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Agenda Item: 3,4-diaminopyridine

We will now move to 3,4-diaminopyridine. We will then have an open public hearing where both compounds will be discussed and then the committee will deliberate on both compounds following that.

First, we have Dr. Donald Sanders from Duke University, who will talk to us on his experience of 3,4-diaminopyridine.

DR. SANDERS: Thank you.

I am going to be talking about the use of 3,4-diaminopyridine in neuromuscular diseases, predominantly Lambert-Eaton Myasthenic Syndrome. For the last 11 years, I have held an IND for 3,4-DAP, primarily to use it in Lambert-Eaton Syndrome. So, I am going to start with an introduction to that condition.

This is a very rare neuromuscular disease, affects probably fewer than a thousand, 1,500 people in the United States at any one time. The exact numbers are hard to come by because it is quite frequently undiagnosed or misdiagnosed.

It is a condition that affects muscle strength, begins typically with weakness of the legs, progresses to the arms. The clinical findings that lead us to the diagnosis are listed here. We find weakness in the hip and shoulder muscles. Tendon reflexes are reduced. Most patients have some evidence of autonomic dysfunction, particularly a dry mouth and occasionally they have weakness of the eyes or muscles that control their chewing, swallowing or talking.

It results from an autoimmune attack against the voltage gated(?) calcium channels on the presynaptic motor nerve terminal. Actually, the condition affects many nerve connections in the peripheral nervous system, but the one that produces the weakness is diagrammed here. This is a neuromuscular junction, presynaptic nerve here, postsynaptic muscle membrane here. On the tips of the folded postsynaptic membrane are located the receptors, which receive the acetylcholine that is released from the nerve terminal.

In the Lambert-Eaton Myasthenic Syndrome, there are antibodies directed against the presynaptic voltage gated calcium channel. These antibodies block the release of the acetylcholine and that produces the weakness.

These antibodies act by cross-linking the voltage-gated calcium channel, which leads to their down regulation, reduction in numbers and there is also some evidence that the IgG, the antibodies, actually block calcium influx through the calcium channels.

About 50 percent of patients with Lambert-Eaton Syndrome have it as a paraneoplastic syndrome; that is, it results from an underlying cancer, usually a small cell lung cancer.

These are cancers that predominantly, if not exclusively affect smokers and, thus, if a patient with Lambert-Eaton Syndrome is over age 50 and has a history of smoking, they almost undoubtedly have a small cell cancer.

In these patients with cancer, presumably these cancer cells, which are rich in voltage gated calcium channels induce antibodies that cross react with the nerve terminal voltage gated calcium channels. In the 50 percent who do not have an underlying cancer, then, presumably, this disease is a part of a more general autoimmune state.

These are the ways that we go about treating Lambert-Eaton Syndrome once it is diagnosed. The first thing we do is to look for an underlying cancer and treat it if it is found. Many patients will -- if they are successfully treated for cancer, will have improvement if not resolution of their weakness and, thus, sometimes don't need any further treatment.

However, the majority of patients do need treatment. This is a disease that produces variable degrees of debility. Most patients have moderate to moderately severe dysfunction, which means they are able to carry out their activities of daily living, but not their normal activities. Rarely, the disease produces such severe weakness as to be life threatening.

We begin treatment by seeing if they will respond a cholinesterase inhibitor. Mestinon is the one that we use most frequently. It doesn't usually do very much, but occasionally some patients will get benefit, particularly in some of their autonomic symptoms.

Based on our experience and the experience of others throughout this country and throughout the world, we considered 3,4-diaminopyridine to be the next treatment of choice, if it is available. If it is not available, then guanidine, which is an agent that has been used for many years to treat Lambert-Eaton Syndrome is sometimes used. It has a very high toxicity profile, however, and most people who have used it, including the patients who have used it, would prefer not to.

We do consider the use of various forms of immunosuppression in these patients, depending upon the severity of their disease and how well they respond to 3,4-diaminopyridine. Things that have been used with variable success include high doses of steroids, such as prednisone, other immunosuppressants, such as azathioprine(?) or cyclosporin, plasma exchange or high doses of IV Ig also can produce significant, though temporary, improvement.

In these patients, even if we don't find a cancer initially, we frequently and periodically reassess for the presence of cancer, which may not have been detected initially.

3,4-diaminopyridine has been used in the treatment of Lambert-Eaton Syndrome now for -- I can't see the date -- is that 1984? Okay. That was the first report of its use in Sweden. The reports were so enthusiastic that whenever or wherever it could be obtained, it rapidly became the treatment of choice everywhere in the world, except in this country, where it has not been available, other than on protocol.

3,4-DAP, like 4-AP, blocks the voltage gate, voltage dependent fast potassium channels in their closed state, which prolongs the falling phase of action potentials throughout the nervous system, which then enhances the calcium entry into the nerve terminals, which then enhances transmitter release.

These are some slides made from studies we did more than 20 years ago on 4-AP in action potentials from normal and myasthenic patient muscles, just to show what it does to an action potential. This is a normal muscle action potential and this is its prolonged form after having been exposed a low concentration of 4-AP. This is what 4-AP does to Lambert-Eaton Myasthenic Syndrome neuromuscular junctions. We infer that 3,4-DAP, which has a very similar mechanism, does the same thing.

Here on the top we see in plate potentials recorded from the post-synaptic muscle, initially in a controlled solution and then at various times after 4-AP is introduced into the solution, showing the enhancement of the amplitude. Here at the bottom is just a longer term diagram of the same thing. The amplitude increases and ultimately becomes normal and effective in producing muscle activation.

This is a slide from that initial report from Hoken(?) Lund(?) and his co-workers from Lund, Sweden, showing what happens to the muscle respond that is elicited by a nerve stimulation in a patient with Lambert-Eaton Syndrome, after administration of initially -- this is diaminopyridine by itself and this is diaminopyridine with an acetylcholinesterase inhibitor at the same time, showing that the action of these two works -- the actions of these two are synergistic and much more than either alone.

There has been one controlled study of DAP published to date. This is a study by Katy McEvoy and Tony Windebank and others from Mayo Clinic, which was published in the late eighties. This was a small series of patients, but the benefit both in terms of their function, the electromyographic muscle recordings and autonomic symptom improvement in patients receiving it for Lambert-Eaton Myasthenic Syndrome.

We have been using it since 1988 for this purpose and to date have treated 53 patients with LEMS. We have had a couple of blinded studies, the most recent of which has just been completed under sponsorship of the orphan products program and the results of which, although we know what they are, I haven't got the data to actually show you the numbers. But this is a summary of the clinical response in these 53 LEMS patients that we have treated so far.

Forty-five percent had a marked improvement. By that, we mean they achieved relatively normal functions of activities of their daily living. Thirty-four percent had moderate improvement, which means a significant improvement in their lifestyle and a smaller percent had either minimal improvement that was not enough to justify continuing its administration and a very small number had no response to DAP at all.

The obvious conclusion here is that in this disease for which there is no other really good treatment, the overwhelming majority gets significant benefit from DAP.

This is a slide for a press release -- you can use this if you like -- showing a patient with Lambert-Eaton Syndrome before and after she received a single dose of 15 milligrams. Here she could not lift her arms over her head and here she was brightly smiling and reaching for the sky. She was delighted when I told her I was coming here and I was going to show her picture. She is one of our enthusiastic customers.

These are some measurements from the most recent study that we have completed. We did a study that involved the treatment of 26 Lambert-Eaton Syndrome patients. It took us five years to accumulate these, but these are the data using as a measurement of efficacy a quantitative function score, which involves timed measurements of the function of various muscle groups in the body that is then summated.

We see that the scores in the patients who receive placebos -- this is the change in their QMG score from a baseline -- is really no different from the baseline value here; whereas, after the administration of 20 milligrams DAP three times a day for five to six days, their QMG scores had significantly fallen.

This just shows the change in QMG score amongst these patients, comparing those who had received placebo, virtually all of whom had very little or no improvement in their QMG score versus the patients who had received diaminopyridine, showing that there was a variable change in this score, but virtually all patients had significant improvement.

Similar observations on the muscle measurements that are used to quantitate the severity in this condition, the compound muscle action potential, which is the size of the electrical response you elicit from a given muscle when you stimulate its nerve. Here on the left, the placebo group showed no change from their baseline values after five to six days; whereas, the amplitude of this muscle response was significantly higher in the patients who had received blinded diaminopyridine.

This study involved an initial blinded phase and a subsequent open label phase during which we optimized the dose to determine the best dose response in individual patients. These are the ultimate doses that we determined to be optimal in the 24 patients, who ended up taking open label drug.

The dose was sometimes as low as 20 to 30 milligrams a day, but occasional patients took doses up to 80 or even a hundred milligrams a day to achieve their optimal benefits. So, there is a variable dose requirement in this condition among patients.

After determining the optimal dose in patients, we then added Mestinon to it to see if that would make them better or if not, would allow us to reduce the dose of DAP to a lower level in order to avoid side effects.

Patients require anywhere from 5 to 25 milligrams per dose in order to achieve their maximum benefit. It is administered every three to four hours during waking hours and in almost all patients, the addition of pyridostigmine, Mestinon, at a dose of 30 to 60 milligrams, three or four times a day, significantly prolongs the duration of action of the medication and/or increases its maximum response.

The side effects are usually trivial. Perioral and digital paresthesias are reported by most patients, who take doses higher than 10 milligrams, these paresthesias occur usually 10, 15 minutes after the patients take a dose and are rarely unpleasant. In fact, I have some patients who tell me that it is actually a nice little buzz.

If the dose is taken late in the day, it has produced insomnia in some patients. Seizures are a problem if high doses are used. When it was initially introduced or described in Europe, doses of a hundred milligrams a day were the recommended standard and that is doses that we used initially in our protocol as well and the Mayo Clinic protocol used that dose as well.

On that dose, there have now been to my knowledge three patients who have had seizures. One of our patients did. We don't use those doses now, primarily because we have found with experience that by using cholinesterase inhibitors along with DAP, we don't need to use such high doses to get the optimal benefit. But it is necessary to titrate the dose in each patient individually in order to determine that.

Since DAP and cholinesterase inhibitors do have synergistic actions, the DAP can enhance cholinergic symptoms in these patients, cramping, diarrhea, that sort of thing, nothing really of major concern.

I am sorry you can't see this slide. I can't either. But it is just to remind me of some of the symptoms that we queried the patients about in this blinded study that we performed and it really showed that there was no -- the only symptoms that were significantly more frequent in patients receiving drug compared with placebo were related to the paresthesias that they had.

In conclusion or at least in summary of our experience, we found that 85 percent of patients with Lambert-Eaton Syndrome obtained significant clinical benefit from DAP with no significant side effects at the usual clinical doses. The benefit is complemented by Mestinon and at least at the present time it is available only on protocol or for compassionate use.

We initially obtained diaminopyridine as a purified commercial product from a commercial chemical company, but about five to six years ago, Jacobus Pharmaceutical took it on as an orphan product and has been providing it for us at no cost since then. They have recently developed a pill formulation. Initially, we obtained it as a purified powder. Our pharmacy mixed it up in capsules for us, but now we are getting it in pill form. It does have to be kept refrigerated in order to maintain its integrity.

We keep it frozen in our laboratory and send it out in refrigerated containers to patients who are receiving it. This works as long as Jacobus continues to provide it for us and we can continue to afford to pay the postage for the patients. We haven't yet figured out a way in which the patients themselves can pay for this.

The way we begin it usually is to have the patients taking 10 milligrams three times a day for two weeks and observe the response. We then increase the dose by 5 milligram increments until we have determined its maximum effectiveness based on primarily the patient's symptoms, not to exceed 80 milligrams a day.

After we have done this, we add Mestinon in graded doses to reassess the maximum effective dose and it is necessary to periodically reassess the optimum dose in these patients because the disease changes over time. We have had some patients who have had spontaneous improvement and don't need as high doses as they previously did. And we would never know that unless we had this periodic reassessment. So, that is built into our protocol.

There has been some concern about cardiac toxicity, theoretical concern, based primarily, I think, on what it does in experimental animals at high doses. To my knowledge, there has not been any report in the literature of any such effects on patients and we have not had any. But to examine the effect on the heart rhythm in the study that we did, we looked at the corrected QT interval, the QT interval and the corrected QT interval and EKGs in the patients on DAP and on placebo and this is just to show that if anything the patients who receive blinded DAP had less of a change in their corrected QT interval than the patients who were receiving placebo. But there is no difference and we don't feel that there is any significant cardiac toxicity at the doses that we are using or likely to use.

What has been the response in our experience to the other treatments? A very confusing graph, I think. Probably this table, if you can see that, is more informative. We did a retrospective study or evaluation to see how well other forms of therapy had benefited the patients that we have seen.

We compared those with the benefit from diaminopyridine and I think if you just follow the top two lines over here, you will see that percentagewise none of the other treatments even comes close to the benefit that patients obtain from diaminopyridine.

So, in conclusion, in treating patients with Lambert-Eaton Syndrome, we always go after any underlying cancer because occasionally treating that can produce marked, sustained benefit. Pyridostigmine, Mestinon, by itself is usually ineffective. Diaminopyridine is usually beneficial and even more so when used with pyridostigmine. Plasma exchange and high dose immune globulin frequently give marked, though, temporary improvement in these patients.

I don't consider these forms of therapy to be viable, long term therapies in patients because of logistics and expense, but, occasionally, they are necessary. Other forms of immunosuppression produce variable degrees of benefit in some patients, but rarely gives marked benefit and in my experience has never given patients as much benefit as they get from diaminopyridine.

I want to take just a couple of minutes to present a couple of cases to exemplify how we use it and how it has worked. This patient had the autoimmune form, non-cancerous form of Lambert-Eaton Syndrome, which began when she was 39 with proximal leg weakness, which progressed over several months to involve her upper extremity muscles. She also had some mild weakness of her eyes and bulbar muscles.

The diagnosis was made by electrophysiologic testing and no malignancy was found. She was initially begun on Mestinon, which produced some mild improvement and then she was begun on asathioprine, an immunosuppressant. Didn't really do very much. She had three treatments with plasma exchange, each of which produced dramatic but transient improvement.

She also received five treatments with IV Ig, which, again, produced some transient improvement. Steroids was given in high doses, which produced what was referred to as good improvement, but she developed a vascular femoral head necrosis, a recognized complication of prolonged steroid administration. She joined our protocol early on. She achieved dramatic sustained improvement with diaminopyridine. Her optimal dose was 10 milligrams every three hours with 120 milligrams of Mestinon every three hours.

She has now been on DAP for, I think, six or seven years and you would be hard put to get it away from her.

This is a patient who has the paraneoplastic form of Lambert-Eaton Syndrome. He was a smoker. At age 39, he began to have trouble with skiing and progressive fatigue, proximal muscle weakness over the ensuing months and the diagnosis was made seven months after onset. His cancer was not found on the initial screening, despite the fact that very vigorous screening was done. He was treated with Mestinon with no benefit. Prednisone produced slight benefit. Guanidine produced increased endurance and strength, but he had lots of side effects from it that were unpleasant and he joined our protocol in 1992.

He had a dramatic improvement with 20 milligrams, three times a day. He was able to walk. He actually went back to work. Unfortunately, about a year and a half later, he developed brain metastases, which were the first manifestations of his lung cancer. Seizures came along with that. So, we had to stop his DAP and when we stopped his DAP, he became bedridden. He died several months later of the results of his cancer, but after his death, he wife wrote me a very poignant letter in which she said he wanted me to tell you this, that you had given him two years of useful strength because of the DAP.

Thank you.

DR. JUHL: Thank you, Dr. Sanders.

Questions? Dr. Gilman.

DR. GILMAN: When I looked through this material and then hearing the commentary this morning, I was rather unimpressed with the beneficial effects in multiple sclerosis of this agent, of 4-AP, but very impressed with the benefits of DAP in Lambert-Eaton Syndrome. I also called colleagues at the Mayo Clinic, the people who had done the initial trial in 1989 with Lambert-Eaton Syndrome.

They have about 30 patients ongoing that they are treating and I would say their e-mail message reflected your experience, that it is very effective and that it is very safe. So, I didn't get any quantitative statements from these people and I wanted to ask Dr. Sanders. So, you go up to a maximum of 80 milligrams per day. What is the prevalence of seizures on that dose?

DR. SANDERS: I don't know of anyone who has had seizures on that dose, other than patients, such as the one that I just presented, who had brain metastases. He had demonstrated brain disease, which is probably the cause of his seizures.

DR. GILMAN: Do you get seizures with any lower dose?

DR. SANDERS: I have never heard of anyone getting seizures at a lower dose, other than those circumstances.

DR. GILMAN: Do you monitor the blood levels in these patients?

DR. SANDERS: No, we don't. We have not found that the dosage that we use produced blood levels that are detectible using the techniques that we have had available to us.

DR. GILMAN: Do you have any evidence suggesting that different compounding pharmacies produce different concentrations or highly variable responses in your patients?

DR. SANDERS: We have only obtained the DAP from the sources that I indicated. I wouldn't have any way of knowing whether a compounding pharmacy would be able to produce the drug at the concentrations and with the reliability that we have been achieving it.

DR. MC BURNEY: Dr. Sanders, as I understand, you have had no difficulty in obtaining the drug when a patient needed it?

DR. SANDERS: No difficulty in obtaining the drug -- well, it is a complicated process. It is a three-way -- you know, it is a three ring circus. We get the drug from Jacobus Pharmaceutical. We store it. We send it out to the patients when they need it. They resupply us. I wouldn't say we have no difficulty, but we have had no patients who have failed to receive it.

DR. MC BURNEY: So, there has been availability.

DR. SANDERS: There is availability but there are problems with the availability, as I mentioned before.

DR. RODRIGUEZ: You mentioned that things have -- the medication has to be kept frozen or refrigerated and the question that I have is realizing the realities of human beings, what is the stability, for example, at room temperature? Would it last 24 hours, 6 hours, 8 hours, 10 hours? You are giving it three times a day and that means that people will have to have access to a refrigerator three times a day. I was just sitting over here thinking as somebody who takes medications regularly, what is the -- would six hours be -- still give you the same amount of strength or potency that you wanted?

DR. SANDERS: I am going to defer any questions like that to someone who knows a lot more about that issue than I do. We keep it frozen in the laboratory until we dispense it out of just precaution. Whether it makes that much difference that it is refrigerated or not, I don't know. We haven't done the sort of studies necessary to demonstrate that.

Considering the inherent unreliability of patients in taking medications the way they are prescribed, I think that if it were really a problem, we would have heard about it from some of our patients. I am sure they leave it unrefrigerated from time to time.

MR. TRISSEL: If I understood you correctly, your initial cadre of patients were treated with pharmacy compounded capsules from raw material.

DR. SANDERS: That is correct. Through our research pharmacy at Duke University.

MR. TRISSEL: And there were successes then, I gather, using that material to lead you to believe that this was a successful product?

DR. SANDERS: Yes.

MR. TRISSEL: I notice that the distribution of patients enrolled on trials is non-uniform in the United States to say the least. That looks like North Carolina and Minnesota have the lion's share of the patients and I can't believe that the patient distribution is really like this.

DR. SANDERS: The patient does go where the drug is, sir. Our patients come from all over the United States.

MR. TRISSEL: They do?

DR. SANDERS: Yes. We turn them into Blue Devils when they get there.

DR. JUHL: This is location of the physician, not necessarily where the patients are from.

DR. SANDERS: Exactly.

I didn't mention the potential value of this medication in other neuromuscular diseases, but we and others have also used it in occasional patients with congenital myasthenia gravis, which is a very rare group of conditions for which there are few good therapies. We have had good results in some of these patients. So, that is another indication for this medication.

DR. KATZ: I just want to reiterate one caveat about the warrant of safety at lower doses with this or any drug, but here specifically. Even if it were the case that we had complete follow-up or complete knowledge of patients experiences at doses lower than a hundred -- and maybe we do have complete follow-up, I don't know -- the number of people who have been exposed to any dose, let alone a dose lower than a hundred, is pretty small, I think. I don't know what the totals are, but I think in the Mayo Clinic -- well, we have the numbers here. Okay. So, it is not that much.

So, even if you had not seen any seizures if they had a lower dose, the warrant that -- the risk that you can cap with that experience is fairly high. So, it is possible it could -- we know the drug or at least we believe the drug is capable as a molecule of causing seizures. It is certainly -- given the variability in the population, it is possible that it could cause seizures at a lower dose of -- and you can figure out what percent and you still wouldn't have seen any in this very small cohort of patients who have been exposed. So, it is just something to consider.

DR. SANDERS: We have been in contact with the groups around the world, who have had extensive experience with this. Dr. Lund now has treated patients for -- well, since before he published his first report in 1984 and the Mayo group, as you mentioned, have treated about 30 patients. So, probably the world's -- these three groups probably represent most of the world's experience with it and none of these folks, to my knowledge, have seen seizures at a dose less than a hundred milligrams a day.

The availability or entry of DAP into the central nervous system is much lower than 4-AP, as you know, and that is its main advantage in treating patients with peripheral nervous system diseases.

DR. JUHL: Thank you very much, Dr. Sanders.

Our next speaker is Dr. Jacobus, who is president of Jacobus Pharmaceuticals.

DR. JACOBUS: Mr. Chairman, the slide projectionist is Laura Jacobus. I am Dave Jacobus and I do work in the Jacobus Pharmaceutical Company. And we are a small company that actually makes the active ingredient and then makes the dosage form and then does the appropriate registration and distribution and so on.

We synthesize the active ingredient, 3,4-diaminopyridine, in addition to making the dosage form. Now, this first slide is the slide to which I think Dr. Sanders responded. There is a huge concentration of patients there. The Mayo Clinic, Katy McEvoy, Tony Windebank, and this is Constance Bowe, B-o-w-e, a pediatric neurologist, and she has patients from this part of the country all the way over to here.

She has been a very active investigator and has done preclinical work as well. Now, for this committee, this committee should understand how these patients got on this chart because these don't represent pharmacy dispensing patients because we don't have a record of them. These are the patients in our roles and these are all physician-sponsored, investigational, new drug applications.

For the major centers, such as Don Sanders center, he has his own IND and the study goes along and it is well-established. But what happens when an investigator from an isolated state has an emergency, has a patient in whom the diagnosis is made. They call us or we get a call relatively soon and we send -- for those of you who are not in either the Agency or maybe in industry, it is nice to hear how this system works.

We send a package of information to them so they can get an investigator-sponsored IND. We help them with the forms, but they have to write the letter. They send it to the Division of Neuropharm. The consumer safety officer, Teresa Wheelis(?), is very effective and if it is an urgent situation, the Agency will take the equivalent of a "Dear Doctor" letter, thank you for sending us this interesting patient, you know, the kind of thing that you do all the time, will take that thing, take the forms by fax, provide an IND number on the telephone. That physician calls us back and we can have the medication there by the following morning.

That is how -- now, for others, the medication is stored, you know. Supplies are sent to the Mayo Clinic in Rochester and to Connie, but for others, who have these isolated ones, it happens very quickly. Actually, that is one of the nice things that is nice here to say. The physicians who call are good physicians. They truly are interested in getting something for their patient that won't happen otherwise, but the Agency, whoever understood publicly that the Agency routinely supplies an IND number on an emergency basis like that. That is not the public perception. It is very nice.

Now, the next slide demonstrates the chemical structure -- and you would expect since we make it we would show it -- 4-aminopyridine is right -- 4 because it is right opposite here, 3,4-diaminopyridine is here. It is unstable. We do ship it cold. The patient doesn't have to carry a refrigerator around with him. The tablets will last a month or so at normal temperature, but not in distribution conditions. That was a good question.

Now, I would like to show the next slide. We have proposed and we proposed kind of before -- we had this system going for another drug in which we gave -- we give away another drug that was not available and now we had -- after having supplied Dr. Sanders and the Mayo Clinic, we thought that we needed to make a commitment to bring the drug to market so that it would be available so that we could put labeling in the PDR, so people would know how to handle it. Therefore, to handle these, we also thought perhaps with all of these isolated INDs roaring in, that it might be helpful to the Agency -- it would certainly be helpful to us to be able to collect all the information and to assembly the safety records, such as it is.

So, we have proposed to the Agency, and the Agency has not had time to respond, a compassionate Phase 3 distribution program, which I am going to outline to you. We do have an IND and we are suggesting this be extended under our existing IND and there is amongst other things, the patients would be covered if -- more easily, perhaps, than a physician filing their own IND.

Then there is an informed consent, which everybody agrees to and we presented it to the Duke IRB. We wished to present it to the Duke IRB because Duke has Don Sanders on their staff and, therefore, they will have a faculty member, who will really be knowledgeable about the risks and benefits.

Then we have a desire to really collect and be sure. It is a convulsant. We think you need to know an EEG. You need to know a basic electrocardiogram. We have developed suggestions of the reasons why an IND is going to help the progress of the drug come forward.

But to make it easy, we thought that we could do most of the initial stuff on the phone. We need the physician. We need all of the information on the patient because when we distribute the drug, the patient's name is on the bottle, as well as the physician's full name and address. We register the patient and we expect to receive that same "Dear Doctor" letter that the Agency receives, along with the latest laboratory information or an agreement to collect this information when the patient first comes back to the office.

On the next slide, we have written the entry criteria and I have sent the slides to Don and I have hopes that it is reasonably right, but we do expect -- the big thing in a compassionate distribution program, I think, is to make sure -- it is true in any study -- make sure that the patient who gets into the study has the disease you are wanting to study. We do really insist on that here and in the next slide you will see the pediatric.

We think it is appropriate. The management of the drug is perhaps different in the pediatric patients, but there are patients in Connie Bowe's place who if there is an hour delay in not taking the drug, then the symptoms will again appear. These, she believes, are the entry criteria that she should have for pediatric patients, but we believe that in standard practice these days, pediatric patients should be included.

Now, this is really -- these inclusion and exclusion slides are standard parts of the protocol. They are parts for our existing protocol, which was primarily dovetailed into Duke. This is what we are expecting to apply broadly and we are planning, however, to put the drug always on top of pyridostigmine.

The next slide shows this exclusion criteria and the next slide. We have rules for this compassionate thing, based on our existing things. We ask that the physician -- if we have to do this fast emergency distribution, there won't be time to get an informed consent because you will shift the medicine and the patient may not be in the office then and so on. So, we ask that the physician start the product only after having had the informed consent signed and in this case obtained the basic entry data.

The tablets are designated only for that patient in a system analogous to the named patient system in the United Kingdom. If that physician has another patient, then that new patient requires another registration. We do receive requests to send sometimes tablets to the patients, but the tablets are sent to the physician's office. There are an occasional -- there are enormous distances in the Midwest sometimes. North Dakota, you can be a thousand miles away from the patient under your care. But we then act as the physician's -- we do that only with established physicians and we act with their -- as their shipping agent.

After one month in this study if the informed consent has not been received back from us and if the patient has not been benefited or the laboratory data is not up to speed, that patient is out. We have one difference here, which was shown in Dr. Sanders' slide. The proof of continuing benefit, 3,4-diaminopyridine is unusual, very unusual amongst medications. There is no fundamental benefit to it. Maybe helping breathe is an important thing. Improved muscle power is important. There is nothing on the underlying effect of the disease progress.

One can stop the medication and all of the symptoms will immediately return. Start it again and they will immediately go back to where you were before. And this forever and forever, for years and years.

We have proposed -- we had said in our first IND and we have said in our compassionate application, that we think that the proof of continuing benefit is something that actually should flow through to the labeling. That is to say, periodically the patient should be retitrated or perhaps one should take advantage of accidental compliance problems. Went to visit his son at graduation and forgot to take something or missed out on a dose and -- or if there has been no evidence of an accidental non-compliance, then our protocol will require a dose delay, a dose reduction or a dose vacation.

We think by that there will not be a tendency amongst patients to -- that will teach the patient, yes, the medicine is good. That will teach the physician it is good. It will also teach them the opposite. If they don't need it, they don't need to take it.

We have made a very simple scale, a global response. We have pediatric endpoints, which are equally easy to obtain.

Lastly, we think it appropriate because there is a rumor, you know, how can you get 3,4-DAP sometimes. We think it appropriate and we have done it before in the past in other programs, that we let the attending physicians who are liable to receive these patients know of the availability of the compassionate IND. So, when that is approved and when we are set to go, we will do it.

Thank you.

DR. JUHL: Questions. Elizabeth.

DR. MC BURNEY: Actually, I have a comment to make and I want to on behalf of patients that have another disease, called dermatitis herpetiformis. Dr. Jacobus's company has made available at no charge another drug called sulfapyridine and this program has been in effect for a number of years. I have had some patients participate in it now that I know for at least six or seven years. So that there is a track record here of this type of program working and working very successfully.

I think that should be taken into consideration and I wish to thank you for that.

DR. JACOBUS: Thank you.

DR. JUHL: Questions of the committee? Sir?

DR. SANDERS: I would just like to make a comment about a question that was addressed to me and perhaps I didn't answer it entirely. It had to do with any problems that arose during compounding of the drug before Jacobus began making it as a pill.

It was packaged in capsules by our research pharmacy and during the seven or eight years we used that, we would quite frequently get calls from patients after they had received a supply of the medication asking if we had changed it because they thought it wasn't working as well as it did before or they would tell us, well, you know, you get a super capsule every now and then and some of them are just duds.

We had no way of knowing whether that was true or not. We would have them bring their capsules in. We would analyze it to see if there was any variability. We never convinced ourselves that there was. Whether that is a problem in the compounding or whether that is placebo effect, I have no way of knowing, but I can tell you that if it is put up in a pill, that is not a question.

DR. GILMAN: I would just like to know whether the company will continue to make this drug available if it is put on the list of drugs that can be compounded?

DR. JACOBUS: We have made it available for nine years or I think nine -- we were trying to discuss, eight or nine years and as far as I know, compounding is possible now and I see no reason -- I think I am neutral on this issue. I think that pharmacy is a very important branch of us and we have pharmacists in our employment. We all depend on pharmacists for dispensing. They are part of the system. I think it is a more difficult thing to do and I think that there is a lot of things pharmacies can do.

I am not sure whether pharmacies want to handle things like this but I think that the advantage of making a systematic way of handling it -- I am neutral on it. I am not an expert in that. I hear the thing -- we will continue to answer your question. We think that we have to collect the data. We think we have an obligation to make it available. We have had our troubles with supplies and manufacturing and all the rest of it.

There is a lot more commitment of the Agency than when you market it, you know. They will need tons of extra data and the district office visits and -- it is a true commitment. We will bring it forward.

DR. JUHL: I would like to echo Dr. McBurney's comment. It is a pleasure to see a good patient oriented system that has been under operation for a long time. It gives us reassurance.

Help me understand the entrance criteria that you have outlined. Amongst neurologists in the area, are these criteria sufficient to distinguish between patients who have the syndrome and those that don't? Or are you looking for a more severe group of patients with which to collect data?

What I am wondering, are there people who wouldn't make it in to your protocol because of the level of the entry criteria?

DR. JACOBUS: I personally think the answer is "no," but Dr. Sanders is here and his answer ought to prevail.

DR. SANDERS: There might be rare patients who don't meet those entry criteria, but these criteria were actually based on our experience in analyzing these factors amongst the patients that we have diagnosed with Lambert-Eaton Syndrome. But since it is such a rare condition, there may well be patients who have an unusual form or a very mild form of it. One could then ask whether they would really need this therapy at that point.

I don't know whether those criteria are open to discussion on an individual basis or not. I would think perhaps so. A lot depends upon the experience of the physician in dealing with this disease. There are not many people who see lots of these patients because there are not many of them out there.

DR. JUHL: Few have your level of experience. I am just wondering how many arguments you get into over the criteria at meetings when --

DR. SANDERS: I can certainly envisage a scenario where someone would call me up and say, listen, I have got a patient. I know he has got LEMS because he has got lung cancer and this, that and the other, but he just doesn't happen to make 50 percent facilitation. I would say he has got LEMS. But I don't know whether Jacobus will be able to make that --

DR. JUHL: Thank you.

Any other questions -- oh, I am sorry. Go ahead, Dr. Jacobus.

DR. JACOBUS: Let me add to that that there is built into the trial the patient itself having -- patient having an opportunity to stop and start. It is built into the informed consent. It is designed -- we originally had a double blind, but not in the compassionate one, so that I think if you have that in as a safety device, then you can allow patients in and see what happens.

So, I think that if a -- I think in our other trial, we have with sulfapyridine, we had originally limited it just to dermatitis herpetiformis, but then there are other conditions that dermatologists use the medication for and we referred those to the Agency and then the Agency said please broaden those things so that we don't have to get all these calls.

I think, actually, with a built-in device, one would tend to allow a trial to see if there was a benefit or not because that is part also of determining the limits of where it works or it doesn't work in writing effective labeling.

MR. TRISSEL: I was glad to hear that it doesn't sound like the cost of the drug would be an issue for patients. It does sound like the cost of transportation to a site might be an issue for patients, who don't have the personal resources to afford that. Am I correct in that?

DR. JACOBUS: It has been more of a problem for Dr. Sanders than it probably would be under the compassionate IND because we send stuff in a little cooler, like you kind of see at a baseball game. Then we send a call tag the next day to pick the cooler up. So, both of those transports are borne by us. What we say in the informed consent, this draft informed consent, that the Agency has yet to see, is that the patient or the physician or the service or whatever has to bear the cost of the laboRatory. We will not cover that in any way.

MR. TRISSEL: So, for patients who have Medicaid or something like that, they are not really eligible for this? There is no funding for somebody in Nebraska to come to Duke to be put on this program and then --

DR. JACOBUS: That is true, but on the other hand, there is no funding from a compounding situation either.

MR. TRISSEL: Well, there are charity hospitals that do provide indigent care.

DR. JACOBUS: Then fine with us. Let them provide it.

MS. JACOBUS: We provide the drug free of charge and the hospital in which the neurologist is affiliated foots the bill. So, it is an indigent program because we don't have a -- we don't charge anything for our compound or the shipping on that.

MR. TRISSEL: Right. And that is different than the previous compound, which the patients have to pay for presumably out of their own pocket.

MS. JACOBUS: I don't know about that.

DR. JUHL: So we don't get confused now, the expanded access that you are proposing would have expanded numbers of investigators so they wouldn't need to come to Duke or to Mayo or they would need to come to Duke or to Mayo?

DR. JACOBUS: They would not come to the main centers to date. The main centers to date have been after us to get the program forward and I have told Dr. Sanders that I think he is actually been instrumental in bringing the drug to a point where we know enough about it that, in fact, it can be considered for development.

DR. JUHL: Good.

DR. SANDERS: Could I just make one point? I want to pick up on the comment made about the hospitals bearing the cost of this. My hospital doesn't bear the cost of this and I don't know that there should be any official expectation that any hospital should take up these costs. These are societal costs.

DR. JUHL: Other questions?

[There was no response.]

Let me first of all apologize for getting us behind. We are. We should have had the open public hearing at 3:15 and we are almost an hour behind and I apologize both to the committee and especially to our participants in the open public hearing for making you wait.

Let us go to that portion of the program now.

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