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Agenda Item: Questions from the Committee

DR. JUHL: Questions of clarification for our speakers?


DR. RODRIGUEZ: I have some questions. Maybe I misunderstood it, but there is quite a number of reports of, quote, unquote, side effects in here of recent vintage. That suggests to me that there is, quote, unquote, an objectionable ratio of side effects to use or aquatic use of the medication. So, I was wondering about that part.

The other one that I was wondering about is in some of these studies where it has been used for alopecia areata, have they reported the number of side effects in those groups because at least you get a general idea. I am not sure that -- obviously, this is not my field, but I am just looking at it from the scientific point of view.

The third thing is a study that compares 20 versus 35, the power of that study must have been very, very, very low. You know, from other areas of the literature you have anywhere within 9 percent and 50 percent. So, again, I have questions about random trials that are that small.

I am not -- I don't use this medication, but I am just raising this concern from a curiosity point of view.

DR. OKUN: Your points are certainly well-taken. It is very hard to assess from a review of the literature what the denominator is. In other words, how many patients are using DCPC and not having any problems. Nobody is going to write up a case report of a patient who doesn't have an adverse event.

All we have a sense of are the numerator, rather than the denominator. Your point also about the randomized trial is also quite valid. In general, I am not sure how much weight you can put on a single trial with relatively small numbers. Again, our responsibility is to look at what is out there.

This is the only randomized placebo controlled trial. Everything else was open label.

DR. LIEBMAN: I am concerned about the fact that you keep talking about long-term use, long-term use. Repeatedly, you have heard Dr. McBurney say it is not used long term and with respect to hair loss, if you discontinued the medication. Is that not true with menoxidil(?) also? And is that not true of rotepropecia(?)? Would you say is that then a downside of those two drugs also or is that just a reality that says when you are taking hair growth medicine, hair grows sometimes when you stop taking the medicine.

The hair that has grown tends to not continue growing. I mean, it sounds like it is presented as if that is bad. I think that is just part of the drug. It goes with other drugs in the same light. The same kinds of drugs give those same kind of side effects.

DR. OKUN: I think Dr. McBurney has characterized the natural history of alopecia areata very accurately. Individual episodes may not necessarily be very long and individual treatment may only need several months to reverse the loss.

However, my impression is that alopecia areata is a long term disease in which there are periods where disease activity has remitted and periods where that exacerbates. Each individual treatment duration may be several months, but most patients who were in the literature, reviewing their case reports, they may need several treatments over the course of an extended period of time as their disease waxes and wanes in severity.

DR. LIEBMAN: You are right, but you keep saying "it may," as opposed to there is documented evidence that it does cause. My concern is that there is kind of the, I guess, implied threat -- and I know that is not what you are saying -- that maybe if you use it long term, maybe you will have side effects.

To me, that skews it a little bit and I am not sure that is not what you are trying to do.

MS. AXELRAD: If I could just make a comment and you might respond, but, basically, I think for approved drugs, for drugs that are approved treatments that we have reviewed, they have been put through an extensive battery of tests to show what the consequences are of whatever use it is going to be put to on the label.

There are, you know, reproductive toxicity tests, carcinogenicity tests and all that -- our experts, you know, elaborate on that, but basically these compounds, we don't have any of that kind of evidence on. I think that is the contrast between the approved drugs and the ones that we are considering here.

DR. O'CONNELL: Dr. O'Connell, Department of Dermatology and Dental Drug Products.

That is essentially what I was going to point out. With an approved drug, there is informative labeling for the physician and the patient so that they can make a judgment, based on the evidence for efficacy and the strength of that evidence. And the known risk, true, all risks aren't known at the time drugs are approved, but at least the risks that are known at the time of approval and then labeling is updated.

But the other point I would like to make, since I am filling in for Dr. Welkin, I am going to steal a statement that he likes to point out to us when we discuss things. The absence of evidence is not evidence of absence and the fact that we don't have this information certainly, I think, weighs at least as heavily as the facts would weigh if we had evidence that they were unsafe. See what I am saying? We don't know is the bottom line.

All we have is what is published, but that doesn't mean that because things aren't out there, that they are not occurring, because it is not published that it is not occurring.

DR. JUHL: I believe we are bouncing back and forth between safety questions and questions of effectiveness that we don't have good information for. I believe if we took Assessment 6 that Dr. Okun presented to us, it says that there is limited evidence of long-term effectiveness. There may be a variable cosmetic quality of the response and the hair may be lost if therapy is stopped. We could put any of the drugs that are used to treat that malady in there and have the same criticism be made of them.

The difference between those drugs that had been labeled as safe and effective, it is more on the safe part and the effective is with quotes around it, I guess, the regulatory meaning of "safe" and "effective."

So, I think we really have a difference in safety and a safety in chemistry and controls and so on that we have with commercial products as the major focus here. We aren't going to have good information. We are not going to have the kind of information you folks are accustomed to looking at, but we are dealing with those patients that didn't fall within the whatever percentage of response. The question we will have to deal with then is is there a way to make other alternatives available for people, but above all, we don't want to do harm and it would be nice to know we had some indication that they worked.

Are there other questions or clarifications? Yes, go ahead.

DR. PECK: I will be probably be going back to this on other compounds. It is a little of a concern to me about multi-commercial sourcing. Then we get into the second thought about poor analytical procedures to evaluate the particular compounds.

The statement about well-characterized physical properties, I am not sure that there are well-characterized chemical properties. Some are mentioned, but it is not that complete.

A good remark is made about the impurity profile may vary with source. That, in turn, will carry over to the patient response if the material is not, quote, as good as one would like to have a clinical application.

So, my thoughts are about the inability to have a good feel about sourcing.

DR. JUHL: We shall then move to our third drug in this category, squaric acid dibutyl ester. We have the same cast of characters from the Agency, please.

Agenda Item: Squaric Acid Dibutyl Ester

DR. HATHAWAY: Again, I am Steve Hathway, Derm and Dental Drug Products. Now I am speaking about squaric acid dibutyl ester.

Squaric acid dibutyl ester is a low molecular weight small ring organic compound, similar to DPCP. And the physical and chemical properties resemble those of carboxylic acid esters. A number of reports published in the chemical literature have established the physical and spectroscopic properties of this compound. It is, therefore, possible to confirm the identity of this material from various sources by comparison of its properties with these known values.

The stability of SADBE has been evaluated by examining the known chemical reactivity as published in the literature. Squaric acid dibutyl ester does not appear to have sensitivity to moderate amounts of heat or to exposure to light, though its structure suggests that there may be a photochemical reactivity.

Squaric acid dibutyl ester has been reported to be unstable in water solutions. This hydrolytic activity varies with the pH and is fastest in basic solution. The hydrolysis also occurs in acidic and neutral pH.

About the synthesis, there are several published methods for synthesis of squaric acid dibutyl ester and related compounds and there are also several commercial suppliers. However, it is not known what methods are in use for the production of this compound.

The literature reports are primarily concerned with the methods of synthesis and there is little or no information reported regarding the identification or characterization of any synthetic impurities or degradation products in the bulk compound.

Finally, quantitative methods of analysis have not been published. They are typically semi-quantitative in the published literature. Thus, we are unable to evaluate how well, if at all, impurities are measured.

Lastly, our assessment of the chemical properties and behavior, squaric acid dibutyl ester's physical and spectroscopic properties are adequately established in the published literature. The material is stable to heat and light under normal conditions. It is known to be unstable in aqueous solutions at all pH's and also in solutions where there is a trace presence of water and, thus, this would limit their choice of vehicle.

And numerous sources and methods of production indicate that the impurity profile may differ with the source and the uncertainties of analysis may be of concern.

Thank you.

DR. BROWN: I am Paul Brown, still. I will summarize the safety information available from the literature on squaric acid dibutyl ester. Squaric acid dibutyl ester is not mutagenic in the Ames assay and it does not cause transformation of hamster kidney cells in vitro.

There are at least two synthetic precursors of squaric acid that are potential contaminants of squaric acid dibutyl ester, hexachlorobutadiene and tetrachloro-2-cyclobutene-1-one. Hexachlorobutadiene is carcinogenic in rats and tetrachloro-2-cyclobutene-1-one is carcinogenic in mice.

Squaric acid dibutyl ester has been shown to penetrate human and mouse skin in in vitro experiments and experiments in hamsters have shown that the dibutyl ester of squaric acid is a more potent sensitizer than the diethyl ester, demonstrating that the different esters are not toxicologically equivalent.

Then this is a table that summarizes the safety information about squaric acid dibutyl ester. Again, the bacterial mutagenicity is negative and information on other aspects of squaric acid dibutyl ester toxicity has not been reported, although there may be some carcinogenicity of potential impurities.

Then Assessment 2 in the written review also summarizes the information that two potential contaminants are carcinogenic and given the lack of additional studies, other potential toxicities and teratogenicity of squaric acid dibutyl ester are not known.

DR. OKUN: Our assessment of the human safety of squaric acid dibutyl ester is that its characterization is limited. There have been side effects described in the case reports. Some are local, manifesting as blistering, itching, eczema. That is fairly common; less commonly, pigmentary changes occur.

The following systemic side effects have been reported: fever and arthralgias, severe generalized dermatitis, distant local dermatitis, generalized pruritus without dermatitis. Clearly, these side effects do not necessarily have to be localized just to the site of application.

We have a clinical picture of a typical blistering reaction with squaric acid dibutyl ester. I think in this case, the health care provider has overshot his or her goal of inducing allergic reaction. This is a little too much. It is hard to titrate.

We have already covered this. Approved alternatives for treatment are the same as with the DNCB and DPCP. So, I think we should skip this.

Historical use of squaric acid, the first reported use in 1980 for treatment of alopecia areata and it has been used as an experimental treatment alternative for alopecia areata, 14 reports in the literature and for warts there is one report.

Evidence for current widespread use is not apparent.

The typical method of use, again, is analogous to what was described for DNCB and DPCP, a sensitization and then an elicitization phase.

Review of its use for treatment of alopecia areata response rate, which includes a cosmetically acceptable or partial regrowth rate, ranges from 29 to 87 percent, with a weighted average of about 59 percent. In the largest study, the response rate was 65 percent, a relapse rate of 50 to 70 percent, even with continuation of treatment.

Again, these studies were predominantly open label, internally controlled.

It is unclear if squaric acid is more effective in patients who are recalcitrant to other treatments.

The same study that was mentioned earlier for the DPCP, another arm compared efficacy of squaric acid against placebo and the numbers are comparatively small, 44 patients on squaric acid, 20 patients on placebo; no significant difference in outcomes.

Our assessment of evidence of effectiveness, limited evidence that squaric acid is effective in the long term treatment of alopecia areata or warts. Treatment may provide increase of hair of variable cosmetic quality during treatment. The hair gained on treatment may be lost even with continuation of therapy.

Our conclusions are that there may be variations in the impurity profile of bulk SADBE. There is limited evaluation of the safety in terms of long-term toxicity, both dermal and systemic, in terms of reproductive toxicity, in terms of carcinogenicity and the photocarcinogenicity.

There is variable effectiveness with limited evidence of long-term benefit.

Thank you.

Agenda Item: Questions from the Committee

DR. JUHL: Additional questions of clarification?


DR. MC BURNEY: I don't want to get technical and bogged down in studies, but I would like Dr. Okun to elaborate a little bit because the study you mentioned by Antonelli Tosti in 1986 that compared the difference immunogens, that is, the topical agents versus placebo, I believe that particular study dealt only with very patchy alopecia areata. There was less than 40 percent of the hair loss.

The real use of these agents are in patients that have very widespread alopecia, recalcitrant alopecia areata. I certainly would agree with your conclusion and that is that people with very limited areas of alopecia areata are the patchy areas, say, one to ten areas less than the size of a dollar, a silver dollar, are going to have a normal response of resolution. Whether you treat them or not, they are going to get better.

I certainly concur with your point, but I do think we need to realize that there is a smaller subgroup out there of patients with very severe widespread non-responsive alopecia areata. I want to make that point and please correct me if I am not portraying that accurately.

DR. OKUN: My recollection is that most of those patients in that study did have comparatively little hair loss. I am trying to recall the details of the entry criteria. I can't remember off the top of my head.

Your point is well-taken. I am not certain that one can be confident that the responsiveness in limited cases is substantially different than responsiveness in widespread cases. But certainly it is a small study. I am not sure how generalizable the results are. That is what is out there.

MR. CATIZONE: Mr. Chair, I have a question of clarification but not to the technical aspects of the products, but more in general of process and the committee's responsibility. So, I don't know if you want those now or at the end of the discussion?

DR. JUHL: Is it something that someone could answer in two sentences or less or will this lead to a discussion? I guess I will let you use your judgment.

DR. OKUN: More than two sentences.

DR. JUHL: Shall we save it for our discussion session?

I would like to move now to the presentation by the American Academy of Dermatology, nominators of these compounds, Dr. William Rosenberg, professor in the Departments of Medicine and Preventive Medicine at the University of Tennessee.

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