but I think we need to anticipate what are the potential problems and try and figure out how to solve them before it goes into effect. That is all. That is my concern.

DR. JUHL: I agree.

Let me suggest a little -- a path for us to take here. A little bit ago, when Dr. Rosenberg was up, I spoke for the committee and stipulated that I think the committee probably believes that these compounds are useful in some patients some of the time. I want to make sure that I wasn't stepping across the boundary. Is that a reasonable -- can be -- does anybody object to that, I guess?

Well, let's make that assumption that that is the case and you will all just have to stop me when I get too far down the road here. And, again, looking at the drugs as a class and we do need to do some individual things, but as a class, we also see if we examine our four criteria of chemistry, historical use, safety and what is in the literature, that there is some difficulties in chemistry.

One of the foundations, the bedrock of drug development is to get a drug that you know what it is. You know exactly what it is. You know its impurities if there are any and you use that all throughout to do your clinical trials so that you can relate back to -- this is actually what happened and how and why it happened. We don't have that with these compounds in that there is variability in what comes down the pike and in some instances we may not be concerned about that, but with these drugs, I think we may be because the impurities may be carcinogenic or have other problems.

So, there is -- in my mind, some chemistry problems. I am satisfied with the thorough work that the Agency has done. Does that reflect the view of the committee at this point?

Loyd.

DR. ALLEN: Yes. I will just go ahead and add that if you recall the USP has stated that they will go into the adoption of any standards that might be required for these. You know, and also keeping in mind that there is a number of products that we have currently in use, that we don't have the full information on. So, these four here may be -- the three here may be just a little bit different. But as far as the standard setting, I don't see that that could not be done within a reasonable, you know, length of time.

Then to our issues of safety, I think there is particular concern here about not only the safety of the patients, but also health care workers. This seems to be in my mind a bit special compared to other products that we have worked on.

I think then the issue before us is whether or not we would like to recommend that these products be listed or not and if we recommend that they not be listed, is the attraction of the IND route one that could be turned into reality without creating a nightmare for patients, as well as practitioners, keeping in mind that the FDA cannot force someone, any group, to submit an IND. They can use friendly cooperation and persuasion, but the Agency isn't in a position to be able to mandate this happens. So, we would be -- if we were going to recommend that they not be listed with the hopes that an organization come forward to develop the INDs, we would be taking a little bit of an act of -- a leap of faith to assume that that would occur.

Now, having gotten to that point, are there differentiations that you want to make between the compounds before we actually take a vote on them? DNCB seems to have fallen by the wayside because of some of its special toxicity situations, although it is still being used.

The question I have, do we want to lump them as three and act on them in general or do we want to do them one by one? I am seeing heads shake "no" about doing them as a lump and to do them one by one. Is that -- head shakes don't do well on the transcript.

DR. MC BURNEY: I would request that we do them one by one.

DR. JUHL: Okay. Then, in turn, let's start with DNCB and dare there any additional items of discussion on that?

Are you ready for the question? My assumption is that the question is to recommend that it be listed or recommend that it not be listed with the hopes that an IND process can be worked out. Is that the question you want answered? Okay.

Let's have a call for the question. Those who are voting members, let me remind myself that David is an industry representative and Joan is an industry representative and the rest are voting members up through Loyd.

Call for the question. Those that favor list

-- recommendation to list DNCB, please raise your hands.

Seeing none, those that to not list DNCB, please raise your hands. I see that as a unanimous recommendation from the group to not list the compound.

Moving to our next alphabet soup, DPCP, let's follow the same process. Discussion?

DR. MC BURNEY: I cannot speak for the American Academy of Dermatology. I am only sitting here as a member of the committee, but I can give some opinions about what their approach would be having sat on their board of directors.

The American Academy of Dermatology is an educational organization and that is what is so stated in its mission statement. There is no organizational structure nor fiscal notes available to support a study that we are proposing. Ideally, it would be a very good place to have it and certainly we could approach the executive committee of the American Academy of Dermatology, but I doubt that that would receive a very high priority. I could be wrong on that. We certainly would need to look at it, but I think on the list of projects before them, that would not be put very high for the reason that it would not affect the majority of its members, would look at it that way.

And that there are more pressing issues, such as skin cancer that they would -- there is a greater number of patients that we treat with that disorder that they would want to put their dollars toward. So, I don't think it is realistic to look to the American Academy of Dermatology. If we did look to the National Alopecia Areata Foundation, certainly that would be very nice for our patients with alopecia areata, but what about all our other patients with warts?

We would then have to look at other individual physicians or institutions. There is no National Wart Society. There should be because there are a lot more warts than there are alopecia areata, but there is not. So, we have got -- we still haven't addressed all those other patients that it is being used for.

As I said, this is only my personal opinion on that.

DR. JUHL: Let me ask you, are the majority of practitioners, who would use these products to treat warts the same people who would probably be using the products to treat alopecia? Are they primarily dermatologists?

DR. MC BURNEY: They would all be dermatologists, I think, generally. Now, some of the warts, they may -- I think the other groups we would need to include, of course, would be our family practitioners who would probably perhaps use some of this. There might be some internal medicine people who would use it.

I cannot speak for pediatricians. I do not know any pediatricians and I couldn't speak to infectious disease. The buck stops with the dermatologists, I think.

DR. JUHL: For the record, Dr. Rodriguez said he would refer those patients to a dermatologist.

Let me ask the question of the Agency. It would seem to be some extra work but not much for an IND to include both. Could the same mechanism be used -- the same IND be used?

DR. DeLAP: Certainly in principle. I mean, we do have INDs that cover multiple indications and don't require additional -- you know, another IND and another set of paper work. Again, I would like to stress that our interest in this is really not to deny this approach to anybody that really looks like they need to have it. Our interest really is just to do what we can to address some of these -- the chemistry concerns and the safety concerns and to learn a little more about the products as time goes on.

So, that is really where we are coming from and we don't want to limit the ability of somebody who really needs these kinds of treatments to get it. And we are very concerned -- again, I come back -- we are very concerned about logistical issues and we will look at these issues as carefully as we can and try and minimize them to the best of our ability. Again, we can -- I would say, again, we can revisit this whole subject if it turns out that logistically that it is too much of a problem to do it the way that we start.

MR. CATIZONE: Mr. Chair, I think there are two issues here and I would ask for some assistance with trying to understand how we differentiate or complement the two. One would be the question of safety. If this committee has a concern with the safety of a product and not addressing that safety by placing that substance on the list means that it is free for use for everyone, every practitioner duly licensed or registered to do so, including patients to self-medicate or self-treat, versus the issues raised by David and Elizabeth, which is access to those medications, can't our recommendation be that if we have those safety concerns, we separate that issue and recommend that those products not be included on the list, with the proviso that these medications be made available through the IND process or through working with the Agency.

If that doesn't occur, if we receive information that the process is too burdensome or patients are being denied access, could we revisit the topic and then place those medications or those substances back on the list?

DR. JUHL: I think that is what was suggested. I think that is reasonable.

MS. AXELRAD: Can I make one comment?

With regard to self-medicating and taking it home, I would remind you that we propose to limit the use of some of the other products that we addressed at the last meeting for office use only. So, we think that that is an option and that would address some of the safety concerns.

DR. JUHL: Other comments on DPCP? Are you ready for the question? Same question?

DR. MC BURNEY: Can I make an amendment to the -- can I make one of them be that we would include -- if we are going to talk about DPCP -- be administered in a physician's office and be put on the bulk list, as we did with cantharidin. Can that be one of those?

DR. JUHL: We could, indeed. The question that we will answer is, number one, to recommend that DPCP be added to the bulks list with the restriction that it be limited to application in the physician's office or, secondly, we could recommend that DPCP not be added to the bulks list with the expectation that if there is sufficient interest, that the Agency would work with a willing group to go the IND route.

Clear on the question?

All those who would favor recommending DPCP be added to the list with restrictions, please raise your hand. We have five voting for that option.

Secondly, those that would recommend that it not be added to the list, please raise your hand. We have five with that option. The chair breaks the tie by siding with the second option of "nay." So, it is 6 to 5 for option 2.

Let us move then to squaric acid dibutyl ester. Is there anything that we haven't covered in the first two that you would like to cover with this one or any difference in the chemical itself that we should consider?

Bill.

DR. RODRIGUEZ: I want to raise a question. Assuming that IND doesn't go through, how long would it be before we get the screamings, for example, to let us know that the system isn't working? In other words, I am just sitting over here, again, as somebody who has no direct effect in terms of my patients, but on the other hand, I am just thinking over here, saying, gee, how long is it going to take before we know that 50, 60, a hundred, 250, for example, and what the mechanism is going to be.

DR. JUHL: I think we have between now and November 21st to get an indication that the process is not only possible, but it is something that can be workable and the Agency has expressed their concern that they want to make sure that this happens in an appropriate way. So, I think between now and then, we would be able to tell that the process could work were the situation such that -- it is not going to get completely done by then. There would be ways to make sure that it happens in a way that it doesn't disadvantage people. I don't want to speak for the Agency, but that is what I thought I heard you say.

DR. DeLAP: I think, again, our primary goal here is that the patients get the best possible advantage out of this. I mean, the best possible advantage for me is that they have access to the product and they have access to it in a good form. It is a good chemical. It is well-formulated. It is well-administered and that they get the best possible results as a result and that we learn more about it along the way.

I don't think it is a black and white situation in the sense that things will -- you know, that November will come and it will be absolutely a total flop or that it will be totally working. I think we will probably be somewhere in between, but we will have to look and see how much of a burden it appears to be placing and if there are limitations on access, we have to look at that very seriously. It is not -- I am sure it is not going to be perfect going in, but we will do our best to make it as good as possible and, again, we can always come back here for discussion if it seems to be just too far out.

DR. JUHL: I believe the committee's next meeting will be in the fall, prior to the November 21st deadline, and, obviously, we would be interested in a report back on that as to whether or not --

DR. LIEBMAN: Point of information.

DR. JUHL: -- we should reconsider the issue.

DR. LIEBMAN: If between now and the fall meeting, someone tries to get an IND and there is a problem, could we possibly look at these drugs again since we now know that the -- if we find that the IND mechanism is not going to make them available?

DR. JUHL: Yes. I think that is what I said. Yes.

Elizabeth.

DR. MC BURNEY: I am sorry to be so persistent, but I just want to be sure we haven't -- I don't want us to blind ourselves that there is not another option, another way of doing it so our patients can still have the medicine.

Is it possible since what I am hearing from our distinguished people at the FDA, who have spent a considerable amount of time looking into the safety data -- and I have great respect for that -- is it not possible to somehow limit it to a mono source for the next drug we are going to look at so that what is available for bulk compounding comes from only one source? Is that possible? So that we could say not only does it have to be done only in a physician's office, but only from one -- we will allow bulk from one area, from one source.

MS. AXELRAD: I am hardly the expert on this, but I would say that it could possibly come from multiple sources, but we would look at the source and we would -- I mean, the way we usually do it for an IND is that they provide information on what the source of the drug is and the method of synthesis and the impurity profiles and we would look at that. If someone wanted to propose two sources or three sources, that would be all right.

We would still be able to look at that and make sure that it was acceptable. We wouldn't want to say it has to be only one source. It might be perfectly fine for it to come from two or three different sources, as long as it is produced in a way that provides a quality product.

DR. DeLAP: I think you are talking about under IND, though.

DR. MC BURNEY: Yes. I was talking about under bulk.

DR. DeLAP: She was asking about under bulk, compounding, whether we could specify a limited number of sources where it was acceptable for compounding purposes.

MS. AXELRAD: No. I am sorry. I misunderstood the question. Compounding, as long as it is a registered manufacturer and it is provided with a certificate of analysis, that is what the statute requires.

DR. JUHL: Other questions?

We shall then move to squaric acid with the same question. We will use the same options. Option No. 1 is to recommend that squaric acid be listed on the bulks list with the restriction that it be used only in the physician's office. Option No. 2 is that squaric acid not be recommended for the bulks list.

All those that favor recommending listing, please raise your hand. We have six.

All those who favor Option 2 of recommending not to list the drug, please raise your hand. Four and the chair votes "no." Five. So, it is 6 to 5 in the other direction, squaric acid being recommended to be listed.

Any final comments?

[There was no response.]

I would like to add my thanks to the Agency for all the reviews that were received. It has been a tremendous amount of work on your part and it has required work across the disciplinary lines within the Agency and I know that doesn't always work smoothly. It certainly doesn't at my university. It requires some extra effort, things that you probably didn't plan on doing. So, I really appreciate the effort that it took to put that together.

We will adjourn for lunch and reconvene at 5 minutes to 1:00.

[Whereupon, at 11:55 a.m., the meeting was recessed, to reconvene at 1:00 p.m., the same day, Thursday, May 6, 1999.]


A F T E R N O O N S E S S I O N [1:02 p.m.]

DR. JUHL: We will reconvene. The group will now make a flawless transition from dermatology to neurology. We have a number of new people from the Agency at the table and I would ask you to introduce yourself in the microphone.

DR. BEHRMAN: Rachel Behrman, deputy director, Office of Drug Evaluation 1.

DR. KATZ: Russ Katz, acting director, Division of Neuropharmacological Drug Products.

DR. FEENEY: John Feeney, medical officer, Division of Neuropharmacological Drug Products.

DR. SOSTEK: Andrew Sostek, clinical reviewer, Neuropharmacology.

DR. JUHL: We have a series of presentations this afternoon on 4-aminopyridine and 3,4-diaminopyridine. These are drugs that are used to treat very serious conditions for which there are few options. At present, these drugs are not of the USP monograph or an NDA'd product and they are made available to patients sometimes through pharmacy compounding and sometimes through the IND route.

We will be reviewing a number of issues regarding these drugs and Dr. Feeney will begin the presentation. I will turn it over to you.

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