Center for Drug Evaluation and Research

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My focus for today's meeting, however, is to help you understand why fampridine, which is also known as 4-aminopyridine or 4-AP, should not be considered for routine pharmacy compounding. I would like to provide you with some background understanding of fampridine and the particular difficulties associated with its compounding that could affect its safety and effectiveness in its performance, particularly in patients who are often quite ill and frequently on multiple pharmacologic regimens.

Fampridine, as you have heard, is a potassium channel blocking agent, which is currently in clinical development for symptomatic treatment in multiple sclerosis and spinal cord injuries. The clinical development is conducted under an IND, sponsored by Acorda Therapeutics.

Dr. Ron Cohen of Acorda will address you as well following my remarks.

Although Acorda is responsible for the clinical development programs for fampridine, Elan has been involved in the dosage form development aspects of fampridine and we supply the clinical trial materials. We believe our experience in the development of the fampridine dosage forms is important to your understanding regarding its suitability for routine pharmacy compounding.

Over the last six years, we have conducted a range of formulation development activities with fampridine covering immediate release, IR, and modified release, MR, dosage forms in both capsule and tablet presentations while the preclinical and clinical development activities for fampridine were progressing.

From our immediate release development experience, we demonstrated product performance, which indicated linearity across a dosage range of 10 to 25 milligrams, a half life of approximately 3 1/2 hours, a considerable food effect with a maximum concentration that was lowered by 50 percent and an AUC that was lowered by 15 percent, a narrow therapeutic index, particularly evident with significant CNS side effects, which appear dose related in MS patients.

Therapeutic levels, as you have heard, were on the average range, 20 to 70 nanograms per ml, with serious side effects often observed in excess of a hundred nanograms per ml. As Dr. Bever mentioned, this could vary. We experienced numerous formulation challenges in developing either the tablet or capsule dosage forms of fampridine.

For the tablet formulation, there were significant interactions with diluent, loss of potency on stability, which was directly related to temperature, humidity and container. For the capsule formulation, we saw significant excipient interactions as well, stability problems, which included loss of potency and unpredictable product release, along with drug migration into capsule shells.

This experience background led us to develop a specific modified release or you have heard sustained release formulation, which was designed to address some of these features, specifically the modified or sustained release product, provided the same extent of availability as with an IR formulation, although reduced the C-Max, thereby reducing peak-related side effects, providing minimum peak to trough(?) variability, if you would, smoothing out the curve, a lack of food effect, improved GI tolerability, twice daily dosing and a more stable formulation.

Even during this modified release development, we continued to experience formulation difficulties, which was consistent with our IR experience. This included, again, polymer interactions, excipient interactions, container material interactions and degradation products.

We are aware of the availability of pharmacy compounded formulations of fampridine, both foreign and domestic. We required a random sample of fampridine from two different compounding pharmacies for analysis. We recognized that as these were randomly selected samples, they may not adequately represent the findings of a broader sample. However, we thought the findings would be of interest to this committee.

In the first sample you see here, identified as Colorado, we conducted content uniformity assessments of nine different capsule specimens. Although the target content here was 10 milligrams, actual content ranged from 8.8 to 15.6 milligram per capsule and would have failed USP content uniformity testing criteria.

Upon assay, four unknown impurities were identified on chromatograms, none of which interfered with the main fampridine peak, which was similar to a known standard of fampridine.

The second sample we obtained, identified as Maryland, again, provides a range of variability on content uniformity testing, which would fail standard USP criteria. Although capsules were labeled as 8 milligrams, they contained a range of fampridine from 3.3 to 9.2 milligram, with a significant variability.

The HPLC analysis of this sample did not indicate any presence of impurities, unlike the prior ones. Both the Colorado and Maryland samples were selected at random and the age of these capsules relative to their date of compounding would not be known.

Although these represent a limited sample, the products demonstrated a failure of the compounded products to meet USP content uniformity requirements, showing significant inter and intra sample variability, both of which could possibly be due to poor homogeneity of the actives in the sample. Unknown impurities were also identified in one of the two samples.

These results are not surprising, given our own experience in formulation difficulties and development with fampridine. We would expect that these results would only worsen if assessed as part of a formal stability program.

To summarize, our experience has demonstrated significant difficulties in compounding fampridine due to excipient interactions, polymer interactions, drug migration into the capsule shell. In addition, we observed product instability with respect to temperature, humidity and container compatibility.

Recalling that fampridine's pharmacologic, pharmacokinetic attributes include a low dose, high potency, narrow therapeutic index, with side effects related to peak plasma levels, which include serious CNS effects, as you have heard, when combining the formulation difficulties of fampridine with its pharmacologic attributes and the intended patient population for its use, there are significant risks for adverse effects.

We hope that you will seriously consider this background as you deliberate the suitability of fampridine for pharmacy compounding.

Thank you.

DR. JUHL: Well, let me ask the question that is on everybody's mind. Compounded products have significant risk for adverse effects, but, yet, your company took a group of patients who was on your product and hung them out to dry. Why did that happen?

MS. HAMM: I would admit that this is something that I am going to let Dr. Cohen address in more detail as he comes to the podium. It is really not quite as simple as it sounds and it just so happened that we were in a state of transition at the end of Chris's trial, both in terms of some formulation activities, as well as transferring of the ongoing clinical research activity to Acorda. It really was a timing unfortunate circumstance in that particular situation, but I am sure Dr. Cohen can address that as well.

DR. JUHL: Okay.

You understand one of the things we are looking for is the -- for you to inspire us with confidence and that doesn't go in the right direction for us.

Other questions of clarification?

MR. CATIZONE: Mr. Chair, while awaiting the specifics from our next presenter, let me ask the question what course of therapy is left or what alternate is left to patients if the medication is not produced by Elan or not made available? Are there any alternative therapies except for the product to be compounded by a pharmacist?

MS. HAMM: You are asking if I would know if there are alternative forms available? I mean, in a domestic sense, I am unaware of any other source.

DR. JUHL: The information that you provided us is not quantitative in terms of impurities, migration of the capsule, those kinds of things, nor have we seen serum concentration versus time to see the effect of your formulation. I presume that some of that is proprietary? Is that information -- has it or will it or is it being submitted to the Agency so that can be scrutinized?

MS. HAMM: Information with respect to the trials and data that would have been obtained from them would be under the IND. Additional information in terms of the testing outcomes on the compounded samples and any of those details, we would be glad to provide in a confidential manner.

DR. JUHL: I was more interested in your product because there wasn't any information about that. We have more information on the compounded product than we have on yours.

MS. HAMM: Sure. It is in the IND and it was because of the proprietary nature we chose not to disclose more detail today.

DR. JUHL: Okay. I guess we would have to look for the Agency not for disclosure of the information but for scrutiny of the information to be sure that it corresponds with the sense of the qualitative information we have received.

MS. HAMM: Thank yo.

DR. JUHL: Any other questions?

[There was no response.]

Thank you.

Our next presenter is Dr. Ron Cohen, who is president and CEO of Acorda and I guess Andrew Blight is presenting with you as well?

DR. COHEN: Actually, Dr. Andrew Blight is here and can answer questions, but I will be presenting.

DR. JUHL: Okay. Great.

DR. COHEN: Thanks.

I am going to depart from my prepared text for just a moment to say that since this issue has come up, I will address in the course of my remarks this issue about the compounded formulation, switching over from that long term study of Dr. Bever.

Thank you and good afternoon, everyone. My name is Ron Cohen and I am a physician and the president and CEO of Acorda Therapeutics. Acorda is a biotechnology company, which is focused on developing therapies for spinal cord injury, multiple sclerosis and other disabilities of the nervous system. Acorda is sponsoring, as you have heard, clinical development of an oral tablet form of fampridine for both chronic spinal cord injury and MS under INDs in compliance with FDA regulations.

As you have heard from Dr. Hamm, the formulation of fampridine that is used by Acorda was developed and is being manufactured and supplied by Elan Corporation. Acorda began its clinical development of fampridine in 1996. Initially, we used an immediate release capsule formulation, which was formulated for us under good manufacturing practices by an experienced pharmaceutical subcontractor.

In the course of this program, we were made aware by our subcontractor that fampridine is an unusually reactive compound and that this reactivity poses significant difficulties for manufacture of the stable formulation, using conventional approaches. Our initial formulation effort, therefore, took several months longer than we originally anticipated. In addition, we were concerned by numerous reports from patients, clinicians and the scientific literature that immediate release formulations gave significant variations in plasma levels and that these variable plasma levels led to unpredictability of both therapeutic effects and adverse effects.

We subsequently investigated Elan's sustained release formulation. We concluded, based on Elan's chemistry, manufacturing and pharmacokinetic data, that Elan had successfully translated fampridine from a compound with significant problems of dosing and side effects to a potentially acceptable therapeutic agent.

We, therefore, entered into a collaboration with Elan, which permitted Acorda to deduct clinical development of this formulation for both chronic spinal cord injury and multiple sclerosis. We also obtained orphan drug designations for both indications to help make it economically feasible for us to develop the compound.

To date, we have completed three clinical trials of fampridine and spinal cord injury and we are sponsoring this year further trials in both spinal cord injury and in multiple sclerosis. We have not yet published these data, but they are in the process of being submitted to the Agency under our INDs.

Based on our own experience and on extensive discussions with clinicians and patients, we believe that the Elan formulation is clinically useful. For example, in a Phase 2 double blind placebo controlled clinical trial that we sponsored, involving 60 subjects with chronic spinal cord injury, we were encouraged to see apparent improvements in outcome measures, including spasticity, clinicians' global impression and control of bladder, bowel and sexual function.

In addition, we interviewed 12 patients, who had experience of both Elan's formulation and the compounded formulations of fampridine. Without exception, these patients said that they tolerated the Elan formulation better and experienced fewer side effects.

However, there do remain issues concerning establishment of both safety and efficacy of fampridine that must be resolved in additional properly controlled and documented clinical trials. We have become aware that increasing numbers of people with multiple sclerosis and spinal cord injury are experimenting with pharmacy compounded formulations of fampridine. We understand that many of these people believe that they receive benefits therapeutically, but we are also aware that there are numerous reports of side effects and significant adverse events, including grand mal seizures and even status epilepticus.

In addition, both physicians and patients have expressed concerns to us regarding what they perceive to be inconsistency and unpredictability of the effects of pharmacy compounded formulations. For example, I received an urgent call from a hospital pharmacist and physician last month, regarding a patient with multiple sclerosis, who had been admitted two days earlier in status epilepticus.

You heard earlier -- this patient was alluded to by Dr. Bever. This was a patient who had been in the long term study sponsored by Elan with Dr. Bever. I think he had been on the compound for about three years. The Elan formulation, without incident, was then switched over when that study was terminated and within approximately six months had this experience of status epilepticus.

At the time I discussed this his physician, this was two days after admission and the patient was still incoherent and unresponsive, although he has since come out of the hospital.

This patient had experienced tremendous rigidity of his legs, which made it impossible for him even to sit in a wheelchair. He had tried every available anti-spasticity therapy without effect and got relief of his symptoms only from fampridine.

To respond now in more detail to the question that has been raised, the issues surrounding the supply of the Elan formulation here were, in fact, a matter more of timing and circumstance than anything. At the time that the study was terminated, Elan was in the process of transferring its entire dossier, the INDs, all of the documentation, to Acorda.

This is a process that actually took the better part of a year for us to get all the information in house and then assimilated in a way where we felt we had a grasp of it. In addition, this is a drug that is in development. So, we continue to need to have Elan formulate the drug to order so that when a given supply has been -- we run out of a given supply, we then have to place another order for the additional studies. In the process of all that and assimilating it, we felt that we really didn't have the wherewithal to jump in and continue the study.

We needed time really to get up to speed ourselves and then to work with Elan to supply. So, in the process, we did wind up supplying at least one patient with drug because we had enough drug in house for one patient. That patient actually is here with us today and would be available for comment. But, unfortunately, we were not able to get up to speed in time to supply this patient or others.

I will continue my remarks and inform this panel of what our intention is regarding future studies of this kind.

To continue with my prepared remarks in this regard, several leading neurologists, in addition, have told me directly that they have patients who have experienced seizures and as this panel has heard, on pharmacy compounded fampridine, three of these physicians independently have told me that they most often see problems when patients perceive that they are experiencing a waning of therapeutic effects within a given prescription. Then they self-medicate, doubling or sometimes even tripling their dose on a given day, at which time they sometimes run into problems with adverse events and even seizures. This is the impression that these physicians have given me and these reports are consistent with the data that you have heard earlier from Dr. Hamm, showing marked intra and inter sample variability, as well as the presence of impurities and loss of potency over time of pharmacy compounded formulations.

The key directive of the Hippocratic oath is first do no harm and I believe that all of us as health care providers are concerned that any potential pharmaceutical agent for serious or life-threatening conditions in particular be developed as rapidly as possible, but at the same time maintaining accountability and responsibility and a concern for patient welfare.

It is difficult to credit adequate accountability and responsibility to the current situation in which thousands of patients receive variable and undefined doses of fampridine without documentation or adequate assurance of safety and efficacy.

We recognize the desire of patients with seriously disabling conditions to have access to an agent that they believe offers some improvement of their condition and we recognize that Acorda finds itself in a position to offer a responsible alternative to the current situation.

With this in mind, Acorda has informed CDER that if fampridine is not placed on the list of allowable substances for compounding, Acorda would be willing to sponsor a long-term expanded access clinical study of our formulation of fampridine within the appropriate regulatory framework.

In such a study, which may require cost recovery, Acorda would provide its formulation of fampridine in an open label fashion to patients who would be deprived of pharmacy compounded fampridine. we would collect data related to safety of long-term administration and we would continue to sponsor this study while Acorda conducts additional Phase 2 and 3 studies in preparation for filing a new drug application or NDA.

If, however, the compounding of fampridine is allowed, we will be unable to offer such a program. Acorda and Elan already have invested several years and many millions of dollars in research and development efforts to develop a safe, reliable form of fampridine in compliance with recognized drug development procedures.

If pharmacy compounded fampridine continues to be made available, we would not be able to justify the significant additional investment of time and resources that an expanded access study would require. Moreover, we would have to seriously review whether it would be economically feasible for us to continue clinical development of this compound. We believe that such an outcome would poorly serve the long-term interests of the patients and their health care providers, who deserve to have a therapy that can be prescribed with assurance of reliable dosing, appropriate indications for use and overall safety and efficacy.

Such assurance can only be obtained for this drug if it is developed under INDs and approved by FDA under an NDA.

Thank you. And I would be pleased to answer any questions you may have.

MR. CATIZONE: Dr. Cohen, if we can, can we return back to the Hippocratic Oath, in which you quoted your remarks and let me ask the question. Doesn't it seem logical that the patient that you talk about in the study that is currently hospitalized, that the hospitalization was caused in some part to being stopped from the medication they were stabilized with and that the compounding pharmacist supplied a medication that was unavailable to that patient?

DR. COHEN: I am not sure I understand your question.

MR. CATIZONE: Any patient that is stabilized, particularly a patient with a severe illness, on a medication, and whose therapy is stopped immediately with no recourse of that patient to access that medication is going to have complications with their disease state. I can't believe that by the pharmacist compounding that medication alone, that was the sole reason for the hospitalization and the epileptic seizures.

DR. COHEN: There is no way in fact to demonstrate on an anecdotal basis that a given event is due to a drug or is not due to a drug. Obviously, we look at the population. We look at the trends and the patterns. My concern is an overall concern, not specifically keying off this patient, but rather on the overall experience in the data you have seen today, which demonstrates that the pharmacy compounded formulations of this drug are widely variable and if we put those in the hands of physicians to try to dose their patients appropriately, we really have not given them any compass whatsoever with which to work with a compound that is known to have the potential for these sorts of effects.

So, whether or not in this particular case, the patient's status epilepticus was directly related to having been on the compounded drug for six months, my concern is a larger concern and that is that you have an absolutely uncontrolled situation out there, an undocumented situation where thousands of people have access to very variable and undocumented, non-GMP formulations of this drug. And this is a drug that needs to have as much information as we can put into the hands of physicians and the patients in order to make it a reasonable therapy and to mitigate the known risks.

MR. CATIZONE: So, I have an understanding of your closing comments then, is Acorda and Elan saying that unless there are economic incentives provided to the company to make this economically feasible for your two companies, you will not conduct extensive clinical trials to prove this medication is worthwhile and useful, but in a small clinical trial in which a limited number of patients were participating, that guarantee to provide the medication was not carried through or honored and at least the few patients were forced to use this inferior product because your company said they couldn't produce it because of some sort of snafu in the transition.

DR. COHEN: I think that is an interesting interpretation of the events, but it does not accurately reflect what my statement was meant to convey. You know, we are talking about a drug for which there are intonations of efficacy. As Dr. Bever told you and as you have seen elsewhere, there is still to date not a single large, well-controlled study that gives conclusive evidence of efficacy. So, to begin with, although personally I do believe that the drug has efficacy and is a useful clinical compound, that still remains to be proved, whether I believe it or not, whether you believe it or not.

Secondly, it is a compound with demonstrable potential for serious toxicity and putting those two elements together tells me that if we are going to do this responsibly, we need to go through the process of controlled clinical trials, dosing studies, so that we know what we are doing and with a formulation that is a controllable formulation, that gives reliable plasma levels. To me, that boils down very simply. In terms of the intonation that we left patients high and dry, I reject that information.

You know, we are a small company and we are doing our very best to do a good job of bringing this compound to the clinic for our patient populations. At the end of the day, that is why we are here. In terms of economic feasibility, we live in a world of real economic constraints. I don't think I have to tell anyone here what it costs to develop a drug in an appropriate fashion. What I am saying is that if compounded 4-AP is out there on a widespread basis, where we have basically uncontrolled formulation and wide access to it, it will make i t much more difficult for us to convince our investors that they ought to invest in us to carry out this program because I answer questions from them everyday about why are you developing this drug in the right way when you have got all this stuff out there that people can just get and no one is investing in clinical trials out there.

DR. JUHL: There are a number of fallacies in what you are going through here and I want to pick them one at a time.

Are you saying to us that you are unable to mount an economic effort to conduct the trials without the revenue stream that you would have from an expanded access program?

DR. COHEN: No. What I am saying is that we are proposing to make an expanded access program available and --

DR. JUHL: I understand that and I appreciate that. I really do --

DR. COHEN: And within that expanded access program, we certainly aren't going to make any money off that. In fact, we have concluded that even with cost recovery, we are going to have to invest significantly additionally to carry out that program. So, that is an issue of actually doing a study that we otherwise would not be required to do and would not choose to do. We would do it because we recognize that the patients out there do need an alternative and they do need a drug that is better controlled and better defined.

So, we are willing to do that. We are not going to make a dime off that nor can we, frankly, under the regulations. We are going to invest additionally to do that study.

DR. JUHL: Here is the part that I don't understand. If you do the study and get the drug approved, then that is an NDA'd product for which pharmacy compounding would not be allowed. So, how does that adversely effect your economics when you get into the market?

DR. COHEN: I have to say that I am not aware of -- if we get an approval, I am not aware that the pharmacy compounded would be -- compounding would be disallowed at that point under the current regulations.

DR. JUHL: Under Section 127, the pharmacist cannot make copies of a commercially available product.

MS. AXELRAD: Excuse me. That is not strictly speaking correct. They cannot compound regularly or an inordinate amount --

DR. JUHL: Unless there is a significant medical need.

MS. AXELRAD: -- copies of a commercially available product and we have yet to define what it means to be regularly or an inordinate amount. Certainly, some compounding of commercially available products would be allowed under our regulations. In fact, don't forget that one of the criteria for the bulk drug substance that you can use in pharmacy compounding is that if it is the subject of an FDA approved application, then you can use it to compound.

DR. JUHL: There has to be a valid medical need above and beyond just changing a milligram or two. I mean, the discussion in Congress I thought was rather clear to prevent that.

MS. AXELRAD: They don't specifically use the words "medical need." There are issues associated with what level of need there is that we will be addressing in the general regulations.

DR. COHEN: So, what I understand about the situation is that it is not cut and dried. There is uncertainty. There is nothing in my experience that scares away investors faster than uncertainty. We rely on investors to allow us to continue our programs. We are not a revenue generating company as yet. We are an R&D company, research and development. So, all the R&D that we do is funded by the good will of the investors, who believe that we are developing important products that ultimately will make it to market.

That introduces more difficulty for us to the extent that there is more uncertainty. However, let me say that that is still not my chief concern. I mention it because it is a real concern and we will have to seriously review what -- how to move forward, where we choose to put our investment dollars if that uncertainty continues to exist. But that is not my chief concern. My chief concern is that we truly have a situation with a compound that in my view and our view ought not to be compounded because what we have seen is that these compounded formulations are nowhere near as reliable as they need to be to ensure a standard of safety, a reasonable standard of safety for our patients and dosing.

We have a formulation that we believe is much superior in those regards and we are willing to make it available and, in fact, we are willing to invest additionally of our time and resources to make it available in the case where there were no compounding of 4-AP.

DR. JUHL: I appreciate the GMP produced drug is going to be better than a compounded drug. The question is is a compounded drug better than no drug at all?

DR. BEHRMAN: Dr. Juhl, could I make a comment because some of what we are debating right now is very common to life-threatening diseases, where there aren't good therapies and there are new therapies coming along and maybe people have access and maybe people don't. It is something the Agency struggles with a lot. Unfortunately, it is not uncommon to see circumstances where people are left without supplies and that is something that the Agency is becoming better at trying to prevent. But, obviously, it doesn't always work.

But the issue before us that concerns the Agency is not what is economically feasible for a particular company or -- well, in particular, that, but rather is something that may or may not be provided to the public safe. In other words, as Dr. Woodcock discussed yesterday, when we think about access, any kind of access, one of the first concerns we have is that the safety of the patients is being protected.

So, for us, it is a question of should this substance be on the compounding list or not. That has to be answered before we can then turn to how to develop it safely and by whom and also ensure that during that process, there is access for those who need it. But they are really two separate questions and the ability to -- or at least it doesn't so much influence our decision about whether to make it available, that other mechanisms aren't available if we believe it is not safe.

So, for us, the real issue, is it safe, can it go on a compounding list or not. If we answer the question that, no, it can't be compounded, then we have to tackle the question of how can we get it developed and how can we make sure that there is appropriate access.

DR. JUHL: The different quirk here is that unlike other compounds that are being developed and are new, you don't have a few thousand patients that are already on it. This is the issue here. We have patients who are already on it, who we have to be concerned about.

Unfortunately, I mean, I understand the Agency doesn't deal with economics, but in order to mount the effort that would be required to provide the entire country with this drug, there has to be some confidence in -- at least from my perspective -- in the company to be able to do that. The only example of performance we have here is was unable to get drug for 23, 29 patients, one of whom ended up in status in the hospital.

So, I want to be sure that --

DR. COHEN: If I could comment on that?

DR. JUHL: Let me finish, please.

I want to be sure that if this committee recommends that they ought not be put there, just as our discussions this morning, that there is a place for patients to turn and they won't get caught up in what you described as a year's worth of bureaucracy to transfer papers and the patients didn't come first in that situation.

DR. BEHRMAN: Well, I think to a certain extent then it is our responsibility to assure you that -- and this is something we are very familiar with and good at

-- that we will represent you in those negotiations with the company and satisfy ourselves that the distribution program, to the best of our ability, obviously, because as Dr. Woodcock mentioned, we can't force any company, but we are fortunate that we hear an assurance that, in fact, such a program would be developed, but that you trust us because we are committed to doing that, to making sure that entry criteria, inclusive criteria, are reasonable and that the people who need the access are the ones that get the access and get it in the safe manner.

DR. SELLERS: I am trying to understand what you are describing, Dr. Juhl. If the company was no longer to obtain the drug that was being manufactured, wouldn't obtaining it from a compounding pharmacy be a better choice than cutting off the drugs altogether?

DR. JUHL: Well, I think that is one of the questions.

DR. SELLERS: Right. And I feel like we are implying that they did the wrong thing by providing a compounded product, but they didn't necessarily know at the time that they were providing a product that wasn't of the same standard as what the patients were getting.

DR. JUHL: Yes. There was no alternative at that point.

DR. COHEN: Actually, if I could add to that because that really was along the lines of what I wanted to say. You know, we are all learning as we go along. It is a development program. So, we continue to learn. At the time -- I am sensitive to your concern and certainly retrospectively how one might interpret the fact that you have this group of patients, who were on drug and then the company cut them off and they went to compound and then we have these problems.

I think the reality is more subtle and more complicated than that in meaningful ways. If we had -- I think if we had had the understanding a year ago that we have now, after having the benefit of studied the circumstance more, having become more aware of the compounding issues and looked into it in more detail, having taken the time to interview physicians in more detail and bringing ourselves down the learning curve, we might well have had a greater sense of urgency amid all of the priorities that one has in the company even as we were transferring this whole portfolio, which does take time.

I would also say that that was a one off event. We are talking about a business alliance, which occurred once in which Acorda entered into an alliance with Elan and consequently there had to be some time to transfer information and documentation. That is a one off. At present and for the foreseeable future, Acorda has the exclusive license to all of Elan's technology related to this drug and to -- and the exclusive license to develop it for multiple sclerosis and spinal cord injury.

So, we do not anticipate a repeat similar event in which there will be any lengthy interruption of the chain of command, as it were, or chain of activity. So, that is an issue that is behind us. I think moving forward what we are saying is we have spent a good deal of time over the last few months studying this, discussing it with Elan in great depth and concluding that we needed to offer to do a large expanded access study.

We are quite capable of doing that study and Elan is quite capable of supplying sufficient drug for that study. As with anything, it is a matter of timing, intent, planning and then execution. I think looking back over the last year is not going -- I would submit to you that that is not instructive for learning what we are capable and willing to do in the future because it really was a one off situation of transfer of responsibility for the project.

DR. BEVER: I apologize. I don't know whether you take comments from the audience.

DR. JUHL: We usually don't, but go ahead.

DR. BEVER: I just want to clarify that we are talking about a group of patients who were in a clinical trial. They were not in a compassionate use program or anything like that. There was never, as was intimated earlier, any promise to these patients that there would be ongoing availability of this drug. It always, with Elan and Athena and Acorda was sort of extending bits at a time. And as you know, the consent form that patients were signing basically says that this sponsor has the right to terminate the trial at any time for any reason and patients were told that.

I mean, I was concerned about that from the beginning and tried to make that clear to the patients that this was a research study and it could be terminated. I mean, that was something that we just dealt with. We tried to deal with it as best as we could and looking back on it, it probably wasn't the best way of doing it, but we know more now.

DR. JUHL: Perhaps it is just one of my pet peeves, but having served on several IRBs, that is one of the things we always put in the consent form as to what happens when the study is done.

MS. LA FOLLETTE: I would just like to make a comment. If Acorda is successfully continuing with their IND studies and then successfully file an NDA -- at our training session yesterday, 90 percent of ADRs that are reported are from companies and that is a benefit if a product goes commercial, that you will actually have a history and you will have information, which we haven't been able to really nail down with pharmacy compounding, how adverse reactions are going to be reported or if they will.

MR. TRISSEL: What is the time span of your development plan now? How many years more in development do you anticipate? It sounds like you are pretty early on.

DR. COHEN: You know, I am quite hesitant to go on record predicting what the length of the development program will be. I think we all understand the vagaries of clinical development.

MR. TRISSEL: It is not a year.

DR. COHEN: Well, you know, it is not a year, but I don't think it is five years. I don't think it is ten years, but, you know, at the end of the day, we don't know until we get into the clinic further. We have done a couple of Phase 2 studies. We are going to be doing more Phase 2 studies this year.

If those go well, then our plan is to get into pivotal studies next year. I say this emphasizing that this is our current plan and it will entirely depend on the actual results of the studies that we see, which is why we are doing the studies, of course, to begin with.

MR. TRISSEL: As it applies to the expanded access program that you are offering, apart from the patients that are going to be on your clinical trials, how many patients do you anticipate that you will have to supply with drug during this time frame from the next two to five years, two to ten years in terms of thousands? How many patients do you think you are really talking about?

DR. COHEN: Here, again, you know, I am reluctant to speculate on what we are talking about. I will tell you that we are capable and prepared to supply as many patients as we believe are out there. I will tell you that it would be many thousands, many thousands of patients, as far as we know, who are out there. We would be prepared to supply them, those who are taking compounded fampridine.

MR. TRISSEL: And you would be ready to start this in what length of time, do you think?

DR. COHEN: Well, again, I think -- as I indicated, we are going to look to see what the outcome is of this panel's deliberations, of the FDA's deliberations, because truly at the end of the day if the compounded drug is allowed to be -- or if the drug is allowed to continue to be compounded, we really will not be able to do the study. We just will not be able to muster up the investment in us that we need to do the study. It is just a fact.

MR. TRISSEL: But if we don't have a time frame for when you can begin delivering that, then we --

DR. COHEN: We could begin delivering it as soon as six months.

MR. TRISSEL: As soon as six months.

DR. COHEN: That is, you know, give or take, but that is a reasonable time frame. If you wanted to say by the end of this year, I don't think we would be far off.

DR. LIEBMAN: When the patients who were told to get their medicine compounded because the study could no longer supply it, were they instructed that this is a very sensitive kind of drug and you need to go to a pharmacy, who is skilled in doing that or was the issue of find the cheapest guy around, such that, you know, it doesn't matter. Price is the issue.

DR. COHEN: That is just an area that we have never been involved with. Maybe Dr. Bever might want to comment on that.

DR. LIEBMAN: Dr. Bever, I don't mean to beat on you. If you were referring a patient of yours to another physician, would you say here are a list of four physicians. Call and get the cheapest one or would you say these are people I know are qualitative and I would strongly recommend these people because they are good at what they do?

DR. COHEN: I should point out that the two samples that were analyzed by Elan that Dr. Hamm presented earlier, the two samples the pharmacy compounded, were obtained from two of the larger suppliers, as far as we know and two of the ones that we believe to be the most reputable, again, I don't know how you make those determinations, but these were not -- both of these places advertise on the Internet. Both of them, as far as we know, distribute a fairly large number of prescriptions annually of fampridine.

And those prescriptions were quite variable in their quality, as you saw.

DR. LIEBMAN: I don't mean to be argumentative. Just because they make a lot of them doesn't necessarily mean that they are skilled at what they do. It only means they make a lot of them.

DR. COHEN: No argument, but then I think one has to face the question of on what basis does the population at large and physicians at large make the determination of what is a high quality producer and what is not. I think, in fact, what happens is people are all -- as long as compounding is allowed, people will obtain the drug from whoever is supplying it and I don't see a good way of regulating that without, in fact, regulating the development of the drug.

DR. BEVER: I will repeat my comment in the microphone that I gave before. And that is we did just give a list of pharmacies to patients and tell them to find out what the cost was. My problem is that a clinician is -- is that it is not easy to get data on compounding pharmacies that would allow me to distinguish a good one from a bad one. We had picked what we thought were fairly reasonable ones through patients to get drug that was analyzed by Elan and that didn't help us.

DR. PECK: You are going to have to be careful about listening to me because I may generate some thoughts by you that you will disagree with.

Data was prepared by your firm or Elan, which talked about the poor quality as was judged by weight variation and so forth from the two sources of this compounded product. These information were given to us and then there were some assay -- limited assay data presented.

You will probably say we don't have to do this, but you have not presented anything that would indicate the superiority of either the capsule or the tablet formulation showing that there is diluent interactions, migration into the capsule shell, which is not uncommon. Many drugs do this. While you can say, however, that the Agency will be given this particular information, but we as a committee have to sit here without this information and make some decision, which is a little bit in favor of you in terms of no compounders can do their work.

I am not sure whether I am clear as to what you were saying out of your letter.

DR. COHEN: If you could clarify the question that you want me to answer in that?

DR. PECK: Do you have data that demonstrates that your products are superior?

DR. COHEN: I believe that Elan does, based on our investigation of Elan's portfolio and Elan's data.

DR. PECK: But that would be available probably only to the Agency?

DR. COHEN: Sharon? Yes.

DR. KATZ: Yes, I think one of the great advantages of requiring that studies be done under an IND is that there are strict standards, as you undoubtedly know, about the strength and the identity and the purity of products that are permitted to be given to people under the IND. Without speaking specifically about any product, I think in this context, one of the great advantages is just that, that we have seen that there is considerable variability in the compounded products and we have standards that sponsors are always required to meet for the composition of products under INDs, just as a generic statement.

DR. JUHL: We have been told that the new product meets these standards and exceeds that of the compounded ones. But we are asked to trust that without data, I guess, is --

DR. KATZ: Well, as Dr. Behrman said, I mean, part of this -- to the extent that certain things are not -- are confidential under the IND and can't be discussed in public without the permission of the sponsor, that is a large part of what we do.

As she said, you will have to consider whether or not you trust us to do our job so that we would permit a product that meets our standards under the IND. Again, it is what we do. We do it everyday and we think we do it well and we have standards that are sort of public and folks have to meet them if they want to give a drug out under an IND.

DR. JUHL: Is that satisfactory, Garnet?

DR. PECK: Yes. I wanted a clarification of this particular situation and the judgment and the data that is available. The IND situation is very important to the development of new drug products and there are certain things that are in there that must be retained in confidentiality. But I don't like mixing economics with this confidentiality. That part -- I am trying to separate that to evolve good products.

DR. BEHRMAN: We are really not -- we, FDA, are not thinking about the economics. We have one decision to make with your help, which is whether or not this product should be on the compounding list.

The second decision is the IND development and actually they are in a way unrelated. The Elan product doesn't have to be superior. As Dr. Katz said, it has to meet our standards. We wouldn't be particularly interested in the comparison, in fact. But we are not particularly worried about any company's economics right now. We are worried about the safety of the patients who will get these drugs.

MS. AXELRAD: I was just going to comment that people that are here from the Review Division weren't here this morning during the discussion, but it was sort of my understanding that we discussed the possibility of whether something should be put on the compounding list or not put on the compounding list, with the understanding that if it was going to be used, it would be done under an IND and we didn't have any information on any formulation of it at that time. We had some generalized safety information from the literature,but I think, certainly, the committee's vote with regard to DNCB was that it should not go on the list and that you would rely on the agency to make sure that if it was made available under an IND, that it was -- that an appropriate quality product was made available and we sort of indicated that we would be carefully considering the chemistry, the impurities and other issues associated with that if we were to allow it under an IND.

So, I think the discussion that we had this morning sort of relates to what we are talking about now and if we are talking about the same situation and we would be looking at the product, the division would be looking at the product very closely under an IND and under any kind of an open label trial.

DR. JUHL: I think the one thing that is different, at least in my mind, I am greatly appreciative of the company's offer to have an expanded access program under an IND where we can collect more information. My concern is your ability to deliver and the past experience made me real nervous because we have patients out there that I think are doing better on the drug than they would do without the drug.

There is no question they would do better with the manufactured product than with the not manufactured product. I want to be confident in your ability to do that and you are essentially putting the gun at the head of the patients and saying either do this or we pull the trigger. I think the committee is reacting to that difficult decision. I am not arguing with you. I understand, but it is an uneasy one for the committee --

DR. COHEN: Well, it is an uneasy one to hear fed back that way because it certainly -- we certainly don't intend it to come off that way nor do we feel about it that way. You know, it is not a -- it is really holding a gun to our own heads if you really want to put it that way.

DR. JUHL: I am reacting to your tone and your forcefulness on the do this or we are out of here kind of thing.

DR. COHEN: Then I willingly stand down from the tone and -- but still want to emphasize the point that it is not a question of us -- of do this or else by any means. We would not be so bold as to attempt to come before this panel and come off that way. It is simply a question of what we are trying to do in good faith, which is to assess what can we do and under what circumstances can we do it because we have our own constraints back home in terms of what we are able to do.

In analyzing that, our best judgment in good faith is that we are able to -- we would be able to supply the drug in a large expanded access study and we want to do so and we are willing to do so, that in the event that compounded drug continues to be unavailable, we will not be able to pull it off. And it is not a question of want to or not want to. We simply won't be able to pull it off.

If I didn't convey it that way, I apologize. That is what the reality is.

DR. JUHL: Yes. And I understand that and I appreciate you being forthcoming and not beating around the bush. Let me put it that way. But that is a decision we end up being -- you understand our --

DR. COHEN: I understand.

DR. RODRIGUEZ: I have concerns about some of the data that was presented and the concerns are not on the data per se, but on the implications of the data. When you have some things in which the actual sample is one-third of the dose and we have such a narrow type of safety, I just wonder what is going to happen in the meantime with this information because we are talking about safety and we are talking about there are a lot of people taking medication, who may cross the state line and go on some other compounding pharmacy and have been used to a 3.3 milligram and end up with the 9.2 milligrams for 8 milligram capsule.

Those things just worry the hell out of me as I sit over here thinking as a consumer to put it bluntly. So, I like the fact that you found that. We have lacked this information in many of the other products. We are trusting the fact through the Agency that this was conducted in an unbiased way and then the information is even if we go ahead and say there should be no compounding, for example, there is going to be a lag in between. This information is, quote, unquote, your information and the question is what do you do with that information in the meantime because the people who use this medication are pretty much I would say involved in their destiny and if they were to find out that there were just differences in between the preparations, they will at least demand that that information be available to them.

Just a commentary.

DR. JUHL: Loyd, perhaps you could comment on the extrapability of those findings. I know there was one study that was published in your journal that showed maybe 10 percent, plus or minus, was about as good as you could expect under the best conditions for compounding. Here we have capsules with very small milligram amounts. What is reasonable to expect?

DR. ALLEN: There is no question those are outside. In fact, pharmacists that compound are required to meet the requirements of the USP for their products and clearly those are outside the limits. According to Phadema(?) 1997, the USP general chapter on compounding, which up until now has been an informational chapter, now moves down into the enforceable area and that process is ongoing right now.

Compounded pharmacists must meet the requirements for the preparation of a product. If there is a monograph in the USPNF, it has to meet that. If not, well then it goes to the general guidelines of the general chapter. And we are looking at generally -- you know, most stability studies and things like that, plus or minus 10 percent of the target quantity of drugs. This would then -- if an individual pharmacist is not performing to that level of expertise, then that would fall into the enforcement agency, you know, the state boards, et cetera, in order to investigate that.

So, you know, clearly, that is outside the area of accepted practice, because plus or minus 10 percent is what is normally reasonable.

DR. JUHL: I wonder if I could ask Jane, does the MOU with the state boards include provisions that lead a board to investigate this kind of detail or maybe I could ask Carmen the same question.

Do you expect boards of pharmacy to go out and purchase samples, do the analysis and do a quality assurance in that fashion?

MS. AXELRAD: I would sort of have to defer to Carmen about whether they would actually go out and purchase samples, but I would say, certainly, at least, we don't have an MOU in place or anything right now. Certainly, the way we are dealing with enforcement issues is if we became aware of a situation through one way or another of something that was really out of compliance with the USP chapter on pharmacy compounding, we would probably want to consult with the state in which the problem was identified and between us decide what kind of an appropriate enforcement action would be taken.

But I don't think we are doing a lot of inspecting right now of compounding pharmacies. Because of the uncertainty, we don't have any regulations in place and we are in the process of implementing it. But I don't think that we, ourselves, are doing a lot.

DR. JUHL: Would this information that has just been presented be fed back to the appropriate state board or to the pharmacy that produced these products in an effort to improve?

MS. AXELRAD: It could be if we had specifics on -- we would have to have specifics of what pharmacy -- specific information about it.

DR. SELLERS: Loyd, this is directed more towards you, but if compounding pharmacists are supposed to be meeting USP specs, how do they know if they are meeting those specs?

DR. ALLEN: Basically, there is no requirements that they have their products tested. What it is based on is whenever you get a certificate of analysis, where the product is 98, 99 percent pure as far as active is concerned, and then you have a formulation -- let's say you are preparing 100 capsules. Okay? 25 milligrams each. Well, then you would weigh out 2.5 grams plus your excipients, prepare the 100 capsules at one time, equal distribution, check the whites, and that basically is all that is required at this point.

I always recommend that occasionally -- of course, you can't do it on compounded prescriptions that you get just occasionally because it wouldn't be financially feasible, but if a pharmacist is doing a product routinely, you know, every week, every couple of weeks, that they periodically take samples and send them all to a contract lab for analysis, of which many of them do. Many of your better ones do, like Dave was referring to awhile ago.

MR. TRISSEL: Apart from those issues, really a pivotal thing is -- I think we can all agree that to get a GMP manufactured product with GMP bulk, GMP manufacturing process in a suitable plant, a consistent product in the hands of all the patients who need it, would be a desirable situation.

The question only is really can that be delivered in terms of several thousand, maybe 5,000, maybe even more, patients. It would seem reasonable to give that a try and see if the company can deliver on their promise and we have a promise from you, right, that you will --

DR. COHEN: You have a commitment from us that we will do that.

MR. TRISSEL: -- for all patients whose physicians believed this would be of benefit.

DR. BEHRMAN: The answer to that is -- it would be impossible for any sponsor to address that because we would want to discuss the contents or negotiate the contents of the program with them. As Dr. Woodcock mentioned yesterday, second to the safety of the patients is the safety of the development program. If we believe that the expanded access program is going to make it impossible to develop the drug, we will put certain limits on that program. It is important to remember that there is not a right to access to drug in this country. That is nowhere in the law. It is done because -- it is done for a variety of reasons, but only when appropriate.

So, that means that it is always appropriate in the programs where the sky is the limit. I mean, when people think about expanded access, they think about some of the very large AIDS programs that we described for you yesterday, where, for example, 35,000 patients received 3TC. But that is not necessarily what is going to happen.

We may not determine that it is appropriate for every physician, who wants to get a patient on this program to do that. We may decide that we don't know enough about the safety. We don't have sufficient efficacy data or there is not sufficient drug supply.

So, again, you would have to trust us to negotiate a fair and appropriate program with the sponsor.

DR. COHEN: I think I will only add that in terms of drug supply, from our point of view, we -- I will just repeat that we are capable, willing, able to supply certainly substantially more than the 5,000 number that you mentioned. If it were necessary and if it were agreeable and appropriate under the regs and in our negotiations and discussions with CDER.

DR. BEHRMAN: Because remember that any experimental drug carries with it -- well, any drug carries with it a risk, but particularly experimental drugs. We in that sense sort of try to stage the expanded access program so that the smaller ones are for the patients that have absolutely no options and clearly want to and are able and, if justified, tolerate the risk, as opposed to when we are much more confident that the drug, in fact, works and we are simply waiting for either the NDA to come to us or for us to finish the NDA, when a somewhat looser program is more appropriate.

MR. GRADY: I am Tim Grady. I am with the U.s. Pharmacopeia that has been mentioned here.

I missed the first 10, 15 minutes, so you may have covered this, in which case I apologize for the intrusion. The high variability is very suggestive of a vapor pressure problem. This was reported, for example, by Professor Ralph Shangra(?), the late, great Ralph Shangra, on nitroglycerine. So, the question I have with the compounded preparations, were they labeled to be refrigerated? Were they delivered with a beyond use state? Or has anybody formulating this material as a salt? I mean, you have got a lot of electrons coming off of the neferadine(?) nitrogen and you have got amino group -- by the way, your amino purity is very easily -- you can bubble air into water with some of those molecules and make a nitroso compound.

So, very hot electron situation. So, the question is anybody making a salt out of these? So, I don't know that you can characterize the compounding situation for something with a high vapor pressure and I don't think the pharmacists should be beat up for the variability. It may well shop within the 10 percent that Dr. Allen is talking about, but a couple of warm days will take care of that.

MS. AXELRAD: I just wanted to clarify my earlier remarks about this and that is that the -- I was reminded that the statutory requirements that you comply with the compounding chapter and any USP monographs, if one exists, goes to the bulk drug substance. It does not go to the finished dosage form. So, there is nothing in the compounding law that actually specifically says that the finished dosage form, the actual compounded product has to comply with the USP standards.

DR. LIEBMAN: Loyd, I thought when we wrote monographs for compounded products, we said the finished product has to be plus or minus. Jim, do I remember correctly, on compounded drugs? Jim, are you still here?

DR. JUHL: We can get clarification on that point because it is written down somewhere.

Let me ask one more question and then we will let you go.

Your distribution system, as you would see it, would be a centralized one or would you make use of pharmacists, who already have relationships with these patients, and attempt to take advantage of that?

DR. COHEN: We actually have been in discussions with a couple of contract research organizations, who -- one of whom in particular has specialized in managing and directing other expanded studies, particularly for some HIV compounds and some cancer compounds in the past, studies that have involved in some cases tens of thousands of patients.

So, our intent would be to contract with those organizations and follow their best recommendations as to how this would be distributed effectively. So, I cannot comment knowledgeably, personally, to you now about that, but I will tell you that we are --

DR. JUHL: You are not considering using the pharmacists that already have those patients?

DR. COHEN: Again, I don't know the answer to that question because this is not an area that I am expert in. This is something that we will rely on the contract research organization to advise on and it may well be. We haven't had that specific conversation with them yet, but if they were to say, you know, an effective way to do this would be through these pharmacies that are already accessing these patients, that would be -- obviously, we would do that.

DR. BEHRMAN: It may be worth noting that that would be very atypical, because you have to have a physician to actually write the prescription or prescribe it. The interaction is between the physician and either the company or whoever is acting on their behalf.

DR. JUHL: I understand but, again, we are atypical because there are already patients on these drugs and how you are going to find them is the question.

Other questions?

[There was no response.]

We are running a bit behind schedule and I thank you. We will probably have some additional discussions after break, but I think we will take our break now and get to our next speakers on the diaminopyridine right after break.

Let's be prompt and be back in the room at five minutes after.

[Brief recess.]

DR. JUHL: Okay. We will resume.

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