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Agenda Item: American Academy of Dermatology Presentation

DR. ROSENBERG: Thank you very much. I appreciate the chance to represent the American Academy of Dermatology. I would like to say that I also serve on the Medical Advisory Board of the Alopecia Areata Foundation, which is a patient advocacy group of people concerned with this disease, which can be devastating to many of them. They have asked me also to speak for them in support of the wish that the practicing community will still have the opportunity to use this treatment when possible.

I want to make a few comments, a little bit of historical review and then be available, I hope, to answer questions from the group.

Of course, benefit to risk is at the heart of regulatory decision-making and in terms of the benefit here, I would point out that we are dealing, certainly at the alopecia areata aspect of it, with some patients, who really carry a very heavy burden of disease. The pictures that were shown of widespread disease are not unusual. People will lose more hair than that.

Many of them are young and terribly upset by what they face with this during the difficult periods of adolescence and childhood. Dr. McBurney, I think, speaks for most of us, who are interested in practice in this area, that systemic steroids are not an acceptable treatment for alopecia areata.

The hair that grows with systemic steroid comes right out after you stop this systemic steroid, which is not the case with this kind of treatment. And the potential side effects and relapsing and remitting disease are well-known and almost the worst thing about the corticosteroids by mouth is that they almost always work while you are taking them. So, there is a great temptation for patients to want to keep taking them, keep taking them while they do themselves further harm.

Most of us who are interested in this disease do not consider that safe and effective. Intralesional corticosteroid is safe and effective, small shots of atriumcynelone(?) asetinide(?) suspension, usually somewhere around 5 milligrams per ml, sometimes 10, will grow hair in a very limited area. This has a limited applicability to people with small area of alopecia areata. It is not suitable for widespread areas.

So, this is a treatment that in terms of alopecia areata, that we would miss very much if we didn't have it. Just a little historical review about this, I suppose I have more experience with this treatment than anyone else. I was, to my knowledge, the first to have used it and it was a patient 25 years ago or a little bit more, the wife of a surgeon, whose office was around the hall from where I was practicing in the sixties, 30 years ago, who had long time alopecia areata and was taking systemic corticosteroid on her husband's prescription.

We got to be talking about it and I told him that intralesional steroids had been introduced since she had been started on that other treatment and that these were much safer. She was a grown woman. She taught high school French. So, we began a relationship with this patient where I would see her two or three times a year and inject five or six new spots every time.

One day in the office after five or six years of this, she said to me, Bill, why is do you think that I have to keep coming in and getting these new spots treated? Why do I keep getting it? And I said to her, Betty, I said, probably the more interesting question is is why most people who get alopecia areata recover spontaneously and have it again maybe once or twice or frequently never again, but don't have the trouble that you have.

And she said why do you think that is. I said I don't know. I said, the trouble, of course, is these lymphocytes that appear around the hair and then the hair goes away. We don't know what the lymphocytes are attracted to there. I said maybe what it is, most people the lymphocytes are able to get the trouble away and then the hair can regrow and there is no more reaction.

And she said is there any way to get more lymphocytes there? I said, well, actually there is. There is an allergist who works in the same office, has a product called DNCB that he puts on people's arms. They are supposed to become sensitive to it and it will bring lymphocytes in most people.

She said, you want to try it? I said sure. So, we put some -- sensitized her to DNCB and put some weak DNCB on her alopecia areata and it grew hair and we reported that or presented her case to a -- at the time, the Archives of Dermatology used to present the transactions of dermatologic society meetings. Dermatologic society meetings worldwide are always -- frequently, one brings a patient to the society meeting and the members of the society see the patients and discuss their case and then those cases always used to be reported in some of the journals.

So, this single case report, which was not really a case report, but what was the transactions of a meeting of the Memphis Dermatological Society was published in the Archives of Dermatology. Rudolph Hopley, a dermatology professor in Germany, read this and began doing this on an organized and thoughtful and extensive way.

We began also to do some larger studies. Hopley then told us that the West German regulatory agency told him not to use it because of the Ames test, but said that these other -- he said that the other two drugs -- first, the SADBE, later the DPCP, had passed that review and that is what most of us started using.

So, on the basis of, as I say, 25 or 30 years and lots of patients personally, I can tell you that it would be very hard to not to have this to offer to patients who come in with this terrible disease. One of the sad things about this kind of disease is parents and patients have been told that it is due to stress and dysfunctional family life and so forth. And that is not true either.

Whether it is autoimmune disease or whether there is actually some antigen there in the form of a virus, it is not at all clear. Hopley feels that it is autoimmune disease and SADBE brings suppressor cells. I still in my heart think that there is some evidence for a virus and the related disease vitiligo also, there is evidence of a virus.

So, the issue is unclear. The fact is that this treatment is helpful for a lot of patients. I brought along a statement from Jim Davis, who is a pharmacist who has been mixing it for me for 25 years. I asked him for that a week or so ago and he said he would, but his wife was ill. He was going to take her to Florida for a couple of weeks to try to recuperate and he left a statement, which I am not sure I understand exactly, but from the point of view of the practicing pharmacist, this is not only something that he can do in the office, but that he feels is important to him and it has been a very gratifying aspect of his career as a compounding pharmacist, the ability to work with these patients.

DR. JUHL: I wonder if I could ask you to clarify. You said that this treatment -- and I assume you talk about the method of the treatment, but we have three compounds. Could you clarify which --

DR. ROSENBERG: I have not used DNCB, again, as Dr. McBurney said, many of us have not used DNCB for a long, long time, since really Hopley first presented these other two chemicals to us. So, my experience is with SADBE and DPCP, apparently is a little more stable in acetone, although I am not sure of that. We have both of them available at the pharmacy.

Patients will sometimes become tolerant of one and need to be sensitized to the other, but I would hate to lose both of them. In terms of the efficacy statement, it does not have a commercial sponsor. It has not had that kind of a study, but Hopley has published numerous pictures and we have seen the same treating one half the head and the hair grows on that half of the head and not on the other half.

Then the other areas will grow hair sometimes, it seems that -- in the same that in the same way they treat few warts successfully and sometimes they all go away, the immune system is certainly active in this disease and it has become now legitimate apparently in clinical immunology to talk about immune modulating substances, which means that it is a very complicated system and we don't exactly know what we are doing but sometimes benefits accrue and I guess we can use that kind of a term here in terms of whether it is an immune suppressor or an immune adjuvant. Certainly, in warts most of us think it is an immune adjuvant.

DR. JUHL: I wonder if I could ask you to offer an opinion on the quality of science, at least as we would like to have -- we would like to have all the answers -- doesn't seem to be there.

The question I have is: Is it possible to know more if we had a better system of collecting information or is this illness so unusual and so patient specific that it is hard to do research on or is it the lack of funds to do research on? But from our perspective, we need to decide if they are to be available or to recommend whether they be available and if so, how they would be available.

I am wondering if a more systematic collection of information would yield anything, either in terms of how well the drugs work or how safe they are.

DR. ROSENBERG: I am sure that could be done in terms of priorities. I am sure it would probably not be on anybody's list. As I say, it has no commercial sponsor and I think the -- I would be surprised if the NIH wanted to do a placebo study. As far as the efficacy is concerned, I think -- again, as Dr. Okun pointed out, the Tosti study, the power was too low in a disease with a high spontaneous cure rate or recovery rate to show a benefit over placebo.

In terms of efficacy, I would say that the practicing community of dermatologists and the medical board of the Alopecia Areata Foundation, which presently includes the dean of the University of Rochester College of Medicine and a couple of very -- really distinguished serious scientists. The efficacy is there. Dr. McBurney can speak from her perspective.

I think there is no question -- certainly, it doesn't work every time, but certainly it will help some people. In terms of the safety, I think the fact that this community is concerning itself with safety must be welcomed by everybody, the Academy of Dermatology, the Alopecia Board, all the patients and all the practicing communities. That is something that none of us wish to treat patients with unsafe products.

DR. JUHL: I guess in a way I consider for lack of other sponsors, the practicing dermatologists and compounding pharmacists to be the commercial sponsors of this product. What I would like to have a feel for is could we get more information from that group if there was an organized effort amongst them to do so.

DR. ROSENBERG: I don't know how it would be organized. The Alopecia Areata Foundation raises funds and it has been giving away -- making grants of two to three hundred thousand dollars a year, but -- and, again, the board looks -- reviews the requests, but the feeling has been that science-based research, laboratory work into a function -- interreactions between the immune system and the hair follicle and some aspects of hair regeneration are more likely to move this forward and then would be a large clinical study.

There have been requests for monies to do these kind of clinical studies and they get low scores so that they have not been done. We have been looking for an animal model and there now are animal models and which may or may not be exact, but, I mean, it is that type -- in one very recent study, one of these agents worked in one of the animal models. I am sorry I don't have that reference. I don't know if you saw that.

DR. JUHL: I guess I am more looking from a practical point of view, from our decision-making process, would the academy be interested in sponsoring an IND such that when people are using this amongst your association of dermatologists, they would have a standardized product that comes from one manufacturer that we know more about, that there be a standardized collection form of adverse effects and a registry almost.

DR. ROSENBERG: I couldn't speak for them. I am not sure that I recall that kind of activity ever having been done.

DR. JUHL: I don't think it has, but I am asking would that be of interest to the academy?

DR. ROSENBERG: I don't know. For those of us that care about this disease, of course, many of our colleagues will refer patients so that I think in terms of everyday practice, lots of people could get along without it, but for the patients with alopecia areata, it is really necessary that there be some doctors who want to do this and some medicine that they can look to with some hope. They really would like to be able to continue this kind of treatment. They find it helpful and we find it helpful.

DR. JUHL: I have no argument with that. The patients have to come first, but we don't have enough good information. We could use more information. I guess I am wondering is there the will amongst --

DR. ROSENBERG: As I say, in terms of safety, we would yield absolutely to your judgment. I certainly would and I am sure everybody would. In terms of efficacy, I think we could -- if you would accept that publication of a randomly controlled evidence based placebo study in a refereed journal is the only kind of evidence, that -- and some people think that about a lot of things, we just don't have that. The nature of this would make it extraordinarily hard.

It seems to me that reasonable people looking hard, of a panel of reasonable people looking hard at the published -- even the published material, not just anecdotal, the pictures of patients and the weight of evidence that these things work in alopecia areata would conclude that they are effective for growing hair in a certain percentage of these patients.

I think -- I would not accept evidence-based criteria, as they now exist in the practice of medicine for the refereed journals and so forth and so forth. We are talking about a sort of a little by -- backwater area here of medicine that for those of us that are in it and have it, it is very important. I truly think that I would not -- would urge this committee not to assume that these things are not effective.

DR. JUHL: Other questions for Dr. Rosenberg? Dr. Sellers.

DR. SELLERS: How many patients are affected by this and what is the breakdown of peds to adult patients?

DR. ROSENBERG: I don't know that answer. It is a high -- of those that want treatment, it is a high percentage of adolescents and some children. I should know the answer but I don't.

MR. CATIZONE: Maybe if you get a clarification of the question, of your patients, the patients which you see and treat, total patients, what percentage of your patients require the use and treatment of the two products that you use?

DR. ROSENBERG: A small number. I could get by with one of them.

At the meeting of the Alopecia Areata Foundation Medical Board, which was just the last week in March in New Orleans, I asked -- I told the group this meeting was upcoming and asked them just what their experience was with it and, first, everyone there uses this treatment. Everyone there uses this treatment, which is something to say.

The second was they felt it worked about half the time. Again, this is -- a lot of experience, though, in that room.

DR. RODRIGUEZ: I just have a simple question. Since you have a foundation that you are associated with and you have just told us that at the meeting that people say -- 50 percent say it works, one of the questions that we are concerned about is safety. Most of these products have been used for over 20 years plus and even though anecdotally, do we have any way of

-- I mean, that -- these people who are highly interested in the disease and who are supporting a foundation and associated, do we have any information that might assure us of, quote, unquote, the safety of this product? It might be anecdotal, but at least it is more than what we have on hand.

DR. ROSENBERG: I am unaware of any serious problems from it. I mean, the contact dermatitis, of course, but it goes away. Jim Davis, who wrote this thing, I said, how about the problems for the compounding pharmacist. So, he rolled up his sleeve. He said, well, here I have got a little redness here. He said I was mixing someone Tuesday and he said I am allergic to it and he said every once in awhile it will bother me a little bit, but it doesn't upset me.

So that I -- one would hate to, you know, bring historical evidence that it doesn't hurt patients, but I continue to -- I think it is safe. I certainly -- compared to the systemic corticosteroid, it is not a contest. It is safe. Compared to puva(?), where there elevations of soralin(?) UVA, of melanoma 15 years later, I think it is safer than puva.

Topical steroids don't work either.

DR. JUHL: Elizabeth, Larry and Bob.

DR. MC BURNEY: Dr. Rosenberg, I have two questions, one of which you have somewhat answered. Of the three agents, which one do you think has been the most effective and is used the most frequently by dermatologists?

DR. ROSENBERG: I don't know that. To my knowledge, at least up to a few years ago, the Mayo Clinic was still running DNCB. They just never changed and then that was -- I was surprised when they told me that is what they were having. I think it was Sig Muller(?) was still there when they were doing that. But I didn't know anybody else was using DNCB anymore.

Do you?

DR. MC BURNEY: No. My impression is that it has fallen off since the other two -- in your practice, do you use primarily the squaric acid or the DPCP, would you say, equally or one over the other?

DR. ROSENBERG: Interchangeably. Mostly, I think, Hopley uses most mostly DPCP now. So, I use mostly DPCP now. He is very good. I am sorry he didn't come to this meeting. He is very, very good. He is very organized and does it in a very organized way.

DR. MC BURNEY: My second question is, and realizing this is anecdotal, just on -- but which I think is extremely valuable coming from someone like you who has treated many patients with alopecia areata, do you feel that of those two agents, the DPCP versus the squaric, do you feel of those two that one is more effective than the other?

DR. ROSENBERG: No. I think if this committee was more comfortable with the safety of one than the other and thought it would be useful to have one and just one, I could live with that, but there are patients who will become tolerant and no matter how strong you -- they say, well, it doesn't seem to make me pink anymore. Nothing happens.

Hopley has his patients come to the clinic once a week, where his -- actually, it used to be his wife painted it on when she was a nurse. My practice all along has been to write the prescription and teach the patient how to use it by -- we won't go into that -- dipping a cotton applicator into this acetone solution and waiting until it is dry and then touching it lightly and so forth for home treatment. So, both of those techniques are possible and patients will come in and say that it doesn't work anymore. They get a fresh bottle. Maybe it has gone off and they get a fresh bottle and that doesn't work and then so we will make it stronger and make it stronger and that doesn't work.

It is evident that they have become tolerant of the chemical. So, it is useful in those cases to have a second one. But that is not very common. That is rare in a rare disease with an unusual treatment. I think we could live with one.

MR. TRISSEL: A couple of points. One is I would suggest to your compounding pharmacist that he should wear some protection, particularly gloves, just as a matter of common sense.

Let me ask the people from the Agency, is there any precedent -- are there precedents set for advocacy groups -- let me ask someone from the Agency, are there examples of interest groups or foundations holding INDs to evaluate some, say, orphan drug, for lack of a better term?

DR. DeLAP: Well, there are some products that have different than conventional approaches to IND process, I would say. Not every product that is under IND is being sponsored by a commercial organization that wants to market it eventually and, of course, a lot of them that aren't held by commercial organizations of that sort are held by individual investigators, but then there are still others that are held by organizations that are interested in having a particular product available.

We do have -- there is precedent for having INDs that aren't necessarily going to lead to a product in the marketplace, where really what it is is serving as a mechanism for having a product available to people in the U.S. for a disease that is perhaps so rare in the U.S. that there is never going to be a commercial development.

I think that the reason that people are interested in that or, you know, the value added, I guess, is the way I would express it for the Agency is that then we are looking at things like how is the product produced and manipulated before it goes to the patient. So, we look at things like what is the source of the chemical? What is the purity? What are the impurities?

That is looked at under the IND process and there is at least some intent to learn as much as possible, understanding -- I certainly respect -- number one, I respect Dr. Rosenberg's experience. I also respect his -- it would be impossible to perhaps get a traditional gold standard kind of randomized control trial out there in this area. But, nonetheless, when we see these things under INDs, even if they are not headed in that direction, a lot of times there is an ability to collect some information that advances the state of the art over time, such that we can develop more experience to the best recipe, as it were, for using the product, the best way of -- you know, for compounding purposes, I mean, what is the best solvent and way of doing the compounding so we preserve the stability of the product and you get the least possible side effects from the patient.

You know, we can learn more about those kinds of things over time with the more organized research effort under an IND. So, you know, I think that that is very interesting concept and I would like to hear further as to what people think about that. I don't know if the academy would be interested in sponsoring that kind of an effort. It is not a trivial thing to do, but we always try and work with people when we know that they are trying to do something like this for a special population of people that we need to be careful to serve.

We try and work with people that are interested in organizing these kinds of efforts to make sure it is not more onerous than it has to be.

DR. JUHL: Joan.

MS. LA FOLLETTE: Speaking of these other types of INDs that aren't from a commercial manufacturer or company, might be a private physician, I am not familiar with that type of IND, as far as what type of documentation goes in, but does that mechanism provide -- some of the concerns, where we are concerned about the source of the drug substance.

I mean, is that filed as I am going to use this supplier and then that is what it is limited to, such as the way a commercial IND would be.

DR. DeLAP: Yes, we do look at the source of the product and what is known about the purity and impurities and whether there are any issues that come to the fore from that. I think you got the sense from some of the presentations that our chemists made that there is a fair amount known about some of these products and there are different impurity profiles, some of which are probably better than others in some bulk products, we would rather people use if they are going to do this, and others, we would rather they stay away from perhaps because of levels of carcinogenic impurities.

So, we do look at that and we do look at that and we do regulate that under an IND to ensure that we are getting an acceptable quality product.

MS. LA FOLLETTE: I had one more question for the speaker, the presenter. I understood in your talk, you were talking about Dr. Hopley and you said in Germany they had made some decisions based on positive Ames tests to ban -- this is what I understood you to say --

DR. ROSENBERG: That was my understanding, yes.

MS. LA FOLLETTE: Are some of these compounds available in Europe or are they also compounded?

DR. ROSENBERG: I think Hopley compounds it. He buys the chemical and compounds it. I don't think they are available as therapeutic agents, I mean, you know, from a pharmaceutical supplier, but I think they have passed -- my understanding was that the squaric acid and the DPCP had passed regulatory review there. They were two that he could use at that time.

MS. LA FOLLETTE: That may be interesting to this committee to know what source of drug substance and maybe there is a history of it being used in Europe. I mean, it just might be another avenue to collect more information since nobody enters into an IND here.

DR. ROSENBERG: It certainly is used in Europe. Just without going over it again -- just what I hoped I was able to get across in three points. One is that alopecia areata is an important disease to people and one not to be dismissed just -- it is much more important than male pattern hair loss, in my opinion -- much, much more important than male pattern hair loss. I would not contribute to a male pattern hair loss foundation or serve on their board.

I voted against propecia when I was on the Dermatology Advisory Committee last year. It is an important serious disease for some people.

Two, I would submit that if you are not convinced it is effective treatment, that it -- we could put together a group of people who would come here, admittedly not with a gold standard peer review journal, double blind placebo, evidence-based, pass all the hoops of standards, but we could come in here with enough data to convince you that this stuff works, at least some of the time.

I have no question about that. I have no question that the committee would be satisfied and I would be -- if you wanted that, I am sure we could put it together.

The third is the safety. We are very grateful that this committee is considering the safety and it shouldn't be there unless you think it is safe. We appreciate the time and effort and thought that is going into this concern very much.

DR. JUHL: Thank you, Dr. Rosenberg. I think we will stipulate to points 1 and 2. Our question is how do we make this available for the benefit of patients in the safest way and at the same time begin to move the science a few inches forward.

The suggestion that I had made earlier that that would be a -- in my opinion, it would be an excellent venture for the academy to be the sponsor of an IND and collect patient information, not in the scale of a full-fledged trial that we would like to see if we had all the money in the world, because we don't, and a kind of a registry, maybe a registry of pharmacists.

Maybe after 20 years, we find all these people develop something and we have no way of knowing because there have been no records kept. It seems to me we could bring more order to the process, which should in the long run benefit patients.

Thank you, again.

DR. ROSENBERG: Thank you, sir.

DR. JUHL: We are seven minutes over our time budget. We will take a brief break and we will start the open public hearing at 10:45. So, please be prompt.

[Brief recess.]

DR. JUHL: Let us reconvene with a few helpful suggestions from our AD man. First of all, when handling the mike, handle it from the base, not from the top. Please don't touch this, meaning the top of the microphone. And also make sure that you pull it so that it is as close to you as it is to me. If it is some distance away, he turns up the power so that you can be heard and that is where the feedback comes from. So, if we could follow good microphone etiquette, we will see if we can improve on the quality of the sound from here on in.

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