Office of Rare Diseases at National Institutes of Health

Dr. Stephen Groft

DR. GROFT:  Thank you very much, Steve.  As Steve mentioned, I have been around with orphan products for so long it just seems like I have never done anything else, and it has been a long time since we started the initiative.  When I worked with Dr. Marion Finkel at the Office of Orphan Products Development in 1982, and there have been activities earlier than that.  So I will go over that history and how we have worked through some of the situations trying to foster more research on rare diseases and trying to get more interest on the part of industry, on the part of academic researchers, on the part of the review teams, the review process at the NIH to try to provide a good focus for rare diseases, which has not always been the situation.  I am sure you are going to be confronted with similar issues as you try to develop products for various species, minor species and minor uses. 

I think just from the start, it is important to realize I think the legislation went very, very nicely.  They did pay attention to some of the things that happened with the rare diseases and that some products would never get to the marketplace as an approved product.  I think everyone has to be willing to say that is okay, and I think we had that realization with the orphan products in the rare diseases as well.  The patient population just isn’t there sometimes to really justify that much money to get an indication approved and do all the studies, but yet we still want to get information that can be utilized by the practitioners and that the public will have some confidence that what has been developed, the information that has been developed, really is useful.  So I think that is what we were are trying to do on several of the products, and that is the best that we can do on some things. 

But it is good to be here, and what is really particularly nice to get out, I have run into some people who I haven’t seen in years, and it is really --- and some of the others that I have known for years.  It is always nice to go to meetings that you do know people, so thank you.  It is just a pleasure.  I will try to just work and see how we do.  Okay.
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The orphan drug, and you see here the prevalence.  It is really based on a prevalence of less than 200,000 here in the United States.  So we had that originally.  The idea was that the products would be designated as an orphan product if a profit could not be made.  After a couple of years of experience the realities came into play that we just couldn’t make sense of the information and the justification that was being presented to us.  The data was soft, and so we asked Congress if they could go back and give us a prevalence figure that we could work around; and even that is problematic, because for many of the rare diseases we really don’t have a good figure for prevalence because we have never really done a thorough survey to determine the prevalence of so many of the rare diseases.  We estimate close to 6,000 rare disorders here in the United States, and probably as we get more into the human genome extension there will probably be many, many more thousands after that that we still -- just get up into the 7- or 8,000s, and it’s -- we are just using that figure.  I think people felt that an industry or a company could make a profit or could be reasonable expected to make a profit if you had a prevalence of 200,000.  So I think that is why they sort of picked that number, and it came out to be I think one-tenth of one percent of the population of the United States back in 1982 or so.  So that was how we ended up with the 200,000 figure, and there still is the provision that if you don’t expect profitability to occur within seven years you can be given the orphan product designation with all the incentives that go with it.
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We can see the issue of orphan products, orphan drugs, rare diseases.  It has been around for many years.  In fact, it really goes back to 1957 when Harry Shirkee, a pediatrician, talked about therapeutic orphans and referring to the kids who really didn’t have drugs that were tested accurately in pediatric populations, and extrapolations just were made from the adult as far as the dosage and the regimen and things like this.  So that was in the ‘50s, and then in ‘64 the US Public Health Service did a review of the situation and felt that things were really pretty much being taken care of.  Things continued, and as you saw almost decade or so we have another review of what is going on because many of the problems persist; and I think you will find the same thing, that despite all the best efforts, all the activities that you have, there are going to be gaps and problems that will remain, things you can’t get resolved.  It is the nature I think of what we are dealing with with so many of the rare disorders.

Probably the biggest group that had the most impact was the Interagency Taskforce on Significant Drugs of Limited Commercial Value.  This really lead the path to the Orphan Drug Act back in 1983, January of 1983.  After the act there were still some problems, and the Congress asked us to form a commission on orphan diseases to again look at the issues.  We have been about five or six years out, and traditionally what happens is they ask you to go back and see where the problems are and what we should be working on.  So we did form the commission to look at how things were going and where the problems remained, and in 1997 NIH in appropriations language was asked to come up with a report on coordination of rare diseases research.  Any of you familiar with the NIH knows that, it is a rather large organization, but it is certainly not monolithic.  As a result, we had a lot of people doing many things with respect to the rare diseases and research in general, and they really wanted us to try to coordinate things.  So they asked us to come up with a plan to give a better idea of how we could coordinate activities at the NIH and in research in general.
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But here are the task forces, the study groups that the task force used back in the ‘70s, and this went on for about four years actually, ‘74 to ‘79.  So they just were trying to identify the issues, trying to identify what products might be included in an orphan products program, what the industry needs were; and even in the ‘70s and ‘80s there still was a lot of resistence to even implementing any legislation like this, the feeling being that industry was really taking care of everything and the government was doing in research.  But in reality when you talked to the patient advocacy groups they were saying, "If they are, we are not seeing the products."  Members of Congress then following the guidance primarily in the support groups as well as this working group, developed some legislation that really helped to move forward, and it did involve the industry, government, academia, patient advocacy groups as well. 

So you can see how we moved through the liability issue, extending government patents and little used drugs of foreign origins.  Still I am sure there are problems that you are confronting, too, as you try to address this issue.  So I think many of the issues probably are very similar.  You know, you just substitute animals for humans on many of the issues, and just how do we address this, how do we get the results, and that is a problem for both of us.  Even for us I think we need to look at NIH a little bit more, how we can interact with what you are doing and bring the people together.  Is anyone else from NIH here?
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There is probably not, but there are a lot of activities that we have going on, and we probably should try to foster some relationships and some other interactions as we go forward.
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But here are the incentives that were suggested by the task force, and they talked about tax incentives, they talked about exclusive marketing, and the patent -- we always hear about patent protection, but I think everybody shies away from that.  They don’t want to play around with the patent laws too much.  They look for other ways of giving some incentive that the industry would be interested in to get it onto the market.  I will give you some of the actual incentives that came by in a little bit,  just another slide or two.  You talked about priority review for the applications, which FDA has done a lot of priority review for the new drug applications for the INDs for investigational products for rare diseases.  They talked about grants from FDA.  That would be a good thing to do.  At that time, FDA really wasn’t in too much of a grant-making mode, so as a result it was a little bit of a novelty thing for them to think about.  Again, always a concern with antitrust when you get companies talking together about pooling data for these rare diseases.  So they suggested perhaps amendments to the antitrust laws would be appropriate, and in worst case situations, the government would purchase orphan drugs and make them readily available to the public.  So many different possibilities were talked about and delivered up to Congress as possibilities.
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Then here is essentially what came for the Orphan Drug Act, and we talked about marketing exclusivity, now for a period of seven years; tax credits for clinical investigations, and actually it becomes a little bit more than that, because some of the other expenses are deductible.  So I think there have been estimates about 73 percent of the cost of clinical studies in support of INDs and NDAs would be available to the companies.  Later on there were exemptions from the prescription drug user fees for review purposes.  It is pretty significant for a small manufacturer or a product that companies do not want to spend a lot of money to develop, so another incentive.  

In the late ‘70s there was a lot concern about the interaction between FDA, and I can say this.  I was at FDA at the time.  The review divisions and the industry, were people really communicating in a way that was very positive instead of as adversarial as what was perceived at the time and perhaps was actually the case, and arguments could be made on both sides whether the adversary position was good or bad.  But many of the researchers felt that they needed assistance in developing the study protocol so that the data that would come from the studies would actually be useful to support a new drug application, and even today I think that is a major problem for many of the rare diseases.  We have a lot of investigators who are good researchers, but may not be clinical trialists that understand study design and what really needs to be done to get that application moving and get it through the Food and Drug Administration.  So you may run into some of the similar problems here with what you are looking at.  

Grant support, which now can be extended towards medical foods and medical services also.  There was again the knowledge, and I addressed this early about the open protocols to increase drug availability for patients who are in clinical trials.  If you are not in clinical trials, many patients didn’t have access to a product.  If there is a body of information that says this product looks like it is pretty safe and it looks fairly effective, that they had the ability to develop what they called an open protocol so that patients who weren’t participating could gain ready access to it.  So again, a significant issue for many of the rare diseases.

Then there was a coordinating group called the Health and Human Services Orphan Products Board that was comprised primarily of Public Health Service, Department of Health and Human Service agencies, Department of Defense, Veterans Administration, Department of Education and others;  Primarily just the government offices.  Several of the groups, the Pharmaceutical Manufacturers Association, they had a commission on drugs for rare diseases.  Then there was the Generic Pharmaceutical Industry Association.  They also had a commission that looked at orphan products development and rare diseases research.  

So a lot of activities in the ‘80s, and I can remember one slide that we had that was sort of the Orphan Products Board, and an out of business sign in front of the store.  I was hoping that we had accomplished everything, and the Orphan Products Board really doesn’t do anything these days other than exist on paper.  So many of the requirements and activities have sort of been institutionalized both at FDA and now at the NIH.
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I think you already had a presentation on this, and so I will just jump over that.  Okay.
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In the ‘90s we had this special emphasis panel on research collaboration, how to increase research on the rare diseases at the NIH, and you can see even though we had an office at NIH it really wasn’t a mandated office.  It existed, but no real authority, no legislative mandate, no source of funding; and so they made a recommendation it should have a permanent presence.  They suggested that in order to foster research that we develop centers of research excellence in rare diseases, both for developing treatments and diagnosis of rare diseases, which seems to be a particular problem for so many of the rare disorders.

Again, a major problem is developing research investigators.  A lot of emphasis on the more common diseases.  Many investigators do not want to get into looking at the rare diseases, even though they present some nice opportunities to really take control of a research product because no one else is looking at so many of the rare disorders.  In fact, one of the individuals who I spoke with the other week said that was the only thing she could get into when she was doing her post-doctoral work.  So she picked up a rare disease, and now she is really an extremely well-known individual in sarcomas.  She said it all went back to her fellowship days and being able to take a disease that no one else was interested in and moving it forward.  So it can work out.  There are a lot of applications from the rare diseases to the more common diseases and back, so I think it gives some good opportunities.

We wanted a little bit better representation of people who knew about rare diseases present on the peer review groups, the initial review groups of the study sections at NIH.  The site visit teams that go out and give the okay to the research sites, we wanted membership on the advisory councils that make recommendations as far as funding and develop programs related to research and the emphasis within the various institutes.  I must say all these things have evolved, and we find now even a greater emphasis on patient advocacy groups than what we have ever had.  In fact, this year looking at the appropriations language that was given to the NIH from the House of Representatives and the Senate, this is probably the most I have ever seen as far as recommending groups, institutes at NIH to work with patient advocacy groups.  So I think they are getting through to members of Congress, and many of the patient advocacy groups have really refined their practices, picked up medical advisory boards with some of the best experts in the United States and in the world.  They have gotten scientific advisory boards, and they are getting through to members of Congress that they do have something to offer, so I think is just part of what we are looking at and probably what you would be looking at, too, as far as different organizations that should be collaborating.
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Here are some of the recommendations, some other recommendations.  They talked about the need for these scientific conferences to really focus on rare diseases, and I will have some information, and we have had some real good success with that the last several years.  I think it really does help to develop a research agenda for rare diseases.   We are looking at trying to increase ready access to biospecimens and improving the development of animal models for so many of the disorders.  There, too, the areas that we are going to be looking at in the coming year, we put that as two initiatives for our office to work with the rest of the NIH institutes.  Again, in the ‘90s we again the increased participation of the patient advocacy groups, and of course one of the recommendations coming out is we need to listen to them a little bit more.  That has really happened to all of NIH and probably a lot of the government, that in opening up and gathering advice from the public a little bit differently than what it was 10, 15 years ago, and 20 years ago when things were very closed even at the advisory committees under --- back in the ‘70s, how much they were closed and how they did open up.  Then to provide better information and better access to information on the research of rare diseases, this actually -- we had the clinicaltrials.gov information on clinical studies that are underway supported by both the NIH, CDC, the Food and Drug Administration, and industry, and there has been a lot of controversy recently about total participation in that activity as well.
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Here was the Act that created our office at NIH, and they talked about establishing these research centers.  They talked about the pilot projects and demonstration projects to show that there is some efficacy related to different interventions for rare diseases.  They suggest that we develop research training programs to increase the number of research investigators for rare diseases.  They talk about also developing diagnostics for rare diseases, and that is something else we are doing within the intramural research program.  We are just starting a pilot project to see if we can develop diagnostic tests and then get them out to the public.  We are going to start with about 10 this year and then get some experience, and then open it up to an extramural research program announcement of some type that will try to generate more interest to develop more diagnostic tests for rare disorders.
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Some more of the recommendations talked about public education, coordination, collaboration, things like this.  Of course whenever Congress gives you something, they ask for something back, and they are called reports.  As any bureaucrat knows, one of the favorite things in your life is developing a lengthy report for Congress that you are never sure if anyone is going to read or not.  But I must say whenever we do submit the report we get questions back, and at least it gives you some feeling somebody is looking at it.  We do provide this on our website, and we make sure that
patient advocacy groups and selected members of Congress who have an interest in rare diseases are aware of the fact that this report has been completed.  They are asking us now to really develop some plans for research and some future activities and becoming a little bit more focused on where we should go.  I think with the consolidation of the NIH budget, it is even more important to get an idea how can we consolidate research and make sure that we get the results that are needed with the least amount of money and with the maximum collaboration.

We have the annual report as well.  It gives two reports.  One we do every-other year and one we do every year.  So we are hoping we can just every two years to include the annual report into that and hope that is acceptable, so that is okay.
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Up to the present day all our current research -- our current budget is about $15.5-million, and we do have an intramural program, extramural program, and up until the legislation was passed we were very focused on information development and dissemination through our website, developing fact sheets for rare diseases.  This year we established a trans-NIH working group on rare diseases research, and for the first time we really have got representatives from all the institutes participating in focusing on rare diseases.  What are the opportunities and how can we work together to foster this research.  This is something we felt we should do for many years.  NIH like a lot of other places, if you don’t have money you can’t do too much.  I mean, obviously in our own lives you spend as much as you make sometimes it seems like, and this is really the case.  So the last two years our budget increased significantly from the $2-million mark up to $15.5-million.  So it gave us the opportunity to initiate new programs, and more importantly I think able to get the institutes involved with us and to cosponsor programs.  This is what essentially happened with several of the programs.
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Our Bench to Bedside grants within the NIH Clinical Center focuses on a multi-institute requirement.  You have to have at least two institutes working together.  There has to be a laboratory component as well as a clinical component.  We give these grants, 10 per year that are co-funded with the institutes.  One of the major problems with patients has been -- and their families, really has been getting to the research sites.  So we are doing a small project with Mercy Medical Airlift to arrange a flight to travel patients to these research sites.  Again, so many of these things are not really applicable to the animal aspect, but to your own personal lives.  So if you need anything with respect to rare diseases, there is some information on our website and other things to call us personally if you need any assistance.  We are there to try to help you get things moving.
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There has always been a problem with undiagnosed diseases, and so we have initiated a program where we bring in patients who do not have a diagnosis and try to work them up through the NIH system to come up with a diagnosis and perhaps admission to a study protocol, either at NIH or through one of the academic research centers, which receives the bulk of the NIH money.  Probably 75 to the 80 percent of the NIH budget goes to the academic centers and research centers throughout the United States and throughout the world.  We also have initiated some training fellowships, both in biochemical genetics as well as rare diseases or clinical research training programs, two areas that people have been saying for years need an emphasis.  So we are funding five physicians at the clinical center now in various training programs.  So things are just starting to happen.
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Here is the extramural program where the scientific conferences have been a real nice program for us.  We spent a lot of time working with the leadership of patient support groups to try to educate them about the NIH and the Food and Drug Administration.  We have representatives from NIH and from the Office of Orphan Products Development at the FDA to join us to talk about what goes on within the NIH, what goes on within the Food and Drug Administration.  How do you get products approved?  What are your interactions with the Office of Orphan Products Development?  How do you get grants approved through the NIH?  So we have weekend seminars for patient advocacy group leaders, and that seems to be working out pretty good.  Again, the new emphasis coming this year will be biospecimens, biomaterials, collection, storage and distribution, including brain banks, tissue collection, DNA and cells.  So again, a very important research resource for many.

We have developed this rare disease clinical research network as requested, and we have 10 centers throughout the United States.  I will bring you a little bit more information on that in just a couple of minutes, and we do have the information center that we fund with the National Human Genome Research Institute.
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Here are some of the outcomes of the scientific conferences, and again I don’t know exactly what your needs are.  We have done I guess over 460 conferences since 1995 in different rare diseases, and I think that of all the programs, one area that we have had a lot of success is bringing this focus to different disease within the institutes.  At these meetings we try to have industry present, we try to have the Food and Drug Administration, the patient advocacy groups, any of the medical societies that may have an interest in rare diseases, as well as the research community, both national and international.  You can see some of the outcomes that we have tried to work through and develop, and not every one of the meetings brings out all these new conclusions and outcomes, but different meetings do different things depending on where the needs are.  So it really has been a nice way of bringing a lot of people together to focus, and with the institutes what we hope to do is get them to buy in to what we think is a major area of emphasis and what they should emphasize and become more agreeable to looking at the research applications that come in to the NIH, and we have really had some nice successes.  We do have a list of all the conferences within our website you can take a look at, and we have the agenda and participants and then the summary of the meeting.
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What we have noticed after the meetings, sometimes things move, sometimes they don’t, and sometimes there are products that are lurking out there that no one is really focusing on.  It doesn’t seem to be moving.  So what we have tried to do in the last year-and-a-half is get the players together and focus on that product along with the FDA, the NIH and others really to look at what is needed now to get over that hump and get things moving once again.  It just seems like we hit lag periods, and everybody comes into the meeting and there is a lot of excitement.  Then they go home.  Things happen or they don’t happen.  Yet if there is a product involved, many times people just don’t understand how do you get it moving now.  How do you get it out of research into development stages, and so we have had three or four of these conferences like this.  Very small and very invited individuals to come and review the state of the research and the state of the development of the product, and we are going to do this more and more.  It is not an expensive process that you have to work with, but you do have to work with the institutes and there are other players that you definitely want to involve.  I think it has been a very, very nice success.  Neurofibromatosis, we did one in Duchenne muscular dystrophy.  So just a couple of examples of what we have been doing.
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This is our network that we have established.  I won’t spend too much time on this.  A group of research centers, and really what we are trying to show is that we are able to coordinate for all of the rare diseases.  What we are doing here is really a model of how we might be able to enter data, how we might be able to collect data and store it, and then make it available to others to look at.  So we have got a data and technology coordinating center that is absorbing this data from 10 centers, and we have 60 different research sites throughout the country and several throughout the world included for about 43 or 44 diseases.  So this is really a model that we are trying to see if this can be done effectively and how useful will it be.  

So we have a five-year program to see if it really can work, and again another group, the General Clinical Research Centers Program, a major group that NIH funds there are 82 different research centers at the academic centers throughout the United States.  We thought that if research could be conducted there it would cut some of the overhead costs, and so there is a requirement that they participate with the General Clinical Research Centers Program at the NIH and throughout the academic centers.  We just finished our first year, and I wish we could say we had thousands of patients enrolled, but we actually haven’t started any of the studies.  

We are trying to develop study protocols, which if any of you are involved in research protocols you know how difficult it can be.  They are having similar problems of getting groups together and developing a protocol that really will generate data that is useful later on.  So it is never an easy task.  It seems like first in clinical research or research in general, but then with the rare diseases there always seems to be more complications.  We think that with some of the funds given the infrastructure costs it really will help spread things up.  So I am hoping here in a year or two that things really start to kick off.

We have 32 different protocols that are under development at the research centers.  So that is an average of three.  One of the big issues for the rare diseases is trying to understand how a disease progresses throughout the lifetime of an individual.  There are different manifestations at different times, and so what we have tried to do is have these longitudinal studies where we begin to capture the natural history of a disease.  So I think that is one of the real nice aspects of the network and the types of studies that we are requiring for each of the groups. 
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There are the purposes.  I won’t spend too much time on there.  Here is our website if you have any inkling or any need for information that you can’t find readily.  We try to have an extensive collection of information on these issues here, theses sections; and we spent a lot of time developing the website, and hopefully it is useful to people.  If you need anything you can give us a call.
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Here are some of the conferences that we sponsored, particularly with the National Institute of Allergy and Infectious Diseases, the National Institute of Environmental Health Sciences, and the Fogarty Center.  Some familiar diseases to many of you, and as I mentioned in talking with several of the people, the possibilities of what we are confronting with different infectious diseases, the re-emerging infectious diseases, it really is phenomenal I think.  Just more and more attention we have got to devote to these disorders, monitoring and the like, that we just can’t emphasize them enough. 
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There is the contact information for the office, just if you need it.  Please call.  We try to be responsive, and we do have an information center, both an international access number as well as a toll-free number here in the United States or email.  What we are finding with the information center, they have a tendency to get requests from individuals who have not been able to find information from anywhere else within the internet, and so there are all these custom-designed responses to inquires.  So it can be rather difficult, and -- but they do come up with some good information.  I think one of the things rare diseases do, so many people -- and maybe mainly in your personal life if you are looking at it, that when you are diagnosed with a rare disease many physicians will tell you there aren’t more than 50 people in the world.  If a paper has been published and they have 45 patients reported, that is what is related to the patients, when in reality I think what is happening is that there are many, many more.  The lack of a diagnosis or good diagnostic criteria is very problematic, and there are many more patients than what is thought of for the rare diseases.  So we just find so many of them under-diagnosed ane undiagnosed, so it is a major problem.  We are still trying to work on those aspects.

I think looking at everything, what has helped us quite a bit is the ability to foster collaboration.  I think there are so many diseases and so many needs that are so expensive, and if you don’t get good collaboration with all the partners, you are not going to move forward.  It is acutely particular here in this situation, too.  We need the industry.  We need the researchers, the academic research community.  We need the Food and Drug Administration, the NIH.  We have advocacy groups and professional societies, all working together, and if we don’t have it, we just find that things don’t move forward.  Looking at many of the diseases for which there has been movement and advances in research in the rare disease area, it is once you have very active patient advocacy groups, patient support groups that are able to foster this collaboration.  

We have to encourage that as much as possible, and the conferences that we hold we try to do that.  We try to get everybody involved as much as possible.  It is important to identify your needs and concerns of all the parties who are your constituency.  Work on those, and really stay focus on them, and then keep moving.  Just all parallel track, everything.  You cannot do any serial way for this to happen or that to happen, because things happen at such a different rate that it is important to keep things moving on different tracks.  It is the only way to go, because things just stop and it makes it rather difficult.  

Another point is to look at existent programs throughout the government or industry or foundations who may support different research, and it is very, very to use what is in existence rather than trying to reinvent things all the time.  That is what we try to do within our office.  We have got such limited staff.  We have five staff members in our office, and you just can’t invent new things all the time.  We have to look at what else is available through the NIH structure, and that is what we try to do, is take what is available.  Fortunately we have had willing partners within NIH to really help us keep a focus on rare diseases.  So again, if you have any questions or if I can answer any questions after the meeting that you might have on how to -- what approaches to take or even to join future meetings to talk about other things, please let me know.  I will be happy to join.  It is always a pleasure.
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  DR. GRIFFITH:  Thank you, Dr. Groft.  I don’t know that we have time for questions.
  DR. GROFT:  Okay.
  DR. GRIFFITH:  But if anyone has specific questions, maybe they could visit with you before you leave.
  DR. GROFT:  Okay.
  DR. GRIFFITH:  We really appreciate you coming today.  It was a very informative talk.  I am Ron Griffith.  I am the North Central NRSP-7 regional coordinator, and I am based at Iowa State University, and I will be introducing the next three speakers here.  The first speaker after Dr. Groft is Dr. Elaine Jetté.  Dr. Jetté, if you read in her biography here, has been at a number of institutions, but currently she is a policy analyst for the Veterinary Drug Directorate at Health Canada.  With that, I will just let Dr. Jetté take over.