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Norvir Advisory

The following presentations were taped and edited by the International Association of Physicians in AIDS Care. Some of the questions were not included because they were not audible on the taped recording, or were not pertinent to the topics of the update.

Norvir Community Update - 10/15/98
Abbott Laboratories, Abbott Park, Illinois
Presentation 1

Eugene Sun, MD
Head, Antiviral Venture
Pharmaceutical Products Division (PPD)
Abbott Laboratories

Additional Comments By:

Steven Byrn, PhD
Professor, Purdue University
West Lafayette, IN

SUN: Good afternoon. On behalf of Abbott Laboratories, I welcome you and thank each of you for attending this meeting - especially those of you who have traveled great distances to join us. My colleagues and I are here today to give you an update on the status of Norvir - to explain what has happened, why it has happened, how we have responded to the problem, and what we are doing to correct the problem. We are here to do our best to explain a complex problem in as open and in as direct a manner as possible. So everything is fair game. We will answer any questions that you may have.

We have tried to structure the formal part of this program to present the most relevant pieces of information that we have in what we hope is a logical manner and in a more or less chronological order to give you an overview of what has happened since we last formally communicated with you about the Norvir capsule manufacturing problem. All of us at Abbott realize our obligation to keep all of you informed about this problem. There are tens of thousands of people throughout the world who are relying on Norvir to meet the challenge of HIV. You and the people with HIV for whom you serve as advocates need assurance about the continued efficacy of Norvir to help meet these challenges.

We wanted to hold this meeting sooner to answer your questions and hopefully reduce some of the stress that may have resulted from the temporary suspension of the capsule manufacturing. But, as I hope you will soon understand, this is a complex situation and we wanted to have as many answers as possible to your questions. We did not want to bring you here to simply answer "I don't know." We may still have to answer "I don't know" to a few of your questions. But at least by waiting until today, we can answer more of your questions than we might have even a few weeks ago.

Today we will review with you what has happened in the interim since our first conference call, both on a scientific and a technical level. That update will be by Professor Steven Byrn from Purdue University in Pittsburgh. Steve is an internationally recognized expert on polymorphism, the term used to describe the cause of the manufacturing problem with Norvir capsules. Steve is one of the first experts that we contacted when this problem emerged several months ago, and he has been one of our principal consultants that we have called upon to help us resolve the problem.

We also wanted to share with you what we are doing to resolve the problem, and provide people with a capsule formulation that will better meet their needs. Steve Lichter from Abbott's International Operations will take you step by step through the process that resulted in the temporary suspension of the capsule production, and how Abbott responded to each issue as it was presented. With Steve's explanation as background, we will then explain we are doing, and where our efforts are currently focused.

This meeting is also a meeting about communication. So we have brought three people from our domestic and international business units - Bill Calhoun, Bob Prachar, and Rob Dintruff. They will brief you on what our communication strategies have been, what we are saying, and in some instances, why we have had to respond to questions in certain ways. We also want to address all of the questions that have been raised concerning Norvir liquid, and to answer any other questions that you may have about this product.

But first, I will try to answer the question that is probably foremost on most of your minds - what is the status of Norvir capsules? . As you will hear from Steve Lichter and which will also follow from Professor Byrn's presentation, the problem we ran into with ritonavir (Norvir) was one in which crystals formed in the semisolid formulation. A formulation is simply a way to present drugs to the body so they can be absorbed. Drugs have to be in solution so they can be bioavailable. Ritonavir was manufactured in two formulations - a liquid formulation and a semisolid formulation. Something unpredictable happened during the manufacturing of the semisolid formulation. After two-and-a-half years of closely monitored and tested semisolid formulation manufacturing, we encountered a new form of ritonavir, a crystal form. The new crystal form is still ritonavir, but ritonavir in a form that could effect its bioavailability. Steve Byrn will go into much greater detail about crystals and the potential of drugs to change forms which is what scientists call polymorphism.

Sometime during this summer, the semisolid formulation of ritonavir which was designed to make ritonavir bioavailable, began to change into a crystal form - a transformation that we believed was a scientific and chemical impossibility with the semisolid formulation. While we have speculated on the cause of this chemical transformation, we don't have conclusive proof what happened. And as you will hear from Steve Lichter, Abbott could not solve the problem for reasons which now are more apparent than they were when the problem was first discovered. You will also hear that the semisolid form of ritonavir is actually a thermodynamically stable form. Thermodynamics govern everything we do in the pharmaceutical industry, so this was not a problem that was going to just disappear. We now have to contend with a totally new form of ritonavir that we call Form II ritonavir.

Form II ritonavir is chemically and molecularly identical to the original form of ritonavir. Once form II ritonavir is in solution, it is exactly the same as the original ritonavir with the same efficacy. Our challenge has been to find a formulation to provide the appropriate bioavailability for the new Form II ritonavir. We have gradually come to realize that the semisolid formulation is not the best way to proceed. So we have turned our attention primarily to the semisoft or the soft elastic capsule, which we call the SEC formulation. Abbott had been developing and testing this SEC formulation for some time.

When we learned about Form II ritonavir, we started to explore the solubility issues in the SEC formulation and found things to be more optimistic. The original SEC formulation that we have developed required some modification, which we are now in the process of completing. I cannot predict how long it will take. I can tell you that it is highly unlikely to be available in the calendar year 1998. But we have made very good progress. We have had numerous conversations with FDA and anticipate more in the future. We have also had communications with the EMEA and anticipate a meeting with them sometime in the near future.

There are a large number of issues associated with the development of any new formulation of a drug. The SEC is no exception. Abbott believes that the SEC holds great promise as a new formulation for ritonavir. And we will keep you updated on our progress in making this new formulation of ritonavir available as soon as possible. The liquid formulation of ritonavir is and will continue to be an effective alternative option for semisolid formulation until the new SEC can be produced. I will also answer any questions that you may have about Norvir liquid.

Before I take your questions, there are two points that I want to make. First, although you have an agenda in front of you, you can interrupt me at any time if you have a question. We are here to answer any questions that you may have whenever you want to ask them. Second, there are a number of Abbott people in this room today. All of us here today and hundreds of others who are not with us here today have made a huge investment in Norvir. I am not talking about an investment of money or an investment of time. I am talking about spiritual and emotional investment.

There are people in this building who actually built this molecule and created this drug. This achievement is something of which each of us at Abbott, individually and collectively, is extremely proud. We believe that we have made a great contribution to HIV therapy. In the course of developing Norvir, we also believe that we have made significant contributions to the understanding of HIV and AIDS. We have our pride invested in this drug and the drug development process as well.

This is why all of us at Abbott have been working extremely hard throughout the summer, often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have canceled vacations and asked our families for their understanding and support. This is not an issue that we take lightly. We will continue this commitment until we can resume capsule manufacturing.

QUESTION: What are the FDA constraints? What are the FDA hurdles here that we have to deal with in order to get the SEC on the pharmacy shelves?

SUN: It is like any other new formulation. We need to demonstrate to the FDA that the SEC formulation of ritonavir is bioequivalent to the liquid formulation of ritonavir- in other words, that

the SEC has the same amount of drug that is able to be absorbed by the body as is absorbed from Norvir liquid. Otherwise, we would have to label the SEC differently, which we don't want to do. We want to say that 600 milligrams of the SEC is equivalent to 600 milligrams of the liquid - and that the label information applies to all forms of ritonavir. The FDA regulatory process requires that we provide data to back up everything that we put on the label. We have to demonstrate that the product will be stable for the shelf life that we are recommending. If we recommend that the product be stored in the refrigerator, then we need to demonstrate why.

We also need to demonstrate stability. If we want a product labeled for a year's storage, one way would be to collect data for a year and submit to the FDA. But there are other options, although this is a gray zone that must be negotiated. The FDA needs to have a scientific rationale for saying that the three, or whatever the number is, months of data that we submit is sufficient to support the labeling recommendations that we are proposing. That is essentially what we have to do. We are not faced with a new clinical development program. We are looking at a very focused set of activities that relates to bioequivalence and stability.

QUESTION: You are a large, multinational company. Your scientists are obviously smart. How could this happen?

SUN: A company's size and the collective IQs of their scientists have no relationship to this problem. Professor Byrn will discuss polymorphism or the ability of chemicals to change forms in more detail. This obviously has not happened to every drug. But it has happened to other drugs.

QUESTION: That Abbott makes?

SUN: No, not that Abbott makes. But you'll hear about examples of other drugs that have been affected by polymorphism and whose manufacturers faced similar problems that we have faced. Science hasn't been able to provide all the answers about why polymorphism occurs. When this happened to us, we conducted an extremely thorough investigation of everything possible to see if there was something that we did that could have caused this phenomenon. We haven't been able to detect anything. We don't have a bottom line explanation from a physical chemistry perspective about why the new form evolved. But the fact is that it did evolve. It has happened before to other drugs and it will most likely happen in other drugs in the future. This phenomenon is, I believe, unpredictable. We are, in some sense, the victim of bad luck. It has nothing to do with being a large multinational company or having smart scientists.

We will try to provide you with some scientific insights into polymorphism later in the program. If you are still left with that question at the end of the day, we can come back to it. Hopefully, you will learn that this was an extremely unfortuitous event over which we had no control. I also hope that you will also leave with the understanding that all of us here at Abbott have done and will continue to doing everything humanly possible to correct this situation.

There are many mysteries of nature that we have not solved. Hurricanes, for example, continue to occur and often cause massive devastation. Meteorologists can not predict months in advance when and with what velocity a hurricane will strike a specific community. Polymorphism is a parallel phenomenon. We know that it will probably happen. But not why or when. Unfortunately, there is nothing that we can do today to prevent a hurricane from striking any community or polymorphism from striking any drug.

Science cannot provide a solution to all of our problems. It is frightening that this could happen to any drug that we take and on which we are dependent, even though it is not that common. This time it happened to Abbott and to the tens of thousands of people taking the semisolid capsule. Thankfully, we had the liquid formulation as a safety net. Next time it may happen to another drug

that may not have a safety net.

QUESTION: I don't know if this is the time to address the temperature range in which the liquid must be maintained, but it's confusing to me. I know children who have been on the same liquid formulation and temperature was never before an issue. Is the liquid Norvir that we are taking now the same as the liquid Norvir that the children have been taking? Their virus was controlled by the same liquid that you're now saying needs to be maintained between 68 and 77 degrees. And that temperature range isn't even found in most normal environments. My house isn't 68 degrees. So I'm wondering how fragile ritonavir really is.

SUN: You raised several important issues which I will try to explain. First is that Norvir liquid is Norvir liquid. The liquid is what it was and remains what it is. The liquid formulation has not changed. What we did was change the recommended storage conditions from what was previously a refrigerated product that couldn't be stored at room temperature for a limited period of time to a product that we recommended not be refrigerated but stored at room temperature within a fairly narrow temperature range.

Why? We encountered Form II. Form II is a chemical form of ritonavir that exists regardless of formulation. It happened to rear its head in the semisolid capsule. But when we looked at forcing Form II into liquid ritonavir, we learned that it can live in there as well. As I said earlier, the crux of this problem is solubility. For example, if you take, two tablespoons of water and try to dissolve 16 grams of table sugar in it, the sugar won't dissolve unless you add more water. That is essentially what happened to the semisolid. With the liquid, we realized that at room temperature, that solution would be OK - just like the table sugar and water analogy you want to use. At lower temperatures, one could potentially have the risk of exceeding the solubility. In other words, one could be in a situation where the potential for crystallization was higher.

So the first thing that we did after discovering the crystal form of ritonavir was to make sure that the problem in the semisolid was not happening with the liquid. Then, in conjunction with the FDA, we made the very conservative recommendation that, if possible, people should store it at temperatures where we knew would decrease the possibility of crystallization. Now, does it mean that if you get at 77.5 degrees, something will happen to the Norvir liquid? No. But we have data to support our recommended storage conditions.

From a regulatory concern, we have data that allows us to guarantee certain things, such as the stability of the product for a given period of time. We know that if we exceed the recommended temperature and go to higher temperatures, and this is true for every drug since all drugs are chemicals, drugs start to degrade, and the molecules start to fall apart. Does that happen instantaneously? No. If I were in Tempe, Arizona in the middle of the summer and it was 120 degrees outside, I would put Norvir liquid in the refrigerator if I didn't have air conditioning.

QUESTION: So you're describing actually a very wide range of temperatures that you're saying you're approving.

SUN: No. I am not approving anything. I am only telling you that Abbott can back up the label recommendations with data. I am only commenting on the pragmatic realities that affect how some of us respond to drug labeling.

QUESTION: Why did you recommend such a narrow temperature range for Norvir liquid?

SUN: A 68 to 77 degree temperature range is very narrow and tight. This recommended temperature range is a maximally conservative position on our part. But as I said earlier, you have to accommodate label recommendations to the reality of your situation. What you have to know is that when you go above 77, you don't need to throw the drug away. But you should try to minimize the time and the excess temperature to which you expose the drug. We may have to marry the practicality of our lives with a drug label which is not always practical.

QUESTION: How can you change the label recommendations for temperature so easily without going through all many months of FDA review?

SUN: It is always easier to change to a more conservative recommendation than to a more liberal recommendation. If we had gone to the FDA and said that we wanted to widen the label recommendations, then we would have to go through a more rigorous and extensive review process.

QUESTION: Wouldn't you have to provide extensive clinical data to justify taking Norvir liquid out of the refrigerator and storing it at room temperature?

SUN: No. The previous label provided for storage at refrigeration or at room temperature. We kept the room temperature recommendation. We changed the label to recommend that Norvir not be stored in the refrigerator.

QUESTION: To your knowledge, has there ever been an instance of any crystallization of Norvir liquid under refrigeration?

SUN: There may have been isolated instances which is not unexpected because of what we know about ritonavir. When we first encountered Form II, we wanted to know exactly what situations one could possibly encounter crystals in the liquid, which is a large part of the reason why we opted to go to the room temperature storage. So it can theoretically happen and it has happened, and so we need to recognize that.

QUESTION: It's my understanding that if crystals form in Norvir liquid all that's necessary is to shake the bottle and they will dissolve. Could you comment on that?

SUN: I can say that with less confidence. As you know, using the sugar and water analogy, crystalline ritonavir is simply solidified ritonavir that used to be in solution. And just like every other chemical in solution, increasing the temperature enhances the solubility characteristics of the liquid. I don't know how long it takes. I do know that there have been instances where small amounts of crystalline materials was observed in refrigerated liquid which disappeared after which it was shook. But I don't know enough about it to say that will happen every time.

QUESTION: If crystallization occurs in liquid Norvir and Form II appears, can you tell by looking at it?

SUN: Yes.

QUESTION: You can actually see the crystals forming in the liquid?

SUN: Yes.

QUESTION ...and that's when you would go and get another prescription?

SUN: I would personally shake the bottle based on what I know about these crystals. If the crystals do not go into solution at room temperature, then I would exchange it.

QUESTION: And if it does go into solution, you can pretty much guarantee that the liquid is still an effective antiretroviral?

SUN: I believe so, based on what I know.

QUESTION: How does the formulation problem affect 378 studies?

SUN: For those of you who may not know, 378 is a new Abbott HIV protease inhibitor currently in Phase II. It is a drug that will be co-formulated with ritonavir because the pharmacokinetics of 378 are significantly better with ritonavir than without. We made the decision at the very beginning of development that they would be paired together. Fortunately, we are still in the early stages of development. We had not selected a formulation for 378. We have obviously been dosing it in Phase I and II trials, but we have had time since this all happened to accommodate Form II ritonavir. And that is ongoing. We expect that the formulation issue will not significantly delay the 378 program, which is still continuing right now.

QUESTION: You're using the SEC in the United States?

SUN. Yes.

QUESTION: You are testing ritonavir and 378 together in SEC capsules?

SUN: Yes. But we're using the old SEC - or soft elastic capsules - of ritonavir that we had originally manufactured before Form II came along. These are investigational supplies that cannot be used in anything other than an in investigational way. We have tested all those capsules. They are fine, as far as we can tell. So that is what we are using for 378.

QUESTION: So people are taking ritonavir in SEC capsules right here in the United States?

SUN: Yes.

QUESTION: Can you tell whether there are crystals in any of the semisolid capsules that some of us may still have?

SUN: You can't tell from the outside. You would have to cut them open.

QUESTION: So I could be taking these and there's not any bioavailable drug in them?

BYRN: The drug's fine. There is no risk to the drug's bioavailability.

QUESTION: What specifically do you have to do to establish SEC equivalency before the FDA will approve it?

SUN: I'll try to expand on my previous answer. We have to do what is standard for a new formulation of a marketed drug. We need to show that the new formulation is bioequivalent to the old formulation. Otherwise, we would have to conduct more extensive testing. We need to conduct a relatively short standard Phase I study in healthy human subjects to show that the new formulation behaves the same way physiologically as the formulation currently approved for marketing. Then there is a whole series of data sets to provide, demonstrating basically the physical and chemical integrity of your product under the conditions that specified on the label. Those are physical and chemical stability tests. I could go into more detail, but it would be highly technical.

QUESTION: And how many months of data do you need to collect?

SUN: It's highly variable. It depends on the product, it depends on the conditions, it depends on the type of approval being requested.

QUESTION: But what has the FDA said to you?

SUN: We are in an ongoing dialogue with the FDA in which we present data and they ask us questions. We have not finalized time lines with them.

QUESTION: What has the minimum time been on other drugs in a similar situation?

SUN: I can't answer that. It's a few months at least.

QUESTION: So you don't know if the SEC capsule is bioequivalent or not?

SUN: No. But we wouldn't be developing this if we didn't think it would be bioequivalent. Based on technical considerations, I believe that we have a very good chance that they will be bioequivalent. We actually went a pretty long way with the old SECs and we have made very minor changes to that formulation. So we have every reason to believe that they will be bioequivalent. But the proof is in the pudding. Regardless of what I believe or what I tell you here today, the data will say what the data says. If the SEC is not bioequivalent to Norvir liquid, I will be very sorry.

Posted 12/28/98