Biological Therapeutics for Rare Plasma Protein Disorders
Public Workshop

Lister Hill Center, Bldg. 38 A
National Institutes of Health
8800 Rockville Pike
Bethesda, MD 20894

June 13, 2005

PDF Version (440 KB)

CONTENTS

Introduction: Office of Public Health and Science
Jerry Holmberg, PhD
Executive Secretary, OPHS

Introduction: FDA
Jay Epstein
Director, FDA/CBER/OBRR

Current Challenges
Mark Weinstein, PhD, Session Chair
FDA/CBER/OBRR

US Consumer Perspective

International Perspective
Flora Peyvandi, MD
Chair, Working Group on Rare Blood Disorders
FVIII/IX Subcommittee, ISTH

Physician Perspective
Amy Shapiro, MD
Medical Director, Indiana Hemophilia & Thrombosis Center

Factors Impacting Industry’s Ability to Bring New Biotherapies to Patients
Paul Walton, PhD
Senior Vice President of Business Development
ZLB Behring

IPFA Perspective
Clive Dash, MD
Medical Director, Bio Products Laboratory

Developing Biological Therapeutics for Rare Plasma Protein Disorders
Toby Silverman, MD

Open Panel Discussion
Mark Skinner, Session Chair
President, World Federation of Hemophilia

Current Opportunities
Jonathan Goldsmith, MD, Session Chair
Deputy Director, FDA/OBER/OBRR

European Medicines Agency (EMEA) Perspective on Licensure of Biological Therapeutics for Very Small Patient Populations with Rare Plasma Protein Disorders

FDA Perspective: Current Clinical Trial Designs Review by OBRR for Very Small Populations with Rare Plasma Protein Disorders
Nisha Jain, MD
Medical Reviewer, FDA/CBER/OBRR/DH

FDA Perspective: Licensure of Products Under Accelerated Approval
Karen Weiss, MD
Director, FDA/CDER/OND/ODEVI

FDA Perspective: Statistical Considerations for Very Small Clinical Trials
Peter Lachenbruch, PHD
FDA/CBER/OBE

FDA Perspective: Current Regulatory Incentives
Orphan Drug Provisions
John McCormack, MD
FDA/OSHC/OPD

Open Panel Discussion
Jonathan Goldsmith, MD, Chair

Research Support

NHLBI Research Support for Rare Plasma Protein Disorders

Small Business Innovative Research Grant Program: Development of OBI-1 (Recombinant Porcine FVIII)
Garrett E. Bergman, MD
Vice President, Research and Development
Octagen Corporation

Reimbursement

Medicare Payment for Drugs and Biologics

Open Panel Discussion of Research Support and Reimbursement
Amy Shapiro, MD, Session Chair

KEYNOTE:

"---" denotes inaudible in the transcript.
"*" denotes word was phonetically spelled.

PROCEEDINGS

Mark Weinstein, PhD

DR. WEINSTEIN: --- Associate Deputy Director at the Office of Blood Research and Review at CBER and I would like to welcome you to this workshop on biological therapeutics for rare plasma protein disorders. I have a few housekeeping announcements before we start this session. There first of all is no food or beverages allowed in the auditorium, and you are permitted to take off your jackets. Unfortunately I couldn’t arrange for the weather here in Washington, but it is hot here. I hope that we -- we have the heat, and I hope that we shed some light on the subject of rare plasma protein disorders. We would like to make certain that pagers and cell phones are set to -- are turned off or set to vibrate. Now when you ask questions please identify yourself and activate the microphone so that we can capture your remarks on the recording. We also must be out of here by 5:30, and they turn off the lights, so we do have to make certain that we end on time. There is a cafeteria downstairs. There is also a cafeteria across the way in Natcher Hall, so you should be able to get lunch there.

We have a very full agenda today, and I urge the speakers to keep within their time limits. Our first speaker today is Dr. Jerry Holmberg. He is the Executive Secretary of the Office of Public Health and Sciences who will present some introductory remarks. The OPHS and the FDA have worked together to make this workshop possible. Jerry.

Introduction: Office of Public Health and Science
Jerry Holmberg, PhD

DR. HOLMBERG: Thanks, Mark, and welcome to hot and humid Washington. Being an old Navy guy, I parked my car across the street at the Navy garage and walked in the hot humidity over here, so I am a little sweaty this morning, and on top of that I went to the wrong building. Somehow I was thinking of the Natcher Building, I walked in there, and they are having a seminar on chronic insomnia.

(Laughter.)

And I said hopefully this is the wrong place, so I pulled my notes out. I think that we have a lot of exciting things to discuss in the next two days, and I hope that it will not put anyone to sleep. We are very concerned about the rare protein therapies, and I am pleased that the Department of Health and Human Services along with its agency, the Food and Drug Administration, could sponsor this meeting to hear what is going on in the field of rare protein therapies.

I have really two wishes throughout this, and I was going to say something about cell phones, but Mark has already said that, but I think I will just add a little caveat. I was at an ISBT meeting last year, and they made a suggestion that we collect a fine every time that a cell phone goes off, maybe throw it into the kitty for the -- defer the cost of the coffee. But at any rate, please honor that. I have already turned my computer to mute so that when I power it up it doesn’t go through the Microsoft jingle.

I have really two hopes through this. First of all, I hope that you will realize that we are one department of the Department of Health and Human Services. We have many agencies such as the Food and Drug Administration, the CDC, and of course the reimbursement people, CMS, along with other agencies that we work with on a daily basis, and so we are very interested in what can we do to close the gap in healthcare. I wish we had a bottomless pit to draw the money from, and of course funding is always an issue. But my other hope is that you will realize that we in DC are extremely interested in plasma protein therapies and also that we are passionate about doing what is right. We are looking at evidence-based data and we want to move ahead, move science ahead very fast. Last year Secretary Thompson got the agencies together as far as what were some of the medical initiatives to move new technology forward, and as a result of that there was a document that came out with all the agencies’ strategic plans. So hopefully with Secretary Levitt we will continue to move forward with that and be able to move expeditiously on some new medical innovations.

I know we have a jam-packed next couple of days and to keep on schedule I will turn it over to Dr. Epstein.

Introduction: FDA
Dr. Jay Epstein

DR. EPSTEIN: Thank you very much, Jerry. It is my pleasure to welcome everyone on behalf of the FDA cosponsor, and my task in the next few minutes is to provide everyone with a brief overview of the meeting program. First I would like to outline our objectives, which our prime objective is to facilitate the development of products to treat patients with very rare plasma protein disorders.

(Slide.)

And pursuant to that, we will attempt to learn about the need for and the current availability of these products, to identify challenges to product development, to review current product development procedures and experience from the perspectives of regulators and sponsors, to identify opportunities to facilitate clinical trials, and to suggest new ideas for product development. So how are we going to do all of that? Well, let me just quickly run through the program.

(Slide.)

Here we are on day one, and our first session will be to look at perspectives related to defining the current challenges to the availability of these products. We will hear about the perspective of patients and physicians; an international perspective, what is the scope of the patient population and what products are available in other countries that are not available in the US. We will discuss factors that affect industry’s ability to bring new biotherapies to patients. We will look at FDA’s historical experience in reviewing products for very small populations, and we will have a group discussion.

(Slide.)

The next session of the agenda will deal with defining opportunities. What are the current regulatory pathways and what incentives to development of biological products for very small populations are available to us? Again, we will look at an international point of view from the perspective of the European Medicinal Authority, EMEA. We will look at the FDA perspective on clinical trial design for very small populations. We will have a discussion of FDA’s accelerated approval process, look at statistical issues pertinent to small populations, and we will look at orphan drug provisions and incentives, and again have a group discussion.

(Slide.)

We will then close the day with an overview of governmental funding support that would facilitate product development. There is research support for the NHLBI for rare plasma protein disorders. We will look at examples of NHLBI support for the Small Business Innovative Research Support grant. We will look at opportunities that may exist in the Medicare payment program, and again have a time for discussion.

(Slide.)

Then tomorrow we will look perhaps in greater depth at some illustrative cases of product development and in particular we will look at protein C, factor XIII, antithrombin III, certain platelet disorders, and an enzyme to treat Fabry’s disease.

(Slide.)

Then in the closing session tomorrow we will explore the role of post-market data collection: the experience of the FDA and EMEA with post-marketing data collection, the experience of sponsors in collecting post-marketing surveillance data through third parties, consumer group-initiated post-marketing surveillance, and opportunities for data collection through registries and through the CDC. We will then have an open discussion and then a concluding panel will attempt to frame a pathway forward.

So in closing these brief remarks, I want to give special thanks to people who made this workshop possible. First, I want to thank Jerry Holmberg for providing both leadership and also cosponsorship support for this meeting. I know that this is an issue important to the Department of Health and Human Services as we have already stated. Then I would like to thank those individuals who helped us to develop the agenda. They formed an ad hoc scientific program committee, Donna DiMichele, Glenda Sylvester, Rainer Seitz, Mary Gustafson, and Amy Shapiro. Lastly I would like to thank the support team at FDA who worked with Mark Weinstein to make the workshop possible, and they included Nisha Jain, Jonathan Goldsmith, Andrew Chang, Trevor Penley, Dot Scott, and Jim Durham. So in the interest of time I will just turn to podium over to Mark Weinstein, who has been the chief architect of the workshop and will also chair our first session, again on current challenges. Thank you very much and welcome to all.

Current Challenges
Mark Weinstein, PhD, Session Chair

DR. WEINSTEIN: The first speaker today is Anthony Castaldo. It is really a great pleasure for me to have Anthony speak with us today. He is the President of the International Hereditary Angioedema Association, and he will discuss on a personal level the challenges the US consumer faces in obtaining products to treat very rare plasma protein disorders. His story is the ultimate reason of why we are gathered here today.

US Consumer Perspective
Tony Castaldo, MPA

MR. CASTALDO: Thank you, Dr. Weinstein. It is really a pleasure to be here today and I think it is quite extraordinary that the patients can have a voice in such an important meeting. I will use my allotted time to share the perspectives of patients with the rare disease called hereditary angioedema, or HAE for short. A plasma-derived protein called C-1 inhibitor concentrate has been safely and effectively used to treat this disease in Western Europe and other parts of the world for well over a dozen years. Our patient community has nothing short of a desperate need for C-1 inhibitor concentrate, and we are delighted there are companies interested in licensing this product in the United States. We are also very excited that the FDA and the industry are here today to discuss ways to perhaps expedite the process for making vital plasma proteins available to treat rare diseases. Even if it is too late to revisit the current regulatory approach to licensing C-1 inhibitor concentrate, perhaps there are aspects of our experience that could influence the process for other groups of patients who are also faced with the desperate need for therapy.

Before I begin let me offer the disclaimer that insures my time with you today complies with federal law. Although the organization that employs me is technically not a governmental entity, we are included in the Office of Government Ethics Statutes. Therefore, by law, I am precluded from representing any third party interest in this government-sponsored meeting. Accordingly, while I am the President of both the United States Hereditary Angioedema Association and the Hereditary Angioedema International, to insure strict compliance with applicable federal statutes let me state for the record I am here representing myself and my family of severely affected HAE patients.

It is always a daunting task for a patient to face such a talented group of scientists and business people who have such a keen grasp of regulatory policy, clinical trial design methodology, and the technical aspects of plasma fractionation. So to level the playing field, at least in my own mind, I came here today with the thought that even the most learned among us could benefit from listening to a range of viewpoints. I have always believed that knowing the full range of an issue’s dimensions results in better judgements because it can insure that we look before we leap.

Now these thoughts brought to mind the experience of twin brothers who actually hit the autosomal dominant jackpot because both boys inherited HAE from their mother. These bright young men did their best to live the normal life in spite of frequent HAE attacks and both were accepted to the same medical school. In the summer before they were to begin their first year, they decided to take a quick backpacking tour of Europe and of course stop off in Italy, which indeed is the mecca for HAE research. When they got to Rome, the twins called the renowned HAE researcher and were ecstatic when the scientist not only agreed to see them, but asked if they could come over immediately and accompany him to Brussels for a talk on HAE pathophysiology.

The conference sponsors had arranged a small private propeller aircraft to take the doctor and his new friends to Brussels. Unfortunately, a few minutes after takeoff the engine’s plane caught fire and it was clear that everyone would have to parachute to safety. As the pilot tried to steer the plane over an uninhabited area, he gave his passengers some chilling news. There were only three parachutes onboard. After that bit of news and a quick calculation the scientist stood up and proclaimed, "I’m a brilliant scientist who has written hundreds of scientific papers. The world’s HAE patients and all of humanity needs me." With that, the scientist dawned some paraphernalia and jumped out of the plane. The twin brother began laughing hysterically, which did not sit well with the frantic pilot who said, "What on earth could be funny about this situation?" To which one of the twins said, "The brilliant scientist just jumped out the plane with my backpack."

HAE is a rare condition with the a genetic defect that causes a deficiency in the plasma protein C-1 inhibitor. Dysfunctional C-1 inhibitor protein permits production of basal active peptides that alter vascular permeability and cause edema. Accordingly, the disease is characterized by an episodic swelling of the extremities, face, bowel wall, and upper airway. While HAE attacks are often painful and debilitating, because edema can affect the gastrointestinal system, attacks can also be life threatening when the airway is implicated. Indeed, studies of affected --- have reported mortality rates of over 30 percent with death caused by asphyxiation due to airway closure. Tragically, Americans are still dying from HAE, and the disease recently claimed the life of a 12-year-old girl from Alabama who expired in her father’s arms from edema that totally obstructed her airway.

HAE is a catastrophic unmet medical need in the United States because there is no therapy available to treat an HAE attack once it begins. 17-alpha-alkylated anabolic steroids are useful for HAE prophylaxis in certain adults. Data from a US HAE Association reveals that many patients continue to experience periodical acute attacks notwithstanding ongoing therapy. The utility of these agents is further limited because they are not well tolerated by women and their use generally contraindicated in children, some of whom tragically are severely affected and suffer frequent attacks. Isn’t it ironic that 300-pound NFL linemen are suspended and counseled for the extreme dangers posed by relatively short course of these drugs, while our patient community is relegated to the chronic use of these toxic and highly undesirable agents.

In attempt to provide the most desperate of HAE patients with relief, the Hereditary Angeioedema Association provides technical assistance for patients wishing to purchase C-1 inhibitor concentrate under the egest of the FDA’s personal importation guidelines. However, C-1 inhibitor is an expensive medicine, and no insurance company will reimburse an unlicensed therapy. Therefore, most of the patients who truly need C-1 inhibitor therapy do not have the financial wherewithal to participate. Many of those who are able to purchase the concentrate, however, soon realize there are limits on the number of times they can remortgage their homes or rely on the generosity of relatives and friends. After depleting available resources, these brave souls are now back to living with the pain, disability, and fear of death that accompanies severe HAE.

From the patient’s point of view the agenda for this meeting today can be condensed into a two-part question. How much evidence is sufficient enough to support licensing of plasma protein for rare diseases, and how can regulatory practices accommodate the multifaceted challenges posed by rare diseases that do not fit any standard mold? Our studies indicate that the regulatory framework for expedited licensure of medicines that benefit severely ill patients with unmet medical needs has been in place for over two decades. Indeed, the FDA’s accelerated approval regulations were first promulgated in the 1980s by Commissioner Frank Young and subsequently codified under the Food and Drug Modernization Act of 1997.

The HAE patient community believes that our unique situation provides an excellent vehicle for exploring the issue of expedited approval. After all, HAE is a dreadful unmet medical need and there is compelling and longstanding evidence supporting the effectiveness and safety of C-1 inhibitor concentrate. For example, in Western Europe there was a sophisticated network of physician researchers who actively treat and study HAE patients. This group of world-class experts has written hundreds of papers on HAE, and every study that we have seen that discusses HAE therapy sites C-1 inhibitor concentrate as the safe and effective treatment of choice for acute HAE attacks. The viral- inactivated preparations made in Europe, and these products are the candidates for US licensure, have accumulated an extraordinary safety record over the past dozen or so years. --- filtration is yet another viral inactivation step that will supplement patients’ and physicians’ confidence in this lifesaving product.

While safety surveillance data collection in Western Europe might not be as methodologically pure as some would like, there can be absolutely no doubt that any safety problems would have been detected and recorded by the formidable group of Western European HAE experts who frequently treat their patients with C-1 inhibitor concentrate. It is our opinion that the magnitude of cumulative safety and effectiveness evidence is sufficiently convincing and unequivocal, and the risks are clearly low enough to consider expedited licensure of C-1 inhibitor concentrate contingent upon successful GNP inspection with supplementary but binding agreements for intensive post-marketing surveillance and other selected studies.

The impact of regulatory decisions on human life is enormous and weighs heavy in the daily lives of many in our patient community. This is certainly the case in my family because my 20-year-old daughter suffers from an extremely severe case of HAE and is --- to androgen prophylaxis. This young woman has upwards of 20 attacks a month and a third or more involve her airway. By dent of the insane Washington, DC metropolitan real estate market, I am one of the fortunate who has been able to liquidate financial resources and purchase C-1 inhibitor concentrate. With access to an intelligent use of therapy, this young woman has been transformed from total disability to an honor student in finance and accounting at a local university. Unfortunately, the severity of her disease is not unusual in the HAE patient community. Since Father’s Day is coming up again I am reminded of the card my daughter gave me on that day last year. Her words were few, but absolutely profound and reflect the power all of you hold in your day-to-day work, and it simply says, "Dad, thanks for keeping me alive."

I will close my remarks this morning with what our patient community has dubbed the HAE clinical trial paradox. A design parameter built into a C=1 inhibitor trial stipulates that patients who arrive at the clinical trial site with a life-threatening airway edema attack will not be randomized, but instead will be given open-label C-1 inhibitor therapy. Ladies and gentlemen, I think that speaks for itself and is the perfect coda for what I have shared with you today.

Thank you for giving the me the opportunity to speak with you this morning.

(Applause.)

DR. WEINSTEIN: Thank you very much, Tony. I think that was a very well-put speech and we appreciate your being here and your personal experience. We will have opportunities after this session as Jay has mentioned here for panel discussion with all the speakers in this session and we will be able to discuss in some detail the proposals that have been made here, and in the rest of this meeting in fact on the suggestions that you have made for your clinical trial approach.

International Perspective
Flora Peyvandi, MD

DR. WEINSTEIN: Our next speaker is Dr. Flora Peyvandi. She is the Chair of the Working Group on Rare Blood Disorders of the Factor VIII/IX Subcommittee of the International Society of Thrombosis Hemostasis. She will give a view of the international perspective on the need for these products and a review of some of the products that are currently available in the United States and elsewhere to treat rare plasma protein disorders. Thank you, Flora, for coming all the way from Italy to attend this meeting.

DR. PEYVANDI: Good morning, everybody, and thank you for inviting me and giving me this opportunity to talk about what is already available for people who are affected with rare protein disorder and what is the situation of these patients in the world and what we have available to treat them. Just to get the section why we need a working group under the subcommittee of the ISTH, I think we need to go a little bit about the background of rare protein disorder, what they are and how these people are usually treated and what is the most clinical manifestation in these patients.

(Slide.)

These disorders are usually inherited as autosomal recessive disorder, and the numbers in the general population is approximately one case in 500,000 for factor VII deficiency for example, and for the rarest one like factor XIII or hyperprotein anemia is one case in every two- or three-million of the general population. These numbers are significantly increasing in some areas of the developing countries because of higher frequency of consanguineous marriages, and the numbers of the patients sometimes is touching like hemophilia B populations in these countries then you can address then they are requiring really a more demand for the diagnosis and treatment.

(Slide.)

These type of diseases as in orphan diseases until very recently there were really neglected by every organization, pharmaceutical companies, and this type of patient, they were absolutely orphans without any type of facility for the diagnosis and treatment.

(Slide.)

So what is the clinical manifestation in these people? We tried to make an international registry to collect more data available in the world because since 1996 there were only a few reports reported by each single researcher or groups around the world, and it was very hard to understand, which is exactly the clinical situation of these patients. So what is the best treatment for these people? What is the best type of prophylaxis? The first is we thought that maybe put together the information and try to find some type of guideline, at least for the starting point. These data that I am reporting here is coming from different patients around the world, with more than 200 families, around 700 to 800 patients. Totally we can say that these types of patients, they are bleeding less severely than hemophilia A and B and the life and limb threatening symptoms are usually less frequent. The type of bleeding in this patient could be very various, from mild to moderate, and could sometimes also be very severe.

(Slide.)

Here is a conclusion of what is the difference between hemophilic patients and compared to the rare bleeding disorder. The grey bars, they are showing the hemophilia patient. You can see the joint and muscle --- are much more frequent. For rare bleeding disorder, the mucosal type of bleeding are really important, and especially in the women. More than 50 percent of the women who are affected with rare bleeding disorder are chronically anemic and they have to be treated with the chronic type of treatment for all their life.

(Slide.)

This slide is a complicated slide but it is a result of four or five slides together. I tried to compare each single disorder compared to the hemophilia, which you can see on the left side if reported. On the left side I have got all the clinical information on 100 patients of severe hemophilia A and the red color in the middle is showing the personal prevalence of each single severe bleeding symptom, and the blue one the mucosal type of the bleeding. On the right side, the group of each single deficiency like --- anemia, factor II deficiency, factor IV, V, VII, X, XI and XIII was compared and the intensity of bleeding was compared with intensity of the color. As you can see, factor X is one of the most severe bleeding symptoms, and I remember when I was in one of the Middle East countries more than 89 percent of these patients, they were HCV-positive just last year. We are not talking about ‘80s, and most of them also were HIV-positive. That means these types of patients, they are requiring a huge number of treatments, and since there is no concentrate available in this area, they are still treated with plasma and not --- inactivated type of plasma. Then factor XIII deficiency is an important disease because a little amount of factor XII is enough and it is sufficient to prevent the bleeding symptom, the severe type of CNS bleeding and miscarriages in the women. Just 25 percent is enough. So the prophylaxis is a very important issue in this group of patients. Factor V and factor V and VIII deficiency are less severe, but once you have a patient with this type of disease it is hard to treat them because the only available product is plasma, and we have no factor V concentrate available. Factor II deficiency and hyper-fibrinogen anemia, they are the patients sometimes that are requiring prophylaxis treatment because of joint and muscle bleeding.

(Slide.)

Once we make the diagnosis it is starting the most severe section of the rare bleeding disorder, how we are going to treat them. So there are few long-term prospective studies only available on the large cohort of patients, and that makes it very difficult to give us enough information about how to treat and how to manage these patients. The coagulation factor support may require the prescription in most of the countries of unlicensed treatment products which are not readily available. The purified factor concentrates are not as readily available as it is for hemophilia, and how we can see now that we are at the third generation of the recombinant product for hemophilia for factor VII, but still we have really no suitable treatment for these type of diseases.

(Slide.)

Mainly the treatment of rare bleeding disorder is focused by replacement therapy and non-transfusional treatment.

(Slide.)

I am just talking about the replacement therapy today, and all of us, we know the backbone of the treatment is fresh-frozen plasma which contains all coagulation factors, is inexpensive, and is widely available in the world. But of course it is very important to find the virus-inactivated FFP, which is really a very small amount of the available product in the world.

(Slide.)

A few single-factor plasma-derived fibrinogen factor VII, factor XII and factor XIII concentrates are licensed in some European countries and hardly distributed uniformly in all Europe, and very few in the States. The prothrombin and factor X deficiencies are often treated with prothrombin complex concentrates, and that sometimes makes a problem when you have a patient with thrombophelia history because that contains an unnecessary amount of vitamin K factor over the actually deficient ones. There was really little progress in the treatment of rare bleeding disorders because we have only one recombinant product, which is factor VII-a recently licensed for factor VII deficiency in Europe, but still not licensed in the States for factor VII deficiency.

(Slide.)

Factor V and V and VII deficiency could be only treated with fresh-frozen plasma.

(Slide.)

Here you can see the factor concentrates available reported by Dr. Casper and the World Federation of Hemophilia. As you can see, there are different companies producing, at least it is reported, the different concentrates. But to my understanding and to my experience, in some of the countries the distribution is not really as reported in the literature. So fibrinogen is completely missing in Italy and once I have a patient with severe bleeding I have to order it by international community, and it is taking me like two weeks to have the product.

(Slide.)

This is the prothrombin complex concentrates, and still you can see there are different companies producing this product.

(Slide.)

But since I had the feeling we need to establish a better distribution in the world of these products, I sent a questionnaire to all the companies asking which product they are still producing which could be useful in rare bleeding disorder, is there any type of variation in the production of the manufacturing, are they using any type of plasma-derived product, how is the situation with the virus inactivation, which method they are using, there was any type of improvement of the virus inactivation methods, which type of rare bleeding disorder is the focus of their products, and in which region of the world they are usually distributed.

(Slide.)

The last question was answered really by very few companies, and this was the result that I obtained. So the questionnaire has been sent to 23 pharmaceutical companies, and 43 percent, they have answered to my question. Four of them, they had no more production, but we will see how is the result. So these are the companies that answered to the question, four persons. American Red Cross is no longer producing this product. Mostly, 70 percent, they have no change and there is no variation, and as you can see they are also reporting the data on factor VIII or factor IX. I was surprised they didn’t even mention for rare bleeding disorders other types of the disorder, and only LFB was reporting the production of a new product, the fibrinogen, and no other product is still in the production of the new manufacturing.

(Slide.)

So only one new product for fibrinogen deficiency emerged from the questionnaire. The trend of pharmaceutical manufacture research is principally focused on new products to treat the hemophilic patient.

(Slide.)

I see in literature very recently where the ZymoGenetics Company is producing a new recombinant product of factor XIII. This product is a recombinant factor XIII A2 homodiner produced by yeast and was used in 50 healthy adult volunteers. The result was good with the product was well tolerated with no serious adverse events or dose-related toxicity. However, I think we need to see the result of this product in the patient affected by factor XIII deficiency.

(Slide.)

What about the guidelines? In the literature we can find two guidelines, one with Mannucci and myself under recessively inherited coagulation disorders published in Blood in 2004. The other one from Dr. Bolton-Maggs reported in Haemophilia in 2004, and still I think both of these two results, they couldn’t cover lots of information.

(Slide.)

Which could not be covered if we don’t put all our forces together making an international registry putting all information together and trying to constantly follow drug production, cost of the product, the distribution of the product in the world. We have to try to make a guideline treatment for difficult situation on demand, prophylaxis, neonate, children, the women during the pregnancy, for the women with a problem of minuartia, and long treatment. We need to know if the patient with heterozygosity and with the mild or moderate level of different factor needs to be treated, and we also need to know how safe is the prothrombin complex. So all this information needs to be done with the different groups, and I think the only working group under --- of the clinical people coming from different areas of the world and the experts who for years and years have to do for these patients could make together the force and make the unique information which could be used for the clinician and also for the patient. Thank you for your information and attention.

(Applause.)

DR. WEINSTEIN: I think we could have just perhaps a few questions if someone has some questions that they would like to ask at this point, or we could wait until the end of the panel discussion at the end of this session. Okay. If not, we will just go on.

Physician Perspective
Amy Shapiro, MD

DR. WEINSTEIN: Our next speaker is Dr. Amy Shapiro. She is the Medical Director of the Indiana Hemophilia and Thrombosis Center and she will discuss the challenges faced by physicians in attempting to treat patients with rare plasma protein disorders. She will present a case study of her struggles to develop a biological therapeutic to treat a rare disease. I should also mention that Amy’s efforts to make the plight of under-served patients visible was one of the major driving forces that lead to the development of this workshop. Amy.

DR. SHAPIRO: Thank you, Dr. Weinstein, and thank you for inviting me here today. I promised Mark that I would keep this to 20 minutes, so I am glad to see that we are ahead of time, and I might have an extra minute or two. But I am also glad that Flora did such a wonderful job presenting this information, so some of what I have is redundant and I will be able to flip over quickly.

(Slide.)

So I was going to present today rare bleeding disorders and the physician’s perspective on therapeutic needs, provide you some background information and some data on rare deficiencies, which Flora has done so we can go over that quickly, present to you a case in point. I brought the handouts with me. They were at the front desk. I hope you all have them. Attached to the back of them are two letters from two families that I take care of that discuss their care, and some proposals for moving forward.

(Slide.)

In the United States, the definition of a rare disorder is a disease or condition that affects fewer than 200,000 Americans.

(Slide.)

As Dr. Peyvandi very well pointed out, factor VII deficiency fits in that category very well, affecting about one in 500,000 population. There are two registries that include these patients. She has discussed some of this information.

(Slide.)

There are other factor deficiencies, bleeding disorder for the most part, that also fit this definition. Some of these have specific replacement products, although they may not be licensed in the United States. However, these products may yet still not be ideal, even though they exist, because they may be plasma derived. But a recombinant replacement product may never be developed for these diseases due to the rarity, the patient pool for which they would be utilized, and the cost of production.

The real issue are other deficiencies that are so rare to preclude development of a specific replacement product, including, as Dr. Peyvandi mentioned, factor V deficiency, X, II, plasminogin, alpha-2 antiplasmin.

(Slide.)

The issues are in treatment the ability to obtain an efficacious product and the knowledge of an appropriate replacement strategy for these patients, and because there are so few patients and because we have not very good products, it is difficult as a treating physician to garner this information. There are clearly barriers in the development of adequate replacement products: the cost of research, the cost of clinical trials which is immense, a limited market in which to utilize them, and the regulatory burden on the manufacturer and the investigator. In terms of development of clinical trials, one of the problems is the adequate number of patients, and the issue is we like to get compliant patients into clinical trials so that we know we can get the required data points. But the problem is that not all patients with rare deficiencies are as compliant as we would like them to be to participate in a clinical trial, but these individuals are still deserving adequate care.

(Slide.)

Well, reimbursement then becomes an issue for these patients. It is very difficult or you are unable to obtain insurance coverage for therapy if this product is imported for personal use or is used off label. Importation and off-label use are really not adequate long-term solutions for treatment of these patients, and given the high price of medications in general this issue is becoming increasingly important as Medicare, Medicaid, and hospital budgets are increasingly constrained.

(Slide.)

So patients with rare deficiencies have very limited options for care. Their standard of care is often far lower than that of hemophilia, and they suffer increased morbidity and mortality.

(Slide.)

So where are you with a rare disorder? And this is sort of an algorithm I put together as I was struggling through trying to find some products for my patients. You could be in the category of having a product licensed in the United States but not for this indication. For example, that could be factor VII deficiency and the use of recombinant VII-a. If you are lucky, the product may be available in the United States. If you are not so lucky, the product may not be available in the United States.

Then the question, which I didn’t know until I bumped into it, was whether the manufacturer’s BLA is up to date with the FDA. You could be in the category of not having a product licensed in the United States for use either on or off label, but maybe that product is licensed outside of the United States for that particular indication. For example, that could be protein C concentrate. Or perhaps the product is licensed outside of the United States but not for this indication. Again, an off-label use. Then you could be in the category of no product in or outside the United States for use either on or off label. That is not a good category.

(Slide.)

So here is where you have a problem. The biggest problem for treating physicians is the product is not available in the United States and the manufacturer’s BLA is not up to date, the product is licensed outside of the United States but not for this indication, which makes importation more difficult, and there is no product available either in the US or outside.

(Slide.)

So I would like to talk just a little bit about a disease called ligneous conjunctivitis, which started my quest on rare diseases. I thought it was interesting when I first got the patient referred to me, and now it has become more of a heart-wrenching event. This is a rare disease that is characterized by formation of thick membranes of the palpebra surfaces which progress to thick nodular masses that replace the normal mucosa. It may be precipitated by an infection or some incidental injury. The pseudomembranes are lesions that may be observed in the mucosa of other areas, including the mouth, tongue, nasopharynx, tracheobronchial tree, female genital tract. They may lead to loss of sight, hearing, teeth, sterility, hydrocephalus, dysmenorrhea, chronic sinus or pulmonary disease and death, and it has been demonstrated to be due to a deficiency of a plasma clotting factor, plasminogen.

(Slide.)

Plasminogen deficiency manifestations, as I eluded to, do not just include ligneous conjunctivitis, but also oral lesions which can be termed ligneous gingivitis; lesions of the female genitourinary tract, or ligneous cervicitis or vaginitis; hydrocephalus; and ear, sinus, and tracheobronchial tree abnormalities, and if the obstruct the tracheobronchia tree may cause death.

(Slide.)

This is a picture of an infant who is reported in the New England Journal of Medicine in 1998 with ligneous conjunctivitis, and you can see that his eyes are completed occluded by these woody membranes, which cause corneal abrasion and scarring and blindness. This infant was treated with a plasminogen concentrate which is no longer available.

(Slide.)

As I began to explore what treatment options were available or had been used and reported in the literature for the treatment of this disease, I developed a list of therapies. There are some therapies that have been used just topically, and there are others that have been used systemically. I have stared -- I have put a personal efficacy rating on some of these. The ones that are unstared are not even considered to be of even minor efficaciousness. The ones that are stared have some efficaciousness, but for example excision may be important to do because of the occlusion of the eye, but it leads to a recurrent cycle of regrowth of membranes due to the surgery and removal of the membrane itself. So it is not a good long-term solution.

The best products that have been utilized include the use of plasminogen, either topically for example as an eye drop as a solution, or systemically.

(Slide.)

This is that same baby after treatment with systemic plasminogen concentrate. You can see there is a huge difference with regression of the membranes.

(Slide.)

So I had patient referred to me in 2002 by an ophthalmologist who had ligneous conjunctivitis when he read some reports that this was associated with plasminogen deficiency and obtained some plasminogen levels on this individual and documented that that was indeed his problem. The review of the literature that I did at that point revealed that a drug called Eminase was efficacious for local therapy. This is a drug that is used as a fibrinolytic agent systemically given intravenously. However, because the market in the United States for fibrinolytic agents has been taken over essentially by recombinant proteins, this drug was no longer marketed in the United States for that specific indication. However, it was still utilized in Europe and marketed there. It contains plasminogen and streptokinase.

I contacted the manufacturer of Eminase, who initially seemed willing to provide the drug to the patient for free. I contacted the FDA to do it right because I didn’t want to do anything behind anyone’s back and break any laws, and I was asked to file an IND. I reviewed with the FDA in a very nice conversation the work that was required to accomplish this from both the investigator side and the manufacturer side. What I found out in terms of the IND was there was tremendous amount of time required from the investigator to put this together, and the manufacturer must have an updated biologics license application at the FDA. Unfortunately because Eminase no longer had a market in the United States, although it was technically licensed, their BLA was not up to date.

So in the end, as Mother Teresa said, no money, no mission. Everything has a cost. There were no funds available to reimburse the time to do this, and the manufacturer decided that financially it was not feasible for them to update their BLA with the FDA when the potential market for the drug did not exist in the US and then what they would be doing is supplying the drug for free as well. So it was a total financial loss for the company from that standpoint.

(Slide.)

So then I went to look for how else can I possibly get this drug. I called Canada and found out it was not available there either, so going over the border wasn’t helpful. We could write a prescription and have either myself or the patient import a personal supply of the drug, and as we heard this morning the company didn’t want to donate the drug due to the cost and the fear of legal repercussions if they donated, and the patient unfortunately didn’t have enough money for travel. Even if we got the travel donated by some charitable organization, they couldn’t pay for the drug once they got, for example, to Germany to get a prescription filled.

(Slide.)

In the end, what I realized is that really plasminogen deficiency is a systemic disease, and I now have more than one patient. I have the patient who has ligneous conjunctivitis who also has sinus disease; I have one patient with ligneous cervicitis, infertility, sinus and ear disease, and a history of ligneous conjunctivitis which she presently does not have now; and I have two patients with ligneous gingivitis, one of who has associated cervicitis, hearing loss, and sinus disease.

The optimal treatment for these patients is either some medication with demonstrated efficacy that can be used locally in a variety of sites -- and it is hard to think about using Eminase as a douche or in other areas, in your ear when it is the middle ear that is affected -- or a systemic medication, a plasminogen-replacement product.

(Slide.)

So I went in search of plasminogen. There was one report in the literature in the New England Journal of Medicine using a plasminogen concentrate, but this company no longer manufactures that product and was not willing to remanufacture that product. Interestingly since plasminogen is part of Eminase, the plasminogen that is part of it is plasma-derived and is of clinical grade because it is used both intravenously and topically. But I could not find out the plasminogen supplier to the manufacturer to obtain this one component. Plasmin is presently in clinical trials. It is manufactured from plasminogen. This is a plasma-derived product, but step at which plasminogen is available is not again at clinical grade. Plasmin itself is not efficacious for the treatment of this disease due to inactivation locally very rapidly in the tears by antiplasmins, and there was a concern from the company that was developing this product about the use of an investigational product for an off-investigational use in terms of how it might potentially derail their entire research program.

So then there were some reports about making your own plasminogen, and on some nights of desperation I thought about this. There are issues about the costs of doing this and how to get financially reimbursed for it. We didn’t think that that was possible, but even if you put that aside there were the issues of the consistency of the product that we could produce on our own and the viral inactivation, which would not be available. Then there were legal and regulatory concerns. So although it is published in the literature that people are doing this, there are concerns about making products such as this and utilizing it for individual patients.

(Slide.)

So how do we move forward for these patients? Well, clearly it seems to me that we need to form a coalition of agencies all with mutual interests in these populations. This could include NHF, ISTH, the World Federation, NORD, and other interested agencies.

(Slide.)

We need to work with the FDA and industry to develop mechanisms to allow improved access to these therapies. Some of those could include obtaining another licensed indication for an already-licensed drug -- for example, NovlSeven for factor VII deficiency; obtain a product that is licensed in another country for use in the United States for which we have no viral-inactivated alternative; or produce a product that does not yet exist -- for example, plasminogen or factor V concentrate.

(Slide.)

We would like to work with the FDA and industry to develop mechanisms to allow improved access to therapies. Is it possible for the FDA and EMEA to harmonize its processes for these rare patients only so that we can pool our data and make things available across borders? Can we explore alternative mechanisms of drug importation with the FDA that may allow payment?

(Slide.)

Due to rarity of these disorders and lack of universal adequate available therapy, trials such as we understand them and utilize them in hemophilia may not be feasible in these patient populations.

(Slide.)

There are different kinds of trials that can be performed: pharmaceutical sponsored trials, investigator-initiated IND processes. These processes may be difficult. Can we streamline them? Is investigator support available for the time required to do this? The use of registry data to support license indication is difficult. It is not always prospective data. It is not always controlled, but maybe we should consider this for very rare diseases, and we need to encourage registries through independent organizations so that they are as unbiased as possible.

(Slide.)

As will be discussed later today, obtaining orphan drug status based upon a therapeutic indication for a rare disorder provides incentives for drug companies, and I have listed these just from my own knowledge so that when I call these companies begging for something and trying to get some help I try to remind them of this in case they are applying for anything else to keep that in mind, and that very small populations in the past have been used to get licensure for some rare products, including Ceredase and peg-ADA.

(Slide.)

Off-label use of currently licensed products, the incentive to the manufacturer may be small business innovative research grants, may be a six-month patent extension, which can translate into a lot of dollars if a drug is invested for example in a pediatric population even if the treatment of the rare disorder represents a non-profitable group. We need to encourage synchronization of European and United States regulatory agencies for these disorders to prevent repetitive work and increased financial burden on the manufacturer. Every time we have to repeat these studies it costs more.

(Slide.)

There are aims that we have to keep in mind when we do these trials. We want safety data. We want determination of efficacy. We want to know at least the risk-benefit ratio, especially when we explain these to patients, and we need some dosing guidelines. We need to collect adequate data to obtain approval through regulatory agencies whenever possible. We need to do our best.

(Slide.)

We need to base these studies on the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice. We need consistent and verifiable data, and we need a commitment for followup from the investigators and the patients.

(Slide.)

In summary, rare disorders have limited therapeutic options. Patients suffering from these diseases need access to adequate therapy whenever it is available. Clinicians require technical assistance to deal with manufacturers and regulatory agencies to assure that their patients have access to these therapies, and we need multinational studies to obtain adequate patient numbers.

(Slide.)

One concept is the development of a multi-organizational clearinghouse or resource center for the purpose of assisting clinicians, searching for treatment options, protocol development, interfacing with regulatory agencies, and to find companies that can assist in obtaining orphan drug status throughout the world. We need to also consider the development and maintenance of listings of interested private and governmental agencies; manufacturers with potentially effective therapies either licensed or in clinical trials, because it is very difficult to find manufacturers with products in clinical trials that could be potentially efficacious for this population; and those companies who may have an interest in assuming a product portfolio for limited indications. Thank you.

(Applause.)

DR. WEINSTEIN: Thank you very much, Amy. We appreciate those comments, and again we have a few moments for questions if you would like to ask Amy a few things. Okay. I again have been reminded to remind you that we do not allow food in the auditorium. Please do not eat or drink in the auditorium.

Factors Impacting Industry’s Ability to Bring New Biotherapies to Patients
Paul Walton, PhD

DR. WEINSTEIN: Our speaker is Dr. Paul Walton. He is the Senior Vice President of Business Development at ZLB Behring, and he will talk to us about factors impacting industry’s ability to bring new biotherapies to patients. I think this is really a critically important topic, because by understanding the costs that are involved in a sponsor’s decision to develop a product for a rare disorder we may be able to identify incentives and opportunities to make their decision to go forward more attractive. So, Paul.

DR. WALTON: I would like to thank the program organizers for inviting -- particularly Mark Weinstein and Mary Gustafson, for inviting me to present today. What I am going to give is a perspective on how for-profit manufacturers approach investments to bring new therapies to market with some concluding comments that I think are relevant for the discussion today on rare disorders.

(Slide.)

So in my outline I would like to walk you through some of the background that impacts decision-making in industry, some background on the value and economics of plasma biotherapeutics. I want to show you one of the mechanisms we use, and it is one of the mechanisms. I make the point this is not the only approach the for-profit industry takes, but this is a very important approach, which is using investment analysis techniques and decision rules to bring new therapies to market. Then to conclude I want to go through some of the factors that impact our decision to proceed or not, and in fact if I have time I have a couple of simulated analysis to show you how these analyses are done and come to a final decision.

(Slide.)

To begin with, I thought it would be worthwhile to make the point that all organizations, whether they are for-profit enterprises like my company or not, deliver value in some form. They fill a need. If the organization delivers value and adds value, then it continues to exist and thrive. If something interrupts that value creation, we end up with change. I make this point because in the plasma protein therapeutic area there has been a lot of change in the last five or ten years precisely due to this factor that owners or stakeholders perceived value not being delivered and changes have taken place. You could probably write several case studies on the plasma therapeutics business in this context.

(Slide.)

I would also like to just simply review some of those factors that we have to consider in running a for-profit enterprise. The business internally obviously under leadership determine strategy, planning, and business processes. Externally though we have to consider our supply chain and our product chain and raw materials for our product, principally plasma. We have to consider safety and supply issues, costs. On the production side for products and services we look at our markets, and quite often consumers are several steps removed from us. The end user often is further down the distribution chain, being a physician or patient who receives the product, so we need to respond to their needs and come up with appropriate products and services.

In addition to this, we have a lot of inputs. Certainly government regulations and polices, economic conditions, particularly for those companies that operate in a number of arenas. We operate in Europe, Asia, the United States, Latin America, and almost all economies, so we have to consider each of those jurisdictions separately. We have to consider society and the community concerns that impact our business. For most of us we have a parent corporation, and they set priorities. The majority of those priorities fit with our strategic goals, some of which are financial. It is important to also consider we have a lot of resource provision considerations. There are organizations that provide for us technology people, money. For publicly-listed companies with shareholders they provide capital. The majority of companies in this sector are publicly listed. The shareholders in return expect dividends and equity in the organization. Finally, we have to consider our competitors, who look to competing with us for resources and also into the marketplace. So this just sort of simply gives the bird’s-eye view of the number of factors that we must consider in running an organization.

(Slide.)

Put simply, I see our business as basically a creator of value, a machine that takes as an input shareholders’ money and plasma and develops products. We have a responsibility to patients who require these therapies and to those shareholders who provide the money to drive the engine. We run through clinical development, capital investment, launch, production, et cetera, and if it works well we produce therapies for patients who need it and we produce dividends for shareholders. But I want to point out, and I think this is fairly obvious, there is a significant risk in this business which would shut down this machinery.

(Slide.)

I will focus on shareholders for a minute. It is pretty obvious if they are not satisfied with their return on investments they have options such as investing in the competition or other sectors or other geographies. So we have to consider their appetite for risk, which is proportional to the return that they expect. We have to understand what our investors are looking for when investing in our organization. They generally have two questions: What they will be paid for the use of their money and when they will be paid. We consider in our thinking the rate of return on investment. In other words, what our investors are looking at in return for the risks in return for the use of their money, and well-managed enterprises should know what their shareholders want.

(Slide.)

Before I go into some of the mechanisms to look at those things, I wanted to put this slide up. This is a slide that I think has been shown quite a lot in the plasma therapeutics area to compare the cost economics of plasma therapeutics versus big pharmaceutical companies. What I have done is here is designated the cost base roughly for the plasma industry, typical plasma products producer, to a large pharma small molecule producer; and I think the point I wanted to make is the plasma industry has one consideration, the cost of plasma, which drives up our raw material costs. The other issue is that the majority of our resources for development of new therapies come out of R&D and marketing, and typically in our business that is about 15 to 20 percent of our costs versus about 45 to 50 percent of the cost base for classic pharmaceuticals.

(Slide.)

So when we are faced with decisions that involve significant capital and other investments, long time lines prior to launch, complexity and risk such as the development of a new biotherapy, we have to use a technique to make decisions; and we employ typically investment analysis techniques. There are a number of these I have listed here. They are essentially financial tools. In our organization we look at cash flow, we look at value that is generated. Basically we follow this decision-making tree. We start with a proposal. We try to build as best the assumptions for that project. We run through our investment evaluation techniques, go through our decision-making rules, look at advantages and disadvantages. We look at qualitative factors, and I will mention some more about these later. We look at investment alternatives and we make a decision evaluation on whether to proceed with the project, and we continually do this. Once a project starts, we go back and reassess whether the initial assumptions were correct.

(Slide.)

The method of choice we typically use is net present value, and this is a calculation of the present value of any investment project, but in this case launch of a new biotherapeutic based on its expected future cash flow generated by the project, but taking into account time, the initial investment, and risks. The advantages of this method for us is that it helps us capture the concept of time over very long time frames, usually a decade or more. We can establish cutoff rate. In other words, a level at which we expect the project to return respective to risks. It is based on cash flow, not profit, so it accounts for capital investment as well as revenue and expenses, which financially is a much more transparent approach. It is well understood and accepted. It is usually combined with net cash flow in or out of the project, and, as I said, it accounts for risks.

(Slide.)

This shows the methodology, but fortunately we don’t have to memorize this. It is one of the pull-down menus in Excel accounting formulas, but it is important to actually understand what it s made of. The R value is annual cash flow for each year that we run the model. Typically you run these over decades. So it shows cash flow in or out of the case for a number of years. The C indicates initial cash outlay, and then we have this factor called discount rate which is the opportunity cost of capital. Again, this is a factor that our shareholders are most interested in. It is the required rate of return or the cutoff rate. In other words, the project has to return this percentage to shareholders to be acceptable. The decision rule is quite simply you would accept a project if the net present value is greater than zero or you would reject it if it were zero or negative. In fact, you often in looking at a number of different projects, so you are doing a comparison between other projects and assessing present value in cash flows.

(Slide.)

There are a number of factors that influence NPV, the NPV investment model or in fact any of these investment models. To begin with capital investment, does this project involve for us to upgrade an existing plant, or in fact build a new plant. This is a fairly significant component in our decision making. Clinical trials, the size, the number of patients, the cost per patient, the jurisdiction, the cost of putting together CMC materials, other regulatory costs. The manufacturing cost of goods. This depends on the yields. If you have a very, very low yielding product, you might find the manufacturing cost of goods to extraordinarily high. It depends on the impact on the rest of the process. Often if you have to remove a new product from plasma it does have an impact on the upstream or downstream impact on the other products that you are pulling from plasma. The commercial expenses, whether you need to invest in sales and marketing, medical marketing, registrations, and post-marketing trials. These are all factors that in fact remove cash from the model and have to be considered.

Now a number of factors impact cash going into the model: The market launch date, the number of patients, the time of peak sales, in-market pricing and reimbursement. The territorial jurisdiction, there are differences in these different markets that impact the costs. Competition, if there are alternative treatments being developed or on the horizon. If you are in a horse race against a product that may in fact increase your risks that has to in fact be taken into account in the model; whether there are replacement therapies, whether you have me-too products that other companies may have on the market or plan to launch.

(Slide.)

To demonstrate how this works in our hands I would like to actually show you some simulations of investment cases, and I have put together -- these are not real cases, but the numbers are in fact the order of magnitude that we would have in a real-case plasma therapeutic. So I have put together a base case that would be fundable, and I put together three other cases. One where we would assume that the original clinical trial assumptions were incorrect and we discovered halfway through the process that clinical trial costs were greater due to either added costs or delay in launch. A second case, a rare disease where we have a small number of patients. The third case would be where we would have all other things being equal, but where we would have a very high risk of failure during the clinical development due to some very difficult-to-obtain clinical end point.

(Slide.)

If we just look at our base case for comparison, what I have done is put together a case here where we are considering registration of a product in both Europe and the United States from today launching in 2010/2011, which I think is actually an optimistic time frame. We would assume this is a product that replaces one on the market, so you would have some advantages in time. You would obtain peak sales in four years with 500,000 treatments per year. So 10,000 patients at one treatment per week. This would certainly be classified as an orphan drug, but it is typical of some of the plasma products that we manufacture. Development costs are quite modest, $15-million for preclinical CMSs, clinicals, regulatory, et cetera. Again, that is quite low by comparison to what the pharmaceutical industry faces, but it could be typical for a product where we already have some sunk investment and skills. A capital investment of $3-million just to maybe upgrade compliance in the plant.

(Slide.)

So you can see this is actually not a significant amount of investment. If we run the investment analysis at a 10-percent discount rate, which is more or less about where we run these analyses, we see that we have a net present value of $27-million over a period in time. We would give this a green light. You can see on the right side here showing cash flows, initially negative for a number of years until launch, and then a building in cash flow for the company.

(Slide.)

If we look at exactly the same case but we vary one aspect, we got the original assumptions wrong, that the launch was delayed by three years, that the development costs blew out to $25-million. We lost time, so therefore the in-market pricing was reduced due to increased competition, and the investment risk is now higher, so we have increased our discount rate to 14 percent.

(Slide.)

This situation gives us a negative net present value. You can see a number of years of negative cash flows before we have the same cash flow from the marketplace. Business would probably decide not to proceed on this basis.

(Slide.)

If we look again at the same situation, keeping everything fixed with the exception that now we have reduced from 500,000 treatments down to 30,000 treatments per year, which would equate to 600 patients at one treatment per week. This would also be similar to if you had a situation where you had a very poorly competitive product.

(Slide.)

Keeping everything the same, what we see here is a highly negative net present value. The cash flow is at the front. The front end is the same. The scale is really impacted by cash flows once the product is launched. We have a very difficult situation. There are few ways that one could remedy this; by looking at the development costs and trying to reduce those to make this a positive decision. Another approach would be a massive increase in the cost of the product, and I have indicated here in this particular model a 15-fold increase in price would be required to bring this to a break-even point.

(Slide.)

If we have difficult endpoint, in other words if our R&D director tells us that we have a much higher risk of failing through the clinical trials, and again keeping everything the same, we can do two things. We can either invest at the front end in decreasing the risk of the failure with the clinical trial. Alternatively, we can add more risk by increasing the discount factor.

(Slide.)

What I have done here is run the same model keeping everything the same, but using investment analysis at a high rate. So I have used a 20-percent discount rate. You can see whilst the cash flow is kept the same as the base case, we have a negative net present value, and the business decision would be most probably not to proceed with this project.

(Slide.)

As I said, this is only a tool. Qualitative factors must also be considered. These are relative factors that can’t be expressed in financial terms, and we do consider these. Moral values of the company enter into the decision. There may be other benefits that are not reflected in the financial model. There may be urgency or persuasion criteria where the company decides on benevolence.

(Slide.)

My conclusions are these. These techniques are used by management when deciding to bring biotherapeutics to patients. Some recent examples in where rare diseases have been successfully subjected to this analysis include alpha-1 proteinase inhibitor, C1 esterase inhibitor. An example of where a decision not to proceed -- and this is not just in my company. Others have made the same decision -- is the aerosol delivery of alpha-1 proteinase inhibitor. There have been projects started and then put on the hold on the basis of failing due to this type of analysis. The technique is impacted by development costs, the size of clinical trials, risk, and patient numbers.

(Slide.)

In the case of rare diseases, the major factors that impact the decision rule are the number of patients that require the treatment, in-market issues such as expected reimbursement and product pricing and competition between therapies, the cost of manufacturing. We are often technically constrained by the manufacturing of other plasma biotherapies, and putting the manufacture of those products at risk is not an option. The cost of CMC preparation, the cost of clinical trials and the practicality of completing these, the time taken to launch and then reach peak distribution, and anticipated life cycle of the therapy relative to other technologies that may cause redundancy. These are all factors that would impact a decision.

(Slide.)

As I said, non-financial factors are also considered, but in the end I want to make the point that companies do require capital from shareholders to survive. This type of analysis secures trust from our shareholders and for us secures a provision of capital to continue to be able to develop and manufacture therapies. Thank you.

(Applause.)

DR. WEINSTEIN: Thank you very much, Paul. Again, we might have an opportunity. Donna DiMichele would like to ask a question, Paul, if you would like to come up here for --

DR. DiMICHELE: No problem. You could probably address it from there I’m sure.

DR. WEINSTEIN: Well, again, we will have time for further discussion and panel.

DR. DiMICHELE: I just wanted to -- Donna DiMichele from New York. I just wanted to thank you for a very wonderful presentation. It helps us at the other end really understand the decision-making process, and I thank you. The plasma industry has always been very honest about that, and I thank you for -- you know, the industry for its past presentations and you for this one.

I was just wondering. Obviously the development costs are a primary issue here, and oftentimes are the make or break point. One of the things that you heard from the previous presentation is that, you know -- and obviously that is available through the FDA and also through the NIH are small business initiative grants and some of the financial incentives that would go into making for instance a rare product, a product for a rare disorder. Certainly less altruistic if you will, and a little bit more of a green light rather than a red light project. The issue of harmonization is also something we are going to be discussing here.

Have you as a company ever redone these analyses looking at the relative impact of, one, small business initiative grant; two, the incentives present, you know, through the FDA for orphan drugs; and, three, the potential for a different clinical design or regulatory harmonization to impact on the up-front costs in order to allow these projects to go ahead. Because obviously these are all the issues we are going to be discussing here, and understanding from industry which of these issues actually have the greatest impact I think helps us and hopefully help the regulatory bodies proceed.

DR. WALTON: Thanks for the comments. To my knowledge and in fact there is a history to our organization of precursor organizations I can’t answer this accurately, but to my knowledge I don’t believe we have redone the analyses on the basis of small industry incentives. Most certainly we would have considered orphan drug programs and any feedback to change the initial assumptions with respect to the clinical trial development costs most certainly. So that develops those as you develop your assumptions and have your discussions with the regulatory bodies and you refine your input. But as far as the first case, I am not aware of a situation where we have, but what I would say is that on a going-forward basis absolutely we would look at that. If we qualified for any of those programs we would certain look and run that analysis. It would be --- of course.

DR. DiMICHELE: Thank you, because in my opinion that would be actually very helpful, and -- you know, because all of the things that we are looking at would certainly appear to me, a non-business person, to really decrease the up-front costs, and by decreasing your development costs and actually minimizing risks to shareholders by, you know, allowing some subsidy. So I think that may change your ratios a little bit. Thank you.

DR. WEINSTEIN: Jerry.

DR. HOLMBERG: Yes. Thanks for this clear presentation. The question that I have, when looking at your economic model and the cost comparison between the plasma industry and the pharmaceutical industry, I noticed two things that stand out. Primarily you say the majority of new therapy development is involved in R&D and marketing, and then also a big hunk of your expenses involve raw material.

First of all, I have two questions. When you see such a large amount of money for the raw material, how do you analyze that in comparison here in the United States in comparison to other countries where maybe the plasma industry more in a volunteer market mode than in a remuneration mode that we have in the United States here? Secondly, if you develop such a orphan plasma therapy it would appear to me that the market would be pulling versus you having to go out and push the market, and so the value would be a pull versus a push; and how would that affect your model?

DR. WALTON: Can you repeat the second question again?

DR. HOLMBERG: Well, the second question was basically the push and pull.

DR. WALTON: Okay.

DR. HOLMBERG: In a push and pull, you know, you would basically have to -- when you are generating the market you are really developing a lot in the marketing tools to go out there and convince the industry that they need this. Here we have the physicians, the patients who know that there is a need, and so you have a pull from the physician. So to me it would appear you wouldn’t need to invest as much money in the marketing. How would that affect your models?

DR. WALTON: Yes. Look, I agree with your second point, and it would have a very clear impact on the model by reducing the cost component, and it would positively impact the outcome to not have to invest in significant pre- and post-marketing expenses.

The first question, regardless of whether you have donor fees involved, cost of plasma in some of the markets that are not traded in the same manner that that is done in the United States is still quite high. The costs come from the infrastructure to collect, testing the serological as well as --- testing, the logistics of handling of plasma. It is a very difficult raw material because all of your costs are up front. So regardless of whether you have donors centers as we use in the United States or some other regions where the donors are not given a fee for donating plasma, the costs are still quite high. There is not a significant difference, maybe a 10 or 15 percent difference, and in fact in some countries where they are fully on a donation system plasma costs may be in fact higher than the United States because of the scale of it. We collect an awful lot of plasma here, and that does enable us to bring costs down. The other issue with this is your cash flow when you collect that raw material is often six months or 12 months ahead of the product hitting the shelves and going through your system because you have to pay for it prior to starting the process. You have to hold it, you have to manufacture it, and you have to run through the full cycle before the product is available, and that drives the cost of raw materials to the levels that I showed there, which are quite high.

DR. WEINSTEIN: Let’s see. I think perhaps we will hold some of these questions for the panel discussion we will have.

IPFA Perspective
Clive Dash, MD

DR. WEINSTEIN: Our next speaker is Dr. Clive Dash. He is the Medical Director of the Bio Products Laboratory, and he will talk about current challenges to product development from the perspective of the International Plasma Fractionation Association. His presentation will deal with some of the practical challenges that fractionaters face when having to contend with different international clinical trial requirements, finding willing patients, and getting reimbursement for these products.

(Adjusting equipment.)

DR. DASH: Well, good morning, ladies and gentlemen. It is my great pleasure to represent IPFA at this presentation. A number of people from IPFA member associations are in the audience, notably --- who is our executive director.

(Slide.)

You will see that he is in his spare time doing a bit of travel agency work because subliminally you will have a picture on the back of the slide there of Amsterdam where he is based. So he is encouraging you to take a holiday vacation in Amsterdam.

(Slide.)

What I would like to do in first in this presentation is introduce you to IPFA for people that don’t know anything about IPFA, and then try to put into some sort of context the way in which our member associations work. I am please to say if you want a short summary at the beginning, as is traditional of course in scientific publications, the three previous speakers have covered many of the points that I will make; and there are not a lot of differences, although there are some between what I will say and what previous speakers have said.

The International Plasma Fractionation Association stems out of the European Plasma Fractionation Association a few months ago. We are made up of not-for-profit organizations scattered around the world. Formerly they were based in Europe, but we do operate by and large in most countries in a competitive and commercial environment. So we are up against if you like, in the nicest possible way of course, people represented by Paul, our previous speaker, and so on. But we are generally ver small or small to medium-sized enterprises, so that takes us apart from the more international organizations. We stem from primarily national fractionators, and I an certainly endorse what Paul was saying just now that the cost of collecting plasma even for a not-for-profit organization where there is no payment for collection is basically the same. There is not much difference. It is the infrastructure. It’s the cost of doing it. We still have that enormous cost, which I will come to in a minute, on the raw material.

Now because we were national fractionators predominantly in the past -- and some still are -- we had, if you like, a remit to satisfy the needs of patients in our localities. Because we were not-for-profit organizations, we didn’t historically have to go through the same sort of models that Paul has just been describing to you, but increasingly we are doing that. We have to do that to survive. Because of the cost of heath care in different countries, the support, if you like, from sponsors, which may be, for instance, the local Red Cross or government agencies, is diminishing very rapidly year on year.

(Slide.)

Now we clearly have to comply with all the regulatory requirements. Because of that and other economic issues, if you like, the withdrawal of some of our traditional sponsors, we have to become more international; and most of us are now putting our feelers outside of our own national boundaries into other parts of the world. We have to do the same CMC requirements. We have to do the same clinical trials. There is no difference. There is no argument about that, and so if you think about Paul’s model and apply it in the 21st century for membership, then we all have the same, if you like, difficulty in raising the capital and the cash flow in order to support the development of new products and the clinical trials. Some of us have experience with discussions with the FDA and working with the FDA as well as the European agencies. Unfortunately, not everyone could participate in this meeting, but there are quite a number of people here from our member associations.

(Slide.)

I will just put up just a couple of slides now to illustrate that some of the membership in Europe, this is just confined to the European Union now, some of our members have national products. If you work through these as has been mentioned before, factor VII, there are two of the members in Europe have factor seven products, and each distribute those products in one country each. Factor XI, again two members distribute factor XI, one country each. Protein C, just one organization manufactures a protein C concentrate just marketed in one country. Antithrombin, a little bit more prevalent, but only slightly; three members, one country each.

(Slide.)

If we move on to the IGG products, then we have specifics again. CMV, one member, one country; rabies, one member, one country. Interestingly enough, that is the UK, where rabies has not been seen for a long time; but I think some of our military were passing around the world and liable to get caught up with rabies as well as other things. Rubella, two members, one country each; hepatitis B intramuscularly, similarly; varicella-Zoster, three members, one country each; intravenous hep B, four members, more prevalent, one country each; and tetanus, more or less the same. So that kind of gives you a flavor that scattered around the European Union there are some of these products that have been mentioned earlier today that are available for certain patients.

Fibrinogen was mentioned earlier. A number of our members are working on fibrin ---, and as part of that of course fibrinogen is an integral component, and that is also available in some countries.

(Slide.)

The national markets really are too small now our sponsorship, if you like, is diminishing, so we are having to look elsewhere. But we do find that there are some limitations in licensure internationally. Sometimes patent issues cause us difficulties. The fear of litigation in certain localities is another major issue to some of our members. The lack of regulatory harmonization has already been mentioned several times, and the changes in health economics also have an adverse effect on the way we perhaps are looking at the way we do our products in the future.

(Slide.)

There is an example here which covers a number of different points I think. One of our members who has now closed down their fractionation facility, the Finnish Red Cross is still collecting some blood there, but they don’t fractionate their own plasma anymore. They developed an apotransferrin product. There were two patients in Finland with congenital deficiency. There are several individuals in the US. Their fractionation facility has now been transferred -- for major products, transferred to Sanquin, which is the Dutch and Belgium organization. One issue I guess that we have to think about that hasn’t been raised this morning is in a situation like this there is the issue of technology transfer and what that might bring and what the cost of that might involve, and at the moment an uncertainty about the trial requirements if we wanted to expand into a national area with that particular product.

(Slide.)

Traditionally as national organizations our membership has had limited number of patients, and even if you take primary immune deficiency as an example where chronic replacement treatment is present. I have avoided factor VIII and factor IX because many parts of Europe now recombinant therapies have largely displaced plasma-derived ones. With primary immune deficiency, the patients have a chronic replacement treatment, as you know, but they are perhaps unwilling to switch from the current product that they have been using for goodness knows how many years perhaps to a new product. If they switch, they go into a clinical trial. What does it mean to them? It means that they have inevitably more visits to the hospitals, many more venepunctures to comply with the requirements, they have more paperwork for themselves, and all this interferes with their life and work style.

(Slide.)

There is also within a particular geographic location generally a competition for willing patients. So those that are willing are highly competed for by a number of organizations developing similar products. This is perhaps not the really rare conditions, but still products that we make from plasma. The duration of the follow-up can be a disincentive to patients, and overall in Europe I don’t think there is any personal incentive to the patients to take part in the trial. They are almost certainly doing it on a high degree of altruism when they do that. How to do a comparative study in patients on long-term treatment poses another difficulty. As part of some earlier discussions with the European regulators, we suggested that some proactive pharmacovigilance might be a good way forward. I was pleased to hear this morning several of the speakers making this particular point. We have heard it before also, the high cost of clinical trials. The cost of a clinical trial, as I said, run by an IPFA member is the same as the cost of a clinical trial run by a for-profit organization. We have a small organization, small --- organization, so the proportionate amount of money spent on developing products is much higher.

(Slide.)

If we look forward, as you might be thinking, "Why don’t you rush out into the international markets and distribute your products there?" as traditionally national organizations we do not have an international infrastructure. So we have to find other ways of distributing our products outside of our own national boundaries. You have heard a tremendous amount from Paul about the economics of plasma fractionation, and this also leads on to another point which hasn’t been mentioned yet this morning. But if we are taking a new protein, let’s say, for a rare condition out of plasma, this might sound quite easy on the face of it; but there are potential complications, and the potential complications are depending on where that protein lies in the process from the beginning to the end of the fractionation will perhaps impact upon other products that are already licensed. So if you are taking something out, a protein out of an intermediate product, then you might affect the other licensed product already coming from that particular plasma. Therefore, that could be an affect on the licensing status of the well-established product, and that is another fact that we have to take into consideration when we are working out the economics of whether to develop a new protein for any condition, whether it is rare or less rare.

(Slide.)

Clearly as has already been said, we need enormous collaboration between patient organizations to help overcome some of the issues that I have mentioned, physicians in order that they can give the right support and work according to the current TCP regulations, the regulators for reasons as already mentioned, and amongst ourselves. I think if you consider a product for a rare condition it is not -- and may require relatively small total number of patients let us assume, it is not necessarily that much cheaper to do that than to run a bigger trial where patients are more numerous. The reason is that the costs of trials do not run proportionate to the number of patients. They are partly generated along that line, but perhaps more importantly the number of centers. So if you have patients scattered very sparsely over a large number of centers and you have to recruit all those large number of centers, that disproportionately pushes up the cost per patient.

(Slide.)

Touched upon before, but perhaps in Europe we have more socialized medicine, although it is not totally socialized across Europe. But the key issue that I think keeps coming back to us when we go through these scenarios is if we are really, even if we are not a for-profit organization, trying to, if you like, break even, will the purchasers actually be prepared to pay the price for that product for that rare condition. The cost of producing it is, as I have said before, is the same whether you are a big organization or a small organization by and large. The pressure on pushing prices down of all products, pharmaceuticals as well as plasma-derived products, across Europe is enormous, and if you come in with a new product the risk is that the real cost, which should equal the price, if you like, for a not-for-profit organization, is still going to be too high for the purchasers to -- and the purchasers have in many parts of Europe the final say on what the patients receive.

(Slide.)

So in conclusion, we have many challenges. Most of them are the same I would say as for the other larger organizations. The resources available are limited, more limited, and the investments required are probably more limited, and they are getting more tight as years go on. We have a difficulty sometimes with patient populations nationally and we have had to expand outside our national boundaries in recent years, and we have to face the availability and willingness in those patients to take part in the long-term trials when they are perhaps, for some products anyway, receiving product already on a long-term basis so there is no real incentive. We would like to have more regulating harmonization and we would like to move towards international commercialization as other companies have done in the past. Proactive pharmacovigilance I think probably works quite well particularly with rare conditions because the patients are almost known as individuals, even with confidentiality and so on, even I would say to most of the manufacturers of the product. So it is relatively easier I think to track those down and to keep a good trace on what is happening to them after the product has been allowed out into the market. As I said before, one point that has not been raised earlier today is the potential impact upon taking a new protein out of an intermediate during the process of fractionation and what that might impact on already-licensed products already downstream. Thank you very much.

(Applause.)

DR. WEINSTEIN: So again we have a few moments for questions if you would like to raise any. Okay. Okay, Donna.

DR. DiMICHELE: Yes. Donna DiMichele. Thank you again for this presentation. It was very informative as well and brings a different perspective. One of your concerns is the willingness of these patients to participate as clinical trial subjects. I think that there may be a difference, I mean, and I think this is very pertinent to an expansion into an international market because there certainly might be a difference in the willingness to participate maybe based on what you have heard already between those patients who have no access to product and those patients who already have access to product. So there is intent among the national organization, national participants in your organization to expand into international markets, I think you may find you have plenty of subjects if clinical trials are redesigned to participate, if that removes that concern.

The second is about purchasers. We obviously are going to have some -- hopefully some purchaser representation later on But the other thing to consider is that when a purchaser, commercial purchaser, has to purchase for a single patient or for two patients, et cetera, although the cost per patient is high, sometimes -- sometimes -- they can still remain below the radar. You know, below the radar screen in terms of a blimp in cost; but that climate is changing, too, and I am not sure we can say that most definitely. But thank you.

DR. DASH: I will just a couple of comments. I think we invented radar, and I think in the UK the radar is so sensitive that we are finding it really difficult now to get below it. But I think you are right. I mean, we have had problems with factor VIII, factor IX primary immune deficiency patients who are on long-term treatment, no incentive for them to change in most countries in Europe. It will be different I am sure for the other conditions we mentioned this morning where there is no other satisfactory treatment.

Developing Biological Therapeutics for Rare Plasma Protein Disorders Toby Silverman, MD

DR. WEINSTEIN: Our next speaker is Dr. Toby Silverman. She is the Chief of the Clinical Review Branch in the Office of Blood at CBER, and she will discuss developing biological therapeutics for rare plasma protein disorders. Her presentation will focus on the usual standards that FDA applies for the licensure of products. In later presentations we will discuss how products for very small populations fit into this overall framework. Toby.

DR. SILVERMAN: Well, Mark has given my first slide. I want to discuss here the usual standards that FDA applies for either licensure or approval of drugs, and it is against this background that discussions this afternoon will take place about how drugs or biologics for rare disorders might meet the standards that I am going to outline this morning.

(Slide.)

One needs to take a step back and look at where these standards came from. In 1938 we had the birth of the modern pharmaceutical industry with was based on research and development of potent new medicines. There was a requirement to test drugs for safety alone before marketing. There was no requirement for companies to inform the FDA of medical experiments for new drugs before actually conducting the experiments, and physicians could administer drugs without consent to an unlimited number of patients as long as the work was deemed experimental. Obviously this would not meet current standards. In the 1950s and into the 1960s there were a number of problems with drug development, including chloramphenicol and most famously thalidomide.

(Slide.)

This lead to a change in the legislation in 1962, an amendment to the Federal Food, Drug, and Cosmetic Act was enacted to add the requirement for demonstration of effectiveness for drugs and biological products basically to assess benefit-to-risk rations. Then as I said, prior to 1962, manufacturers were required to demonstrate only safety.

(Slide.)

Now what is the quantity of evidence generally necessary to support effectiveness? This standard is outline in section 505(d) of the Food, Drug, and Cosmetic Act, where substantial evidence is defined as evidence consisting of adequate and well-controlled investigations by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved on the basis of which it could be concluded that the drug will have the effect it purports to have under the conditions of use prescribed, recommended, or suggested in the labeling. Now I heard earlier today a number of people say that they would like to have adequate dosing guidelines, they would like to know a risk-to-benefit ratio for their patients, they would like to know how to use drugs. These standards are designed to achieve that goal.

(Slide.)

This standard has been interpreted by FDA to mean generally two adequate and well-controlled studies, each convincing in its own right, is necessary to establish effectiveness.

(Slide.)

However, on occasion FDA has relied on pertinent information from other adequate and well-controlled studies of a drug -- for example, studies of other doses, other regimens, other states of disease in other populations of different endpoints -- to support a single adequate and well-controlled study demonstrating effectiveness of a new use for a drug.

(Slide.)

FDA has relied on only a single adequate and well-controlled efficacy study to support approval. But this is generally only in cases in which a single, multi-center study of excellent design has provided highly reliable and statistically strong evidence of an important clinical benefit, such as an effect on survival, and a confirmatory study would have been difficult to conduct on ethical grounds. Now this is obviously a very difficult standard for rare plasma disorders, so again later this afternoon there will be discussion about how to address this standard for these disorders.

(Slide.)

The FDAMA, the modernization act, amended section 115(a), amended section 505(d) of the act to say that FDA may consider data from one adequate and well-controlled clinical investigation and confirmatory evidence to constitute substantial evidence if FDA determines that such data and evidence are sufficient to establish effectiveness. Well, that is a judgement call obviously.

(Slide.)

Now the Public Health Service Act, under which most of these products will lie, licenses for biologics are issued upon showing that the products meet standards designed to ensure continued safety, purity, and potency. Potency being defined as specific ability of the product demonstrated in laboratory tests or adequately-controlled clinical data to effect a given result.

(Slide.)

Now proof of effectiveness consists of controlled investigations as defined in the provision for adequate and well-controlled studies, unless these requirements are waived as not applicable to the biologic product or not essential to the validity of the study.

(Slide.)

Now in the Code of Federal Regulations at 601.25(d)(2) there are provisions for alternative methods to substantial effectiveness acceptable for biological products, and among these specifically listed in this section are serologic response data, and one example is -- one example is serological response data, provided that a previously-accepted correlation with conical effectiveness exists.

(Slide.)

What is the scientific basis for the regulatory requirement? Well, there may be unanticipated, undetected, systematic biases. There is inherent variability in biological systems that may result in a finding of efficacy by chance alone. Results may be driven by outcomes form one center and unfortunately, on occasion, scientific fraud.

(Slide.)

Now, whether to rely on a single adequate and well-controlled study is of course, as I have mentioned earlier, a matter of judgement, and it is apparent a conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study. The endpoints of course of mortality, irreversible morbidity, prevention of disease with potentially serious outcomes are obviously all endpoints for consideration.

(Slide.)

So what makes a single study okay? Well, a large, multi-center study in which no one site provides a disproportionate percentage of the subjects would meet the standard. A study where there is consistency across subsets in large trials with relatively broad entry criteria. That does not pertain here. These are small populations. Multiple endpoints involving different events, and statistically very persuasive findings.

(Slide.)

There are some caveats. One must always consider the possibility of an incorrect outcome, and this of course is very important if one is looking at only a single study, and the available data must be examined for their potential to support or undercut the results.

(Slide.)

So how do you get from a good idea to market? Well, everyone in the room knows that there are several phases to studies. We meet often, FDA meets often, with companies and investigators at the pre-IND phase to outline clinical trial designs, CMC issues, et cetera, preclinical work that is needed. Under IND, investigational new drug application, the ususal course is to go through phase I, phase II, phase III, leading to licensure, and then often phase IV commitments or post-marketing commitments are made.

(Slide.)

Clinical trials. A clinical trial is a prospective study comparing the effect of interventions against some control in human beings. The purpose is to distinguish the effect of the drug or biologic form other influences, such as spontaneous change, placebo effect, or biased observation.

(Slide.)

One assesses efficacy by comparing outcomes in a group receiving the drug to the outcome in groups treated with a control. Once tries to isolate receipt or non-receipt of the drug or biologic as the only important difference between the groups; and the gold standard, one which will be difficult here, is a randomized well-controlled trial where balance is ensured by the randomization process.

(Slide.)

Again the usual course in phase I, phase I trails are generally run in normal volunteers. They may have no benefit from the drug or biologic. One may run phase I studies in patients for whom the agent is intended. This population may have more advanced disease than the ultimate intended population. In later phases of the study, one studies the intended population, and one is left with the question of how to extrapolate data from patients in a trial to the more general population. It is also necessary to include groups previously under-represented in studies, such as women, children, or the elderly.

(Slide.)

How does one choose an appropriate control for studies? The proper choice for a control is necessary in order to determine if the drug works. There are different types of controls. In the right setting one might run a placebo controlled trial, which is the clearest way to demonstrate efficacy. Obviously that may be difficult for some of the populations that we are discussing today. One might have as a control an approved therapy, in which case one would design a trial to show either superiority to the active control or equivalence to the active control. One might evaluate different doses of the same agent to evaluate dose response; and, last, one might consider historical controls.

(Slide.)

If there is a known effective treatment, some groups have raised concerns about the use of a placebo, even if there is no lasting harm. Of course it would be unethical to withhold a known effective treatment if withholding the effective treatment would do irreversible harm. In some cases, one could consider the addition of a placebo or the active agent to a standard of care where one would compare the standard of care plus the agent to the standard of care plus the placebo.

(Slide.)

Non-inferiority trials attempt to show efficacy by showing a new treatment is as effective as a known effective therapy treatment. One demonstrates that a new agent is not worse than the control by some narrow margin which remains to be defined.

(Slide.)

There are some disadvantages to non-inferiority trials. Assay sensitivity, if the active control does not show consistent results, it is very difficult or virtually impossible to reach firm conclusions about whether the new treatment is as effective as the old treatment; and, unfortunately, non-inferiority trials require very large sample sizes to rule out small degrees of inferiority. Again, not an option, not a readily-available option, for these small populations.

(Slide.)

The choice of the endpoint depends on the phase of development, the clinical setting, and the intended effect of the drug. There may be many choices of endpoint; range of safety in phase I, and activity and effect, especially in phase II. Generally, for approval for most drugs or biologics an efficacy endpoint should be a clinical benefit or be a validated surrogate that best measures the clinical benefit of interest. Now, I heard discussion about accelerated approval, and that is certainly a consideration for some of drugs, in which case the surrogate endpoint might very well be an -- or would be an unvalidated surrogate that is likely to correlate with the clinical benefit.

(Slide.)

Surrogate markers are used to diagnose disease or evaluate patient response to treatment. The effect on the surrogate marker should reflect the equivalent effect on disease or true clinical endpoint of interest. It has advantages, as has been noted earlier. It is easier and faster to measure a surrogate than to measure an actual clinical benefit. The surrogate may occur in more patients and may decrease the cost of the study. There are some disadvantages, however. If the surrogate does not correlate, it may result in an overestimation or underestimation of the true effect.

(Slide.)

There are some confounding factors to consider in clinical trial design as well. These include bias, regression to the mean, imbalance between study arms for studies that have two arms, dropouts, and multiple endpoints.

(Slide.)

The appropriateness of the study design for the indication is very important in these considerations. Randomized, controls, a well-defined selection of subjects, appropriate endpoints and appropriate choice of control groups are all very important to determining efficacy.

(Slide.)

In the final analysis, though, all of these comments and considerations are aimed at evaluating whether the results show that the product is safe under the conditions of use in the proposed labeling, and, the second question, do the results of well-controlled studies provide substantial evidence of effectiveness so that treating physicians understand dosing, understand the effect of the product, and can use the product safely. Thank you.

(Applause.)

DR. WEINSTEIN: Again we have time for a few questions. We again would also have time at the end of the panel discussion for a question period. I think, Donna, do you --?

DR. DiMICHELE: Thank you for that. You know one of the things that you mentioned and spoke quite a bit about is surrogate markers, and obviously one of the toughest markers for a clinical trial is clinical efficacy, because as clinicians we really haven’t developed good markers for clinical efficacy for you all to use as endpoints. You mentioned surrogate markers, and I was wondering if maybe in the discussion we could explore that a little bit more. For instance, such as plasma levels, you know, understanding that there may be some correlation between clinical efficacy and plasma or serum levels of drugs in certain cases, or replacement products, and maybe whether we could explore that a little further.

The second is if you have limitations in clinical trials, which of course for the rare bleeding disorders we would be talking about that in a significant way, I would be interested in your opinion as a regulatory as to what would be needed in phase IV pharmacal surveillance post-licensure in an effort to assure the FDA with a small clinical trial size that we would continue to do the best surveillance possible and what are the elements of that surveillance.

You don’t need to necessarily answer these questions now, or if you have some thoughts that would be good. Maybe we can discuss it more in the discussion.

DR. SILVERMAN: I think Dr. Jain will be talking about some of these issues as well this afternoon, and I think most of the speakers this afternoon will be discussing some of these issues. It is obviously very difficult, a difficult issue as to what to follow, what to look for. We can talk about plasma levels. This is certainly the endpoint for pivotal trials for factor VIII and factor IX because we understand that surrogate reasonably well. It might very well be a surrogate for some of these other replacement factors as well.

DR. WEINSTEIN: Okay. Keith?

DR. HOOTS: A question about backdoor entries into getting an indication. If for instance we have heard that factor V, there is no likelihood of developing a factor V concentrate. We don’t presently have a pathogen-attenuated fresh-frozen plasma. How do regulatory agencies look at say trying to develop a solvent detergent or some other pathogen-attenuated fresh-frozen plasma for rare diseases knowing that were you to license it for that indication the broader use would be far beyond a rare indication use? Or maybe you don’t. I mean, maybe that is a politically-charged question that you don’t really want to address, but I think it does present a problem if someone really wants to develop that for that purpose and has the technology. But perhaps is concerned that it may be a detriment for a broader use I guess is what I am asking.

DR. SILVERMAN: Well, as you know we had a solvent detergent-treated pooled plasma product. We have never had a solvent detergent-treated fresh-frozen plasma product. The particular product, the pooled product, had all of the indications for which FFP was licensed, and obviously that would include rare disorders for which no licensed concentrates were available that was specifically on the label. Certainly specifically on the label for fresh-frozen plasma in the circular.

DR. WEINSTEIN: Okay. We will have a 15-minute break. We will reconvene promptly at 10:30 for panel discussion where we will have the speakers at the front of the room.

(Whereupon, a break was taken.)

Open Panel Discussion
Mark Skinner, Session Chair

DR. WEINSTEIN: Panelists, please come to the front and be seated. So we are going to have a panel discussion now. The leader for this panel discussion is Mark Skinner. He is President of the World Federation of Hemophilia. Mark has a long history of involvement with the bleeding disorders community, principally through his work with the National Hemophilia Foundation. Mark is also a member of the Advisory Committee on Blood Safety and Availability. Mark.

MR. SKINNER: Good morning. Before we move into the questions, Mark thought it would be helpful if I just give a bit of a perspective about the role of the international patient organization in addressing the problems that we are talking about here today, so first I just -- this was mentioned by Amy, and this really is -- you know, kind of captures what it is that we have been trying to achieve here in the US.

(Slide.)

In particular, the bullet under item two. Most of the world, and a lot of the developing world, still relies on fresh-frozen plasma, and we know the history and experience when you are relying on non-virally-inactivated products. So the issues were are talking about here today aren’t just appli

Biological Therapeutics for Rare Plasma Protein Disorders Public Workshop

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Biological Therapeutics for Rare Plasma Protein Disorders
Public Workshop