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Friday, February 16, 2007
Grand Hyatt Hotel
Washington, DC
FDA
Mark Barnett, M.P.H., Moderator
Andrew C. von Eschenbach, M.D., FDA Commissioner
Janet Woodcock, M.D., Chief Medical Officer
Steven Galson, M.D., M.P.H, Director, CDER
Theresa Mullin, Ph.D., Assistant Commissioner for Planning
John K. Jenkins, M.D., Director, Office of New Drugs, CDER
Malcolm Bertoni, M.S., Director, Planning Staff, Office of Planning
Deborah Henderson, Director, Office of Exective Programs, DCER
Jane Axelrad, J.D., Associate Director for Policy, CDER
Ralph Lillie, R.Ph., M.P.H., Deputy Director for Operations, Office of Surveillance and Epidemiology, CDER
Public
Mary Beth Buchholz, Bates Neimand
Mary Gustafson, Plasma Protein Therapeutics Association
Lili Ann Stiver, Drug Safety Institute
David Cavenaugh, Committee of 10,000
Fred Hannett, Capitol Alliance
Amy Comstock, Parkinson’s Action Network
David Fassler, Mental Health America.
Jeff Allen, Friends of Cancer Research
Perry Cohen, Parkinson’s Pipeline Network.
Steve Gibson, ALS Association
Kim Witczak, on behalf of herself
Bill Vaughn, Consumers Union.
Judith Cahill, Academy for Managed Care Pharmacy
Brian Meyer, American Society of Health System Pharmacists
Alan Goldhammer, Pharmaceutical Research and Manufacturers of America
Bridgett Ellis, Plasma Protein Therapeutics Association
John Kamp, Coalition for Healthcare Communication
Alan Kirchenbaum, Hyman, Phelps and McNamara, on behalf of the Council on Radionuclides and Radiopharmaceuticals
Alison Lawton, Genzyme Corporation, on behalf of the Biotechnology Industry Organization
Anthony Wisniewski, U.S. Chamber of Commerce
Andrew Sperling, National Alliance on Mental Illness.
Ellen Liversidge, Alliance for Human Research Protection
Wilson Decamp, on behalf of himself
Mr. Barnett: Are we on? Can you hear me in the back? I always feel bad when I have to interrupt Tony Bennett, but we have to get the meeting started. Maybe we can hear more of Tony at lunch. I'd like to welcome you to this public meeting on the Prescription Drug User Fee Act, or PDUFA as we've come to call it.
I'm Mark Barnett with FDA and I'm going to be introducing the meeting today. Now, as we all know, PDUFA authorizes the FDA to collect fees from manufacturers to help offset the cost of reviewing applications to market new drugs and biologics. Over the past fourteen years, there have been three consecutive PDUFA programs, PDUFA I, II and III. And now a new version of PDUFA, PDUFA IV, is coming up for reauthorization in the Congress.
Well before that happens, the FDA wants to be sure that the agency has taken into account the views of the people and the organizations that are going to be affected by this legislation and that's where this public meeting comes in.
Actually, this is the last in a series of public meetings on PDUFA IV in which the FDA has solicited the views and suggestions from a broad spectrum of interested parties.
Now based in part on what the agency heard at those meetings, the FDA published in the Federal Register its recommendations to Congress for the reauthorization of PDUFA, in other words, for PDUFA IV. And we're here today to hear your reactions and comments on those recommendations.
Now if you read the Federal Register, you know that proposed PDUFA IV recommendations contain four key elements that we'd particularly like your comments on.
First are steps to ensure a sound financial footing for the program that reviews new drugs.
Second are steps to enhance the process through which new drugs are reviewed prior to marketing. Third are steps to modernize and transform the post-market safety system. And fourth, fees that are going to help the agency review direct-to-consumer television ads.
Now, let me explain the format we're going to use today in order to listen and take your comments. If you look at the agenda, you can follow along. You'll notice that in the morning, basically the FDA will be in an explaining format, talking about the details of PDUFA IV and what's been proposed, and in the afternoon, the FDA will be a listener, listening to you give your comments and reactions to what you heard.
So beginning at 9:15, we'll have brief talks about the history and significance of PDUFA, and then our panelists, sitting right up here with us here, they're going to be with us all day. And they are going to talk about what we anticipate from PDUFA IV, including those four key elements that I just discussed.
Let me introduce those panelists now. They've all had lots of experience in planning for PDUFA IV, and some of the also worked on PDUFA II and III. I'm going to ask the panelists to raise their hands when I call on them, because I think the folks in the back can't see the cards, and they won't know who's who without a -- without you doing that.
Let me start out with Dr. Theresa Mullin, who's FDA's assistant commissioner for planning. She served as the lead of FDA's negotiating team for PDUFA IV and PDUFA III, and she played a key role in implementing and evaluating PDUFA III performance management initiatives.
Dr. John Jenkins is director of the Office of New Drugs in FDA's Center for Drug Evaluation and Research, or CDER. He served as chair of the Pre-Market Safety Subgroup for PDUFA III.
Malcolm Bertoni is director of the planning staff in FDA's Office of Planning. He served as co-leader of the Information Technology Working Group for PDUFA IV.
Deborah Henderson is director of the Office of Executive Programs in CDER. She co-led the Post-Market Safety Working Group for PDUFA IV.
Jane Axelrad is associate director for policy in CDER. She led the Direct-to-Consumer Advertising Subgroup for PDUFA IV.
Bob Yetter is associate director for review management in FDA's Center for Biologics Evaluation and Research, and he was the CBER lead on the PDUFA IV negotiating team.
And Ralph Lillie is deputy director for operations in CDER's Office of Surveillance and Epidemiology. He co-led the Post-Market Safety Working Group for PDUFA IV.
Now if you go back to the agenda, you'll notice that after lunch begins FDA's listening part with a public comment session that's going to be devoted exclusively to hearing comments on those four key elements of PDUFA IV. We have a number of organizations and individuals who've signed up to speak during this segment and in order to give everyone a chance, and still end this meeting on time, we're going to limit each speaker to ten minutes. We're going to let you know when you've reached eight minutes and then we'll call a clear halt at the ten-minute mark. And by the way, if you're scheduled to speak and you haven't yet given us your PowerPoint presentation, please do so during the morning break.
The final segment, which is scheduled to begin at four-fifteen is for general public comments, and that's for speakers who want to talk about PDUFA-related topics other than the four key elements we've talked about, or who want to address FDA-related issues other than PDUFA. Speakers during this segment will be limited to five minutes each
Before I introduce our first speaker, one of the questions on people's minds during a meeting like this is what's going to happen to the information and the viewpoints that the FDA receives.
You know, it's one thing to sit here and listen, and it's another thing to actually go back and use what you hear. So we want you to know that there are people scrupulously taking notes here today and that the presentations we hear will be carefully considered as the FDA takes the next steps to making PDUFA IV a reality.
And on that positive note, it's my pleasure to introduce the Commissioner of Food and Drugs Dr. Andrew von Eschenbach.
Dr. von Eshenbach: Thank you Mark, and good morning ladies and gentlemen. Let me begin this morning by first of thanking just many, many people who over a period of months have worked so hard to bring us to where we are this morning. And that is not only the effort on the part of many of the people of FDA, who you been introduced to some of this morning, but so many others, including many in the industry and many stakeholders and advocates who have really helped to be informative and contribute to this entire process, and we really owe you a debt of gratitude.
I want to thank all of you for being here this morning and throughout the day for your commitment and your interest and your concern and your willingness to be here, braving the elements and the weather to really contribute your perspective and your input.
The reauthorization of the Prescription Drug User Fee Act is an extremely important step for the Food and Drug Administration. And Congress, in its wisdom about how this process should unfold, made certain that we would have an opportunity to inform you, and to listen to you as well. And that is very much in line with an ongoing commitment of the FDA to an open dialog and to our value of communication. And so we look to today as just a core and central part of how we will, in fact, continue not only to deal with issues like PDUFA, but our entire portfolio, to engage in this dialog with you.
It's an opportunity to inform, and you will hear throughout the rest of the morning the details of the agreement that we have reached, that we believe is an exceedingly important contribution to public health.
And later on in the afternoon we will listen, and we will listen with the same dignity and respect to your input as the spirit of the dignity and respect with which you offer it. And that will also help to continue to inform us as this process goes forward.
For me this morning, at the very outset, in keeping with that spirit, I think it's essential for me as the commissioner that you hear from me some of the overarching principles that I believe are extremely important in this entire process, and what has guided the PDUFA IV development, and what, in fact, will guide and determine the PDUFA IV implementation and utilization.
First and foremost among those principles that I believe are extremely important is that this proposal is about a user fee. It is just that: a fee for service. And I know that as the user fee program has evolved, there have been some who have been concerned about what, in fact, those user fees are and how they are being utilized, and the impact they are having. This is a fee for a service. No one is buying the FDA. We all recognize that there is a need -- a need to process applications, and a need to be able to move our ability to regulate drugs in an efficient and effective fashion. And both the FDA and the industry agree that there is a need to continue to enhance that process so that its efficiency and its capacity enable us to bring safe and effective products to patients.
And in the process of doing that, the process of enhancing that drug application review mechanism, there is an opportunity for fee for service where we can apply these resources in a very specific and detailed way that you are aware of and informed of that will allow us to enhance that capacity, and to improve that process. And clearly that has value for the industry, but even more importantly, we believe together that it has great value for the public we're here to serve.
And as we look at our entire resource base to continue to achieve the mission of the Food and Drug Administration, we will use this specific portion of that resource base only for those services for which it's applied and was intended. And we will deliver those services in a timely way with the quality to which we are committed. And we will, in fact, deliver what we have committed to in return for those fees, and we will provide that service.
Some of you are concerned as it relates to the relationship between fees and appropriations, and some of you are supportive that there should be a place within our resource portfolio for fees, and others of you are concerned. But there should be no confusion about the FDA and who, in fact, the FDA serves, and what, in fact, our purpose and our function is all about.
I couldn't help but notice on the television the other night as I happened to be looking at the news to see a long line of trucks that were caught up in an ice storm up in the Northeast. And to think, in fact, about all of those truck drivers who, like many, many others, were driving through difficult conditions through the dead of night, and at the end of that, they would bring home a paycheck so that they could put food on the table for their family. But a portion of that paycheck, some of their tax dollars were, in fact, coming to the Food and Drug Administration so that we could be certain that the food that they were putting on the table was safe.
I got a phone call from my daughter, who's a social worker, who was purchasing medicines because my grandson has bronchitis, and I know that a portion of her salary, the taxes that she pays, are coming to the Food and Drug Administration so that she can know that when she gives that medication to my grandchild, it is, in fact, going to be safe and effective.
They and you and millions of Americans are whom the FDA -- and serving them and you, and protecting and promoting their health is the only reason why we're here, and it's the only purpose for which our resources will be utilized, regardless of their source.
And you should know and must know that there are thousands of FDA employees who come to work each and every day with the courage and integrity to make decisions regarding approving those drugs, and they're not concerned about where the dollars came from, but only about what good those drugs will do. They know who they're working for. They also have families who eat and need medicines. And like you, they know that we need a strong FDA with adequate resources, and they also know that we need a strong pharmaceutical, biotechnology, device and food industry so we can get safe and effective products that we then can be able to deliver to patients.
We need a strong FDA, a strong FDA that will be a bridge, not a barrier, to our ability to get these products to the people who need them.
And as the FDA commissioner, I am also a physician, and first and always a physician. So I often have the time to be able to still speak to patients, and just yesterday and the night before I spoke to a woman with disseminated cancer in her abdominal cavity for which standard chemotherapy is no longer working. And on her behalf I queried a couple of my friends in some of the cancer centers around the country about what's happening, what's coming next that might be a potential solution for this kind of a problem. And I heard about exciting new work being done in new cancer drugs that have the hope of now being able to offer a further solution when our old standard therapies are no longer working.
FDA must be a bridge, not a barrier, to getting those new drugs and those new solutions to that woman and to millions of others like her. And to do that we need resources, and to do that we need collaboration and cooperation among our partners.
FDA will be a bridge to use these resources to make that hope possible, and we will do it in as rapid and efficient fashion as possible. But rapid does not mean reckless.
We'll be open and transparent in the administration of this user fee program and we'll be open and transparent throughout its entire course of implementation. We'll be open with Congress, with you, and with the industry who are providing these fees.
We will administer this program with the integrity that comes with us being good stewards not only of the dollars, but good stewards of the trust that's been placed in us. The FDA knows that our actions and our decisions require adequate resources for us to be able to accomplish and achieve that mission. But in making those decisions and taking those actions, we are not focused on where the resources come from, but only the purpose for which those resources are, in fact, necessary to protect and promote the health of the public we serve.
And so as you listen to the presentations this morning you will learn about the details of this user fee program, and the critically important role that it can play in helping us accelerate and improve the processes by which we approve drugs. You'll have the opportunity to ask your questions and address any concerns you might have about the program later on today. But at the end of today and throughout the days that will follow, there should never be any question in your mind about the purpose and the functions and the programs at FDA, and the reason why we are, in fact, making the decisions and allowing the products that we regulate to come to the marketplace. It is so that we can protect and promote the health of the people we serve, regardless of where the resources come from.
Dr. Barnett: Thank you Commissioner.
Our next speaker is going to stand back and give us a broader perspective about the whole issue of how human drug review has been funded over the years and what's needed. Now we have a slight technical difficulty right now because the slides that are loaded here are the wrong ones, and so if we can get Anthony, the audiovisual person up here to fix things up, that would be great.
Dr. Woodcock: I'll get started while my slides are being put together here. I'm going to talk about -- because the user fee programs at FDA are basically a resource mechanism, another stream of funding to allow the agency to perform some of its functions, and as Dr. von Eshenbach said, these functions are both that we do and assist the industrial sector in, you know, meeting its statutory obligations, so that's why we can collect fees for these activities. They are not in any way, as most of you probably know, related to approving any product, but rather the function we serve of overseeing the development of these products, as well as the function of seeing whether they're eligible for marketing, whether they're safe and effective.
Now, FDA funding over the years, which we're going to show soon, has not been growing rapidly and industry user fees of all kinds, including medical device fees and so forth, but primarily prescription drug user fee has represented a grow share of FDA funding. The slides I'm going to show you on resources for FDA are in current dollars rather than constant dollars and so they don't show the effects of inflationary increases on the actual available budget for the FDA. And although I'm going to show you slides from 2001 through 2005, which represent the period of this particular program, more or less, if you went back another decade, you would see the same trajectory for the human drug review program.
In the time since 2001 to 2005, the FDA budget has grown overall from a little over $1.1 billion to a little over $1.6 billion in the 2005 time frame. And the -- a large proportion of this growth has been related to user fee programs that have grown during that time.
All right, now those of you in the back might not be able to fully see this slide, but this slide represents the entire FDA budget between 2001 and 2005, and the different areas, the different shaded areas represent the contribution or the earmarking or trajectory of funding, and I'll walk you through that.
The base is funds that are not specifically dedicated to a specific area. And, as I said, this chart shows current dollars, so these are not adjusted for inflation over the time of this period that is displayed. If they would be adjusted for inflation, obviously they'd have a more downward trend for all of them.
The bottom part of this shows the general funding. The next small slice of this shows earmark funds that we need to spend directed in one way or another that would not go into general drug review.
The next part of the graph, which is in the middle, shows the user fee trigger amounts. These are amounts of appropriated dollars that must be dedicated to the user fee program in order for FDA to continue to be collecting user fees, and this is in all the different user fee programs that FDA has.
And the top piece is money that has been allocated specifically for counterterrorism activities.
So sort of the bottom line here is that user fees represent, first of all, an increasing proportion of FDA funding, and that that proportion has been increasing over this time period.
Now the next slide displays a similar type of graph just for review by the Center for Drug Evaluation and Research, one of the centers that is primarily involved in the prescription drug user fee program. And one you see if you look at these budget figures, which are, again, in current dollars, not inflation adjusted dollars, you'll see at the bottom that the amount of more or less discretionary appropriated dollars available has decreased, that more money has been put in the category of earmarks. That's directed. Much of that represents directed funding for the generic drug review program, which I think everyone would agree is a good thing.
The next fairly large line in the middle represents how the drug center is constrained by the user fee triggers, and dedicating that money toward the review of new human drugs, the user fee activity.
The next very large segment there is the contribution in -- if you look at the very end, in 2005 to CDER's review of new human drugs by user fees.
And then the very top line -- it's very narrow -- is appropriated dollars for counterterrorism.
So overall, again, I think the lesson from this slide is that user fees have provided much of the increased funding for the Center for Drugs and for the review activities that go on within that center since 2001. And the same would actually apply if you went backward in time into the '90s.
The next slide is a very similar slide but showing funding for the Center for Biologics Evaluation and Research. The Biologics Center has a disparate portfolio and a number of their activities are not covered by user fees, such as regulation of the blood supply. The activities are, however, very important.
PDUFA fees provide a significant share of funding for the Center for Biologics Evaluation and Research. If you look at this graph, you can see at the bottom, again, the amount of more or less discretionary appropriated dollars. The next large segment over time has been the user fee triggers. That, again, is the amount Biologics Center is constrained to use on review of new human drugs.
The next segment is the actual user fees that go to CBER's resources.
And the very top line, again, is counterterrorism, where CBER has a small but significant appropriated funding for counterterrorism activities.
So the bottom line here is that, again, for these important activities that are done at the Biologics Center, the user fees play an important role in funding these type of activities.
Now what are these activities? There's been much discussion of this over time, and I think there's a tremendous amount of misunderstanding about what these fees actually fund.
The fees fund what's known as the process of human drug review, and I'm going to go through some of these. They have a very broad scope. For example, prior to manufacture, especially with very innovative therapies, doing human testing, human experimentation, they have the opportunity to come in and discuss with the FDA how these initial trials might be done, and this is very important to avoid problems in Phase 1 one trials of volunteers. And this activity of consultation by the FDA is covered under the user fee program. It's primarily -- it's almost totally focused on human subject safety and protection.
Review of IND applications -- this occurs in both of the centers as well -- and this activity, up to the middle of the activity, is pretty much concerned with the safety of human subjects in experimental trials. Later on during development there are some other activities I'll talk about that have to do with effectiveness as well as safety.
But importantly, the staff spend much of their time making sure, number one, that the subjects of these trials are adequately monitored and have a very good assurance of safety; and number two, that the kinds of safety testing that need to be done during a development process are actually put into the protocols and are executed.
So the staff -- this is the third bullet -- have multiple meetings with sponsors to review the development program at multiple, sometimes, stages, depending on how the innovative the therapy is. I'm going to get to the numbers in a bit, but this is a very important activity.
It also is extremely important to the public that trials not be done that are wasteful of human subjects. In other words, if companies would do trials without FDA consultation and then it would turn out that those trials were not acceptable to the agency, then those trials might have to be repeated, and that is not an ethically acceptable situation.
The next bullet talks about special protocol assessments. These are late in development usually, where the FDA and the firm will reach agreement on a critical trial, and the design of that trial. Not that the drug will be approved -- it's not that kind of agreement -- but that the trial is an adequate test of the performance of the drug, and a lot of effort is put into that. Many thousands of people may be subjects in that trial, and it's very important to do those trials correctly.
So human subject protection, in addition our, what we call our BiMo program or our auditing of clinical trials or IRBs is also a part of the process of review in new human drugs, and this is a very important activity, of course, that FDA is one of the major players in across the country.
Then review of new drug applications, which also include biologics license applications, efficacy supplements and manufacturing supplements. This is the pre-market review portion, which is clearance for products that will get out on the market, or manufacturing changes. Again, safety review is about fifty percent of this. And the entire reason for doing the manufacturing reviews, which are numerous, is to make sure that the manufacturing changes have not caused a change in the product which will impact its performance, particularly its safety.
The next bullet is about reviewing label changes. This is a very important activity. As many of you in the room know, the label is a legal document that actually lays out what FDA accepts are true statements, actual statements about the drug. And also it is a major source of information for the clinicians who prescribe the drug. And so what goes in that label is extremely important, and it's a very time-consuming activity that the agency does.
Risk management plans may be put forward when there are remaining uncertainties about the performance of the drug. The benefit-risk overall may seem positive, but there are some things that are of concern, then there could be a risk management plan. This was started in about 1999 and is still somewhat -- we're still learning how to do this correctly. And a lot of effort and time is put into this for pre-market, and the user fee program funds this activity.
Currently, we can -- the adverse event reporting is funded -- the function of reviewing adverse event reports is supported up to three years after the approval of new drugs.
I would like to add to this list one that isn't on here that is our IT systems, because I think without the user fee programs, we wouldn't be where we are in electronic submissions and so forth. And with the volume of data that is submitted to FDA, this actually becomes a safety problem if we do not have access to the data in some kind of form that we can actually use. So it is crucial that FDA be able to go to electronic access to all this information that is flowing in so we make sure we use it. And it isn't just adverse event reports. It's all the marketing applications and so forth, and that has been supported by this program.
I talked about what we do. Now here are the, sort of, widgets that we do it on. Okay, the things that are counted, and all these activities already mentioned then are performed on these submissions.
And what we've seen during this five-year period, six-year period is that submissions in general have continued to grow. NDA submissions have increased. Efficacy supplements have increased, and that is good news. We used to get pretty few efficacy supplements. And what an efficacy supplement means is what used to be an off-label use actually gets studied and it gets put on the label, and that helps with reimbursement and it also tells us whether or not that off-label use is safe and effective. So it is very important that we keep studying drugs after they are approved.
Manufacturing supplements, if you look particularly at this, this has gone up about from about 2,000 to about 2,700. It's up more now, I think. And these, again, are to make sure that the changes in manufacturing are not affecting the quality of the product and its performance.
ne of the biggest changes is in meeting requests. There were agreements put into place about meetings with industry as part of the user fee negotiation and I think uniformly, I think everyone agrees that this consultation with the FDA by the industry is a good thing. It enables our scientists and our clinicians to bring the breadth of their experience, which they see all across the industry to the sponsors, give them advice and also give them advice on how to meet our standards, both for safety, efficacy and quality. However, this increase from about 1,700 to about 2,500 meetings, and it had increased greatly up to the 1,700, is a tremendous burden. Each one of these meetings is a pretty big deal and requires many FDA scientists to do a lot of preparatory work, and so forth. So this is kind of a service that the FDA supplies in providing access to our scientists and our expertise.
And finally special protocol assessments. This one is also a big deal. This is where we agree on the protocol that will be done for human subjects and also, actually, for animal subjects. It is very important that we agree on this so it doesn't have to be repeated. We have to make sure that the right trial is done the first time.
Now, I'm just briefly going to go over how user fees leverage appropriated funding and provide some synergy so we can do better in some important public health initiatives than we might have done the given appropriated funding alone. And this is counterterrorism, for example. Our whole apparatus that we have in place for pre-market review has helped in our review of contermeasures for counterterrorism.
The Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, we have worked tremendously to try to increase the number of drugs that actually have been studied in children where there's information on the label about how to use the drug in different age groups, and whether or not it is safe and effective in those children. And this again, having user fee resources has helped tremendously in this.
The President's Emergency Plan for AIDS Relief, PEPFAR. There are a number of these -- some of these drugs are generic and some of them aren't. And the user fee program has helped with the review of the non-generic PEPFAR HIV/AIDS drugs, and a large number of these have been approved by the FDA and made available in other countries.
And then pandemic influenza in the Biologics Center. This has been a huge effort over the last few years to help with development, and oversee the development and evaluation of additional flu vaccines, including trying to get some vaccines to be effective in pandemic flu.
So I hope -- my point has been PDUFA continues to be of importance to us. It provides us an opportunity to improve and modernize our processes, and it increases the stability of our program in an area of scant resources and growing public health needs, but where we and our contribution continues to be essential.
So thank you very much.
Dr. Barnett: Thank you Dr. Woodcock. You know, we said earlier PDUFA actually has a long history, fourteen years old, through several iterations. So our next speaker is going to talk about how PDUFA developed over the years, and what we might have in store, and that speaker is Dr. Steve Galson, who is director of FDA's Center for Drug Evaluation and Research.
Dr. Galson: Thank you, and thank you to everybody in the audience for spending the time today to give us your feedback. We are listening carefully. I also want to thank Dr. Woodcock for laying the groundwork here this morning with that presentation. And, of course, our great team at my left that's been working more than a year to bring us to the point we are today.
My role today is to spend a few minutes making sure we all starting from the same understanding of the background and the history of the PDUFA program.
As you know, the program has been authorized in five-year increments starting back in the federal fiscal year 1993, and it has had a slightly different focus depending on the circumstances each time we have sat down to redo the program. It started out in 1993 with a primary focus on decreasing review times, the drug lags that you've all heard about. The long time it took between the drug companies starting and when the products came out the other end at the FDA. So that was the major focus the first time the program was implemented.
The second round, which lasted from '98 to 2002, was put in as part of the FDA Modernization Act, and the focus was specifically on decreasing review times, but looking also more broadly at the whole drug development enterprise, and the role that we could play earlier in working more closely with industry, and making sure the whole process was sped up more.
In the third round, starting in 2003 and lasting to where we are now through to October, we focused on expanding interaction and communication during the first part of the review process, during the first cycle review, and for the very first time we supported some post-marketing activities that Dr. Woodcock has gone through exactly what we do that follow a drug between two and three years after approval.
The program really has been spectacularly successful by most measures. The user fees added really critical review staff to allow us to focus on improving timeliness and really making the whole process in the centers that review these products more efficient through intensified numbers of meetings with industry.
In return for these funds, as you all know, we agreed to meet specific performance goals, and we've done really very, very well at meeting those goals that we set.
Again, I think most people would agree that the result of this has really been a revolution in the regulation of pharmaceutical products. When companies send their applications to us, they have a pretty good idea at least of the process that's going to happen when we have a decision coming out of the other end of the process.
And as you've heard, the review and the approval times have gone down dramatically, and I have a few charts that show that.
This reflects the overall funding graphs that Dr. Woodcock shows, and this looks specifically at FTEs or just the people that are engaged in doing the work that we do at the FDA, the purple bar being the total number of people and the yellow and, I guess one is blue and one is purple, the blue showing the total and the purple and the light colored one showing balance between the number of positions that are funded by appropriated dollars and the number of positions that are funded by user fees, and you can see the gradual increase over time that match the graphs that you saw in the earlier presentation, showing that, actually today we have a little bit more of our staff involved in the process of new drug review, which just is across the agency in the two product centers and then support in the commissioner's office. A little bit higher number of those staff are funded by user fees and appropriated dollars.
And this looks at the impact on a particular measure, which is the median approval time for a new drug and biologic licensing applications over time. This actually doesn't have the most recent numbers on there, the FY '06. The standard number is down again and we're really this year in our most recent evealuation at historic lows in our median review time for both the standard and priority applications.
And, of course, the products that have come out the other side, we don't have time to go into even the most spectacular successes here, drugs for cancer, metabolic and endocrine diseases, anti-infective drugs. We've really stepped up to the plate in getting treatments out to attack the AIDS epidemic here and overseas. One hundred and fifteen drugs for neurologic and psychiatric diseases. And drugs for, of course, one of our top killers, cardiovascular and renal diseases.
But there have been problems, and it has been impossible for us at the beginning of each of these five-year periods to predict the circumstances that were going to exist at the end. And one of the things that has really come through in this last five years of PDUFA III is the actual cost of inflation. Even though we tried to predict this, the actual cost of inflation has been greater than the adjustment factors that we put into the last round of PDUFA.
We put in place a term called the workload adjuster to do this and it really has not kept pace with our actual increases in review work, and you saw in Dr. Woodcock's chart the number of different types of applications and supplements and meeting requests and other types of workload that have increased dramatically over this time period.
We tried to predict what that would be. We did not do the best job in that, and we've sort of lost our ability to use the user fees adequately to support that work.
And as well, as you all know, our demand in the post-marketing area increasing dramatically. There's been a very significant increase in reports of serious and unexpected adverse events. Our overall -- this is all of our adverse events are approaching a half a million a year, and this is a huge analytic and scientific challenge to be able to separate the wheat from the chafe, and we need more experts, more IT systems, more analytic ideas to move forward on this, and we just haven't been able to keep pace in that resource area. And this latest work that our team has been doing over the last has really sought very strongly to improve that situation.
We have been listening over the past year to many people and the next couple slides, my last two, just summarize some of what we've heard from four groups, and, of course, there's a lot of overlap between those groups, but just to characterize generally what we've heard, and you will, of course, embellish and elaborate on these later in the day, I hope.
From patient advocacy groups, we've heard that they support this mechanism to speed access to new drugs, and they really want to see the fees increased to do even more work in the post-marketing area.
The consumer groups have told us that they believe in many cases that we should be getting more of our resources from appropriated dollars and not user fees. As we've said many times, we're agnostic about where the funds come from, but this is what we've heard from the consumer advocacy groups. That there should be more funding, as well in the post-market area, and they really support seeing -- you support seeing more support for direct-to-consumer ad review, including potentially a separate fee. And you're going to hear more about that later.
The health professional groups have supported PDUFA as well, would like to see more post-marketing funds, and removing the time limit that is currently on the our use of funds for the post-marketing period, and, as well, support for review of direct-to-consumer ads.
And we've heard from regulated industry, of course, as well, that support increased stabilization and strengthening the program, modernization of our post-marketing system, and also some support for advisory review of specifically DTC TV ads.
So that's it for the background part of the talk, and we'll move on to the next speaker.
Barnett: Thank you very much Dr. Galson. It's time now to go to our panel of experts up here, not that our previous speakers weren't experts, they were. But now we're going to speak about specific aspects of PDUFA IV in some detail, and you're there already.
Dr. Mullin: I am.
Dr. Barnett: Okay. And I'd like to start with Dr. Mullin talking about things that we can do to place the drug review process on a sound financial basis.
Dr. Mullin: Thank you Mark. Good morning. I'm just going to take off from where Dr. Galson left us, and based on the input and the information that we have obtained over the -- from various stakeholders, FDA is making proposed recommendations, a number of proposed recommendations for PDUFA IV, and we've put them under several broad headings, and these are generally to ensure that we fix those problems of strengthening, keeping the stability and strength in the pre-market program, and in addition, try to transform and improve the post-market safety program, as well.
So these basic themes that we have for our proposed recommendations are to ensure sound financial footing, enhance the pre-market process, and transform post-market safety through modernizing pharmacovigilance, enhancing proprietary name review, and increasing the capacity of DTC television review. And the other panelists are going to tell you a lot more about them, so I'll just go on to my next slide.
I'm going to be focusing my comments on the sound financial footing. And in order for us to ensure sound financial footing for PDUFA, we need to address some flaws that we've discovered, as Dr. Galson mentioned, in PDUFA III, and the adjusters that we have there.
The current law does allow us to adjust the fees for increases in inflation and increases in workload, but they have some shortcomings that we've discovered.
The inflation adjuster that we have today in the statute allows us to increase the fees to reflect increases in federal pay, but they don't include other important payroll costs that we and every other employer, I'm sure, experiences, that offers health benefits, retirement benefits, and other types of costs. Those have grown significantly more than just the federal pay increase. Those are costs that must be paid, as are other costs like rent and rent-related costs.
The workload adjuster we have in the statute accounts for some of the work -- some of those things Dr. Woodcock showed you. Numbers of submitted applications are primarily what's captured there. What's not captured are the growth in sponsor-requested meetings, special protocol assessments, labeling changes, and changes in some of those areas, and the result is that the workload overall has grown much more than we've been able to capture in the adjuster that we have today.
This chart just gives you a little bit more data. I hope that your handout provides it in a size that can be read. It's maybe a little bit small, but just to give you a sense of the dynamic I'm talking about, with increases in payroll and benefit costs. We have a breakout for CDER and CBER, as well as FDA as a whole here, and you can see that, in fact, with the large number of senior scientific staff, the centers are growing even more than the FDA as a whole. But we're looking at and proposing that that 5.8 percent for the agency as a whole for payroll costs be something that we use as another type of adjuster that we can have to account for this.
Federal pay raise increase, as you can see there, the five-year average has been 5.2 percent, compared to 5.8 percent for FDA as a whole for the payroll and benefit cost increases.
We've also experienced cost increases in rent and rent-related areas. This reflects both the security requirements for federal agencies and federal buildings post 9-11, and also just living in the D.C. Area. GSA rents are supposed to reflect market rates, and so our rent and rent-related costs have gone up 21 percent per person, per FTE and that's really not been captured in our current fee adjuster.
In addition, we have a lot more contract services, and those costs have gone up as well. So those are areas where we're trying to address the shortcoming we have. We can afford to pay for fewer people as a result.
This is just a quick graphic. It shows you -- it's kind of dramatic to see it visually, some of the -- a breakdown of some of the numbers that Dr. Woodcock had shown earlier. This is sponsor-requested meetings by type of meeting, and you can see some in particular have grown pretty rapidly. Type A meetings, which have a thirdy-day response, have grown by more than 200 percent over a three-year period. Type B meetings, which have a sixty-day clock, have grown more than sixty percent. These are significant review of components, so that's been a challenge for us.
This is an even more dramatic graph. This is the special protocol assessments. We have to provide a written response to the sponsor within 45 days of their submission of the protocol, and they've grown a great deal as well. And as Dr. Woodcock mentioned earlier, these are very valuable for improving the drug development program protecting patients, and there are a lot of good things about it. But we hadn't captured it in trying to account for how much work people were going to have to do, and the number of people we have.
And so we're recommending some changes to these adjusters to address these issues.
The first is the inflation adjuster, and we'd like to propose that that adjuster be changed so that in the statute we include a third component in addition to federal pay increase that we allow for another component in there and use whichever is the greater, and that third component would be based on FDA's most recent five-year average experience of total pay and benefit cost, so we can account for that.
In addition to the workload adjuster, we're proposing that there be two modifications to that. One, instead of using commercial IND submissions, which only occur at the very beginning of the development program, we instead use a measure of the number of commercial INDs that are active, that are still undergoing and there still in the development process, which is a bigger number, and actually a more stable number, but it's a better reflection of the totality of IND-phase work.
In addition, we'd like to capture and account for these meetings, special protocol assessments, labeling changes, and other components that have grown significantly and are very important components of human drug review work.
So we've proposed a particular methodology. We've also proposed that we have a CPA come in and review that within the first year or so of the program in PDUFA for to determine whether they think the methodology is the best we could use or if they have recommendations for perhaps making it even better.
This is my final slide, and it gives you the overall amount of money that we're talking about going into or proposed for PDUFA IV. And I'll begin with the baseline figures, that first line. The FY 2007 baseline brings forward the adjusted from PDUFA III, the amount in the statute, applying the adjusters that are in the current statute, and that would be $305.5 million, approximately.
Added to that would be an adjustment for fiscal year 2008 that would go forward to account for inflation that we haven't covered to date that we've incurred, so we can make up for that, and the number of people we've not been able to support or hire because of not having that in there, and that would be $17.7 million.
A further adjustment to cover rent and rent-related costs, FDA's going to continue its move to the White Oak facility in Silver Spring, Maryland over the next five years, and there are some costs associated with that and others as well. We're proposing that we put $11.7 million into the baseline to help cover a proportionate share of fee dollars for that cost.
In addition, covering this increase in workload that was experienced during PDUFA III, a one-time adjustment to account for that workload, and then going forward applying this new adjuster we're talking about, and that addition would be $20 million. That gives a total baseline of $354.9 million, and to that we would add costs that we've estimated would be associated with certain enhancements to the program.
And just briefly in the pre-market area, expediting development, a set of initiatives there for $4.6 million is what we think it would take to support that. We're proposing improving our IT infrastructure further by adding $4 million per year, further adjusted in future, to our IT spending so we can move closer to all-electronic submission and review of the applications for the reasons that Dr. Woodcock mentioned before.
And modernizing and transforming our post-market safety system, $29.3 million for that. And in addition, as you'll hear later, we're proposing a separate user fee program for direct-to-consumer TV advertisement, and that's a program that would have a total funding of $6.5 million.
And with that, I'll turn it over to Dr. Jenkins, who will tell you more about the pre-market enhancements.
Dr. Barnett: Thank you. Dr. Jenkins, please.
Dr. Jenkins: Good morning. I'm going to be speaking about some of the changes we're going to be proposing for the pre-market program, and first I should make a couple of definitions. One, that the name pre-market is a bit of a misnomer.
The activities that are encompassed in this aspect of the program actually can begin as early as a pre-IND submission, so even before a sponsor is proposing to do human clinical trials, they can request pre-IND meetings with the FDA to review their drug development program.
The pre-market program also includes all of the IND phase of review so the investigational drug development phase is included here.
It includes the actual marketing applications, such as the new drug application or the biologics licensing application, but it also improves some things that you may traditionally think of as post-marketing activity, such as supplements to an approved application. I think Dr. Woodcock previously mentioned the efficacy supplements and the manufacturing supplements. So these are supplements to the application that come in after it's already been approved to add a new indication, to change a manufacturing facility, to change a manufacturing process. Those are all included in the pre-market review function.
I've only got a couple of slides because I'm focusing primarily on the changes we're recommending to the program that either modify or build on what's already in the PDUFA III goals letter, so I would refer you to the PDUFA III goals letter for the entire scope of the program.
On the first areas we're hoping to build on from PDUFA III is to try to further implement the goals we articulated for ourselves and for industry in a guidance we issued a few years ago called the Good Review Management Principles and Practices Guidance. This guidance was designed to outline for ourselves and for industry best practices for the management of the review process. This is a process guidance. It's not a scientific guidance in that it does not address the issues of how to review the scientific data. This is about managing the process, which is a very complex process of submitting the application and then FDA reviewing the application in order to reach a decision at the end on what the regulatory action will be.
Theresa showed you in the slides earlier that we've seen significant growth in our workload in the past five years, and in particular the workload in areas such as meetings and special protocol assessments, which were not captured in the current workload adjuster. The result of that workload growth, without commensurate increases in our staffing is that we're continuing to struggle to get our reviews done in time to meet the PDUFA goals. So it means that reviews are often completed just in time to meet those PDUFA goals, and that continues to put a strain on the process at the end.
There are a lot of very important activities that have occur late in the review cycle, after the primary reviewers have completed their review. Some of those activities include time for the supervisor and the signatory authority to review all of those documents that have been put together, and make their own assessments of the data and what the regulatory action should be.
There need to be discussions with the sponsor about the labeling if the product is going to be approved. In essence, the labeling documents FDA's conclusions about the review of the application, so it's very important that those discussions and those decisions about the labeling have plenty of time to be done in an accurate fashion.
Also, if there are any post-marketing study commitments that the FDA is asking of the sponsor, there needs to be time to formulate those requests, decide why we need a certain study, what type of study we need, and then to discuss with the sponsor what the study protocol might look like, what are reasonable timelines to be expected for completing those studies and submitting
the results to the FDA.
And one of the new components that we have recently added to the process are risk management plans. So if there is a need for a risk management plan for the application and the review, we need time to work internally with our colleagues in the Office of Surveillance and Epidemiology and other parts of the agency to decide what plan we think is necessary, and then we obviously need time to work with the sponsor to discuss those plans and come to agreement.
So those are the end-of-review-cycle activities that are very critical and very important and really under a time crunch because the workloads is making it hard to get the reviews done earlier.
So, as Theresa outlined, we're proposing significant changes to the workload adjuster for PDUFA IV, and also some one-time adjustments to try to capture the increased workload. And with those new resources that we're expecting under PDUFA IV, we're able to commit to the following pre-market review enhancements for PDUFA IV.
Number one is that we're proposing to maintain all the current review goals for applications. So we're not proposing to change the six-month review for priority applications, the twelve-month -- excuse me, the ten-month review for the standard applications. Those would all remain the same as are currently described in the PDUFA III goals letter.
We are agreeing with the additional resources we could develop a review plan for each application that would include a projected time for when we would complete certain milestone activities during the review cycle, and that we would be communicating some of those milestones and projected timelines to the sponsor in a communication that we currently have that's come to be known as the 74-day letter. It's a letter that we send to the sponsor of the application within fourteen days after the sixty-day filing date that previously was used to inform the sponsor of any deficiencies we'd already identified during our early review of the application. Now under this proposal, we would add to that our projected timeline for interacting with the sponsor on certain key aspects of the reviews, such as the timeline for when we expect to start discussing the labeling for the application and the timeline for when we would begin discussing any post-marketing commitments that we would be asking of the sponsor.
It's important to note that there are aspects of this that are designed to enhance our ability to enhance our ability to meet the goals that we set for ourselves in the Good Review Management Practices Guidance. There's also aspects in here to try to encourage the sponsors to try to meet the goals we set for them, most importantly for submitting complete applications at the time that they submit to the FDA.
So the review timelines that we would be developing under this program would be based on the application as submitted, and if the sponsor submits amendments to the application after the original submission and we choose to review those amendments, the review timelines could be modified in response to those changes.
The other aspect of the program we're proposing to enhance are several activities we have grouped under the heading of expediting drug development. There are two groups of activities here.
First, there are a lot of new initiatives going on about study design, study analysis, and we have agreed that we need to communicate to industry what are FDA's current thoughts on best practices, and what are our expectations in several of the critical emerging areas. So we've agreed to develop a series of guidances that will be very important for FDA and for industry to understand FDA expectations in these areas.
And you'll see here these have certain milestone target dates where we've agreed to publish draft guidance for public comment. In each case it's by the end of the fiscal year that's noted on the slide, that we would publish a draft guidance.
I'm just going to run through them quickly.
Hepatotoxicity is one of the more common causes of safety concerns that arise for drugs both before approval and after approval so we are working on developing a guidance on how to assess products during development for potential to cause hepatotoxicity. We hope to have that draft guidance out by the end of next fiscal year.
You've probably heard a lot in the media these days about non-inferiority trials. They are a valid form of study design in certain circumstances, but they are a more complicated type of study design than placebo-control trials, and we think it's important, and industry thinks it's important for us to articulate more clearly our expectations for non-inferiority trials, again something we've committed to by the end of next fiscal year.
There's been a lot of buzz in the industry in the past couple years about something called adaptive trial designs, something FDA has not yet articulated our expectations regarding, and so we've agreed to have a draft guidance in that area by the end of next fiscal year.
We've been operating a pilot program for the last few years called End-of-Phase 2A Meetings. These are meetings -- bring the sponsor in before they actually complete there Phase 2 program so we can try to have input into designing a better Phase 2 program so that they can, for example, get the dose right that they then subsequently take into their later phase trials. We are proposing to have a draft guidance on our expectations for that program by the end of next fiscal year.
Multiple endpoints in clinical trials, this is an area that comes up in the statistical analysis of a trial where the sponsor may select multiple endpoints that they're going to be evaluating to see if their drug works. It's an area that leads to some very complex statistical questions and analyses and adjustments. So that's a draft guidance that we hope to issue by the end of fiscal year '09.
Enrichment is a hot topic these days about how to better enrich your study designs to select the patients who might most benefit from a drug or patients who might least likely be harmed by the drug by developing an adverse event. So that's a guidance we're working to have a draft by the end of fiscal year 2010.
And then finally, imaging standards for use of imaging as endpoints in clinical trials. This relates to what are our expectations for situations where imaging techniques are being used as the primary or pivotal endpoint for a clinical trial. So, for example, if you're using a CT scan or an MR scan as your endpoint in a cancer trial, or a pulmonary fibrosis trial, what are our expectations about how you go about standardizing the collection of those images, the interpretation of those images by blinded interpreters, etc. So that guidance we're proposing to have a draft by the end of fiscal year 2011.
We're also proposing some areas where we will have dedicated staff time from FDA that's protected to allow to us to work on some emerging areas of science, to further develop the science and maybe lead to guidance in other areas, as well. These include areas such as predictive toxicology models, how to qualify biomarkers for regulatory purposes, and how to handle missing data in clinical trials.
inal slide for me, there are couple things that we're deleting from the PDUFA III program. You may recall in PDUFA III there were a couple pilot programs relating to continuous marketing applications. We have decided to not continue those pilot programs into PDUFA IV. We did have an independent contractor, Booz Allen Hamilton, that did a study of those pilot programs to see whether the added value that were being seen with the program offset the cost to the agency and the industry, and our conclusion, and I think the conclusion from industry as well was that while the programs had some added value in certain areas, the value did not really offset the cost, so we've agreed to delete those programs from PDUFA IV.
Finally, there was a program in PDUFA III called Independent Consultants for Biotechnology Products that provided sponsors with the opportunity to request that FDA engage an expert outside consultant for biotechnology protocols if they were concerned that FDA did not have in house the expertise to review those protocols. We have not received a single request to engage that program during the PDUFA III program, and FDA already has existing programs by which we can select and engage outside consultants in areas where we need assistance, so again we've agreed and proposed to drop that program from the PDUFA III goals letter.
So that's my overview of the pre-market changes. I'll be happy to take clarifying questions or comments later, and I think we'll move on next to Malcolm Bertoni who'll be talking about the information technology program.
Dr. Barnett: But before we do that, let me ask you in the audience, you've heard two presentations now. Does anyone have any clarification questions; things that you heard and didn't understand, or need elaboration on. I don't want to spend a lot of time on this, but I think if we spend five minutes or so, it might be productive, and then we'll go to our next speaker. So if you have a question like that, this is not the time to give your comments on PDUFA. That comes later. But if you have clarification questions on the two presentations you just heard, come up to the mic in the middle of the room and ask them.
Okay, I guess everybody understands everything. Congratulations to you guys for being so clear. All right then, let's go on -- actually, yeah, let's go on and we'll hear now from Malcolm Bertoni on information management.
Mr. Bertoni: Good morning. I hope I won't confuse you with this brief talk. We're going to spend a little bit of time talking about the information technology enhancements to the program. It's a very important supporting function, as Dr. Woodcock mentioned. In fact, we believe it's really one of the important aspects of enhancing the science and safety at the agency.
The goal for the proposal here is really to speed progress toward the day when we have a fully automated electronic human drug review program, and we really used a couple guiding principles as we were working through the issues in this particular aspect of the program.
First, we wanted to build on some of the successes that we have had under the PDUFA III information technology program. We did make some progress toward the electronic application by developing electronic common technical document, or ECTD, standard format, which has been used now and is starting to be used more by the industry in submitting new drug applications and biological licensing applications.
We've also established a single FDA electronic gateway where these electronic submissions can come in, and they're being used actually beyond the PDUFA program into the other programs and adverse events, and that sort of thing for the electronic submissions.
We've also made some progress toward consolidating some of the information technology infrastructure. We're trying to do a better job of managing our networking and storage resources, consolidating some things in the White Oak facility in the data center there, and trying to look at where we can have more common approaches across the agency.
And I think we've established some very important communication and technical interactions practices working with the industrial counterparts because these are very complex systems that we're trying to get to interact and we've had quarterly meetings over the PDUFA III time period where we've been able to iron out some of the technical issues as we're developing things like the electronic gateway.
We're also -- another guiding principle in general is that we're trying to build toward this vision that FDA has for our operations in the 21st century where we are going to a standards based electronic -- fully automated electronic review environment.
I would like to focus on results, so we'd like to really cut right to the chase in terms of describing some of the results we're trying to achieve through these investments in the information management area.
The first couple of bullets on this slide really describe just two sides of the same coin in a sense. We want to make sure that when industry submits their electronic application that they're able to have automated crosslinks to some of the information that they've submitted previously, say in the investigational new drug application phase, where they've clinical trial data, so that they really only have to submit things once, and we don't get into any confusion around that.
And then on the flip side of that, we want to make sure that the FDA reviewers have the systems, have the equipment at their workstation, and the networks and storage are all working seamlessly so they can call up all that different information, and that they'll have appropriate analytical tools at their fingertips to support their review.
We also, in the third bullet here, are going to work toward making sure that we really build on the promise of the new structured product labeling standard, and have the right tools so that we can conduct those discussions and negotiations with the sponsor around what's going to be included in the label, and make sure that we can do that in a way that tracks the changes and eventually will mean that we don't have to submit different formats to support those discussions. It will be just the one format.
We also want to make sure that we build in the technical capability to handle two-way regulatory correspondence with industry, so that we can have can have an end-to-end approach where all of the interations with industry can be done through an electronic system.
Now Dr. von Eshenbach spoke about our commitment to a process that has transparency and integrity, and we spent some time focusing on that when we were talking about the information management aspects of the program. We are going to develop a five-year IT plan. We're going to be spending a lot of time on that over the coming year. It's going to be a more comprehensive look at where we're going with the PDUFA funds, as well as other funds that go toward these systems. We're going to make sure that we have a draft of this plan out for public comment by the end of the calendar year. That's our commitment.
We're also going to make sure that it is integrated with all of the other, many other aspects of information technology development that are going on at the agency, and that these are being reviewed by the appropriate boards and committees in the agency. So PDUFA is not standing apart, it's part of a larger grand scheme at the agency.
And we're going to make sure we're doing an annual assessment of how we're doing against the plan, and making adjustments to that plan. So it's going to be a living document. We hope that it will be useful for stakeholders in industry to look ahead and look at how they're making their IT investments so things can be coordinated over time.
We're also going to continue these quarterly meetings. It's been very valuable. We think it will be important for the transparency and to iron out the technical kinks as we work through these complex systems.
We're also going to be measuring our progress in some objective manner. We have what I think is a PDUFA first where we're going to have metrics on how industry is complying with some of these agreements in terms of how often they're submitting their electronic applications in a form that can be read and is according to the standards.
We're also going to be offering some metrics about how well we're making the transition from the older systems and approaches to this modern integrated, automated electronic review environment.
We think that there are many benefits to patients, as well as industry and FDA from these investments. First and foremost, we truly believe that there will be improved public health outcomes by have better information analysis available.
We also think we're going to improve our productivity and efficiency when we have an all-electronic environment.
We think that this also helps enhance greater consistency in movement toward best practices at FDA so that the sponsors can see one FDA.
We also think it will enhance the ability of industry to efficiently plan their technology investments because there will be an updated plan showing where FDA is going.
And with the resources that we have, I think that we're going to be able to do a better job of reaching out and participating in a lot of these international standards harmonization efforts, because this is truly a global enterprise, and we want to make sure that FDA is continuing its leadership role in this area.
And that is all that I have, so I can see I'm not coming between you and your timely break.
Dr. Barnett: Thank you. It always amazes me when we're running exactly on time, but we actually are. It's exactly 10:30, time for our break, fifteen minutes, and we should be back here ready to go at 10:45. Thanks.
[Break.]
Dr. Mullin: Our moderator Mark was having some back pain so he needed to go home and get some rest. Our next speaker is Debbie Henderson, director of the Office of Executive Programs in the Center for Drugs, and she is going to present a proposal for modernizing and transforming post-market safety.
Ms. Henderson: Good morning. As Theresa said, I'm going to describe the enhancements that FDA is proposing under PDUFA IV related to enhancing our post-market safety program for drugs and biologics. want to start by taking a look at sort of the typical measure of workload that we look at in the post-market safety arena.
Adverse events. Specifically this chart shows you the growing volume of the serious and unexpected adverse events. As you can see, the number has grown rather dramatically over the past fifteen years, surpassing 200,000 reports a year now. Recall if you will that this really just the serious and unexpected adverse events, which is now representing nearly half of the total number we receive. In 2005, looking at that last column, the number you're looking at is part of only 465,000 reports that we received in total. Interestingly, the proportion of the reports that we're getting that are serious and unexpected is increasing slightly as well.
In PDUFA III, as most you know, for the very first time FDA was authorized to spend our user fee revenues to fund improvements in drug safety. Use of these revenues, however, was limited to a period of up to two years post-approval for most products, and up to three years for products that required risk management beyond standard labeling.
And as you can see from this slide an FDA analysis of FDA-related labeling changes that were made between October 2002 and August of 2005 demonstrated that the number of these labeling changes remains high for eight years after approval before starting to decline. And so the various colors that you see represent the different kinds of labeling changes. Talk about tiny print, this is very tiny, so you will have to look at your handouts. The labeling changes that are made post-approval go anywhere from very serious labeling changes, such as putting a black box warning, our strongest warning that can be put on the label, to just adding an adverse reaction into the label. As you can see, although we were only funded for up to a maximum up to three years to do this sort of work using fee-related revenues. The amount of work that we had to do to change the labeling, the continuing review of human drugs goes on for quite some time afterwards.
So as we headed into our discussions about possible design of a PDUFA IV program, we wanted to address the following challenges, some of which you heard about from the previous speakers.
That we had inadequate resources, actually, to address the dramatic increase in the number of serious adverse event reports that you saw on the chart, let alone the substantial portion of the critical post-market risk management that has to occur far beyond that two- to three-year window that we were limited to.
In addition, the agency was suffering an inability to keep pace with the very rapidly evolving science of safety, technology, and the increasing emerging use of linked databases that we're seeing in this field now.
We were seeing an inadequate IT infrastructure, including our Adverse Event Reporting System, or AERS, linked data handling and tracking systems, all quite inadequate to do the kind of work that we are now being asked to do.
Our final challenge is that there really was a need for a more predictable, timely, and scientific process for the review of proprietary names. And we're going to talk about each one of these areas in more detail.
So not surprisingly, to address those challenges are broad proposed solution is to implement a transformational strategy that would enhance and modernize our drug safety program in total. To adopt new scientific approaches and maximize the utility of our existing tools for the detection, evaluation, prevention and mitigation of adverse events, we are proposing to produce guidance in several critical areas, which I will describe as we go along.
To increase our pre- and post-market staff interactions, improving the communication and coordination across the spectrum of drug safety activities that we do, starting, as John described, in the earliest days of the pre-IND discussions and all the way through the life cycle of a drug.
And finally, to enhance our informatics infrastructure.
The overall strategy of our proposed program is to enhance the FDA resources, both our human resources, so our proposal involves a significant increase in the number of staff in the post-market safety area and other technical sorts of resources -- IT, data access, and so forth, to ensure timely, predictable, consistent, and, most importantly, scientifically sound regulatory decision making related to drug safety, again, throughout the product life cycle.
I'm now going to describe each element of the proposed program in a little bit more detail.
So starting with the first, we want to provide adequate resources to address the increased workload throughout the product life cycle, and we wish to do that by eliminating the three-year post-approval restriction on the use of fees. As part of the reauthorization, FDA is proposing to change the statute to eliminate the time restriction so that PDUFA can be used to assess safety issues post-approval regardless of the product's approval date. In other words, allowing the agency to review a drug's safety in whatever timeframe the risks are identified using all of the available resources that we have.
So to clarify, we've had many questions about this as we've been describing the program, this does not represent new activities for the agency, or things that we have been unable to do to address the safety issues that arise during the life cycle of a drug. It is to enhance our ability, or actually to add our ability to use PDUFA fees to support those kind of activities.
So PDUFA funds will be used to support a number of activities that will modernize the process of pharmacovigilance, and they're shown on this slide.
One key initiative would be the awarding of an FDA contract or perhaps a series of contracts yet to be decided to one or more outside research organizations to determine the best way to maximize the collection and reporting of serious and non-serious adverse events throughout the product life cycle.
Some of the central questions that we're hoping that this contract might address is to look at the number and types of safety concerns that are identified through various mechanisms of surveillance, the age of the products at the time those concerns were identified, the actions that were taken in response to finding those adverse events, and what was the public health impact, or the impact on patient safety of finding those events and the actions that were taken. Sort of in summary, I see this contract as looking at where FDA can get the most bang for its buck in terms of surveillance methods.
As you all know, epidemiology studies using large, automated databases are becoming a much more common way to evaluate drug safety. These studies are very complex, and they use a variety of non-standardized analytic methods and non-standardized assumptions. I view them as being reminiscent of sort of the state of science of clinical trial design a couple of decades ago. Part of our PDUFA IV proposals is with input from academia, industry and the general public. Many of the experts that we know are out there besides the FDA. We would like to write a guidance on how to carry out scientifically sound observational studies using quality data resources.
Another key component of our transformational strategy is to maximize the usefulness of the tools we have for adverse event detection and assessment. To do this well, FDA need access to data other than spontaneous reports, including population databases, epidemiologic data, and other types of observational data. As mentioned previously, these are data that we need in order to the best scientifically sound assessment of post-market problems. And so under this PDUFA IV proposal FDA will have expanded access to important population databases to do additional epidemiologic research and targeted safety surveillance.
This proposal will give us money not only for access to much of that additional data, but also to be able to hire additional staff, epidemiologists, safety evaluators and data entry folks, people who can manipulate the databases, programmers, to be able to use this data in the very best way.
As mentioned previously, PDUFA III provided funds to FDA to review the design and implementation of risk management plans. Risk management and risk communication tools and programs are much more commonly used than they once were, and yet many of these tools and programs are unproven and unstandardized. And so under the PDUFA IV proposal we would like to conduct a program that would maximize these tools and programs by conducting assessments of their effectiveness of certain specified risk minimization action plans and other risk management and risk communication tools.
We'd like to hold these discussions in public, get a lot of public input on how effective these plans have been, again getting the most bang for your buck as we implement these sorts of programs that are actually hard on the health care system, and we know they are, but which need to be used, and need to be used where they are the most efficient and effective.
In addition, FDA would like to enhance our standard-based information system to support post-market drug safety activities. We would like to enhance our adverse event reporting systems and surveillance tools. We intend to enhance our IT infrastructure to support the access that is be described to these large databases in order to be able to analyze them effectively, and we'd would like to enhance our workflow tracking systems.
Enhancing this IT infrastructure is critical to ensuring the best collection, the best evaluation and the best management of the vast amounts of data related to safety that FDA needs to handle.
Lastly, we would like to improve the communication and coordination between the pre-market and post-market review components. This would be CDER's Office of Surveillance and Epidemiology, and the Office New Drugs, and to enhance collaboration between the Center for Biologics Office of Biostatistics and Epidemiology and their pre-market review offices.
We believe that interaction and close collaboration between the pre- and post-market review staff is critical to ensuring the appropriate balance of risk and benefit continuing throughout a product's lifecycle. This would allow us to implement the additional staff that will be acquired under PDUFA IV. In order to enhance this collaboration, we believe will help us to address some of the suggestions made in the recent IOM report about the need for closer communication and collaboration between the pre- and post-market review staff.
A final element of PDUFA IV post-market safety program is related to preventing medication errors by modernizing our proprietary name review program. This would be intended to reduce medication errors related to look-alike and sound-alike names, as well as allow us more staff to be able to fully evaluate factors such as unclear label abbreviations, acronyms, dose designations and error-prone packaging designs.
Under this program, fees would be used to develop three guidances. The first would be a guidance on the content of a complete submission by the sponsor for a proprietary name evaluation; a guidance designed to look at good naming, labeling and packaging practices; and a guidance to look at ways that one would best evaluate the best practices for evaluating proprietary names once they've been chosen.
This program would have phased in performance goals, including a complete review of a proprietary name as early as the end of phase 2, should the sponsor choose to submit it within 180, and the goal at the time of NDA submission of the proprietary name of ninety days. In addition, this program would institute a pilot program using an new review paradigm that would shift responsibility for evaluating the proprietary name, which is currently done under sort of a different model than all of our other review activities. It is actually done hands on at the FDA. Under this PDUFA IV proposal, we would like to institute a pilot program to allow the industry to review their own proprietary names under the good guidances that we would put out there, and submit their data to review by the FDA.
These guidances, in consultation with many of the stakeholders involved, again, in this as in all of our other areas, would be designed to provide a scientifically sound, consistent and timely approach to the selection, evaluation and review of proprietary names.
Lastly, one final element that's not listed on the slides, but I was spurred to mention it listening to Malcolm talk, is under our PDUFA IV proposals the drug safety team is also proposing to put forth a five-year plan on which we would publish and seek public comment describing the steps that we hope to take to enhance and modernize the post-market drug safety system, and, again, to look at that plan every year to see how we're doing and to modify the plan as necessary.
Dr. Mullin: Thank you Debbie. Jane Axelrad is now going to present FDA's proposed recommendations for the advisory review of direct-to-consumer television advertising.
Dr. Alexrod: As the last of a long line of speakers, I'm going to try to be relatively brief so we can stop talking to you and get to the real purpose of the meeting, which will be to hear from you about your questions and concerns about the proposals we're describing today.
Second only to drug safety, the subject most frequently mentioned by stakeholders is one that should be addressed by additional FDA resources is direct-to-consumer advertising. Many stakeholders have expressed concerns about DTC advertisements that overstate the benefits and do not adequately convey the risks of the products they promote. And the most widely view consumer direct-to-consumer advertisements are clearly television ads. TV ads, because they're so time limited, also present the greatest challenges in terms of adequately conveying both the risks and benefits of a product.
One thing that people may not know is that generally companies are not required to submit ads to FDA for review before they are used, but many submit them voluntarily to get FDA comments.
In fact, the guidelines that were published by PhRMA that took effect in January of 2006 said companies should submit all new TV ads to FDA before they are used. But because of limited resources, FDA has not been able to give timely comments on the advertisements and some companies have either chosen not to submit them for FDA review or have submitted them then withdrawn them before they got our comments because they wanted to proceed with the planned advertising campaign.
We think that timely FDA advisory review of draft direct-to-consumer television advertisements will increase the incentives for voluntary submissions, resulting in greater confidence in the DTC advertisements that are broadcast. As a result, we're seeking funding for additional resources through user fees.
You'll notice that we're calling this program a separate user fee program instead of part of PDUFA IV. The reason for this is fewer than 30 firms actually do direct-to-consumer television advertisements while over 400 companies are assessed application, product and establishment fees. So rather than just tacking additional money onto the existing PDUFA revenue targets, we're recommending a system that assesses fees only on those who are going to participate and directly benefit from the program. The total amount of revenue we want to collect will be $6.25 million in the first year of the program, and a similar amount in subsequent years, adjusted annually for inflation and workload. These fees will be collected from individual advisory review submissions which are going to be prepaid at the beginning of each fiscal year.
In addition, because the number of advisory review submissions is likely to fluctuate from year to year, and we want to make sure that we have a stable funding design for the program, we are going to assess in the first year of the program a one-time participation fee that will be based on the number of anticipated submissions in that year, and will be designed to collect an additional $6.25 million that's going to be placed into a reserve fund from which we can draw if target revenues fluctuate in subsequent years.
The fees are going to be used to fund 27 FTE - full-time equivalents, which is one person working for a year, essentially -- for pre-market advisory review of direct-to-consumer television advertisements. The fee revenues be used to recruit additional staff for our Division of Drug Marketing Advertising and Communications, and our other branch that does it in the Center for Biologics, including direct review staff and experts in science of communication.
And the resources will also be used to fund capacity in the Office of New Drugs so that we'll be able to get timely advice from the medical experts familiar with the products being advertised when we need to consult them about the risks and benefits of the products and the appropriateness of the claims being made.
These additional resources will allow us to provide more timely review of television ads in accordance with performance goals that are modeled after the PDUFA performance goals.
These goals, like the PDUFA goals, will be phased in over five years of the program. By year five, FDA will commit to review a specified number of ads submitted for advisory review within 45 days, and a specified number of resubmissions of previously reviewed ads in thirty days.
Let me explain in a little more detail the mechanics of the program, because in this case it's fairly complicated, and I think much more complicated in terms of a fee structure and what we're doing here.
First I'm going to address the fee that will be assessed for each advisory review submission. One hundred and twenty days before the start of fiscal year '08, or the start of the program if it get's delayed because the statute isn't passed on time, FDA will issue a Federal Register notice asking sponsors to identify the number of TV ads that they intend to submit for advisory review during fiscal year '08. They will be told in the notice that identification of the submissions will be considered a commitment to pay the fees for however many submissions they identify.
Sixty days before the start of the fiscal year of the program, we're going to issue a second Federal Register notice establishing the fees for the fiscal year based on the number of submissions that sponsors identify in response to the first notice. The per-submission fee will be established by taking the target revenues of $6.25 million and dividing by the number of submissions identified.
So for example, a sponsor said that they were going to submit a total of 150 submissions for advisory review, the per-submission fee would be $42,000. Because we can't predict how many sponsors will participate in the program, or how many submissions will be identified, we're recommending a cap on the per-submission fee of $83,000.
This is one of several protections that are built into this to protect against uncertainties in the amount of participation in the program. This fee cap protects sponsors from unexpected low participation in the program. Other protections, including the reserve fund, are built in to protect FDA from underfunding.
Once the second Federal Register notice is issued establishing the per-submission fee FDA will invoice companies fees for the number of submissions that they identified. So if a company identified that they plan to submit five advertisements for advisory review in the fiscal year, and the per-submission fee is $42,000, we'll send them an invoice for $210,000. The fees will be due and payable on or before October 1 of the fiscal year.
We're also recommending that the statute provide for late fees for late payment of invoices and for advisory reviews that are not identified at the beginning of the fiscal year. It's really important so that we can go out and hire the necessary staff, that we know how much money we're going to get, and how many reviews we're going to need to do. So there's a bunch of protections built in here so we bill in advance and we get the money in advance. And the program will then work the same way in each subsequent fiscal year. We'll send out a notice asking how many ads are going to be submitted, and then a second notice setting the fees based on what we hear.
Now, the second part, as I said, is the participation fee that will be put into the reserve fund. This participation fee is a one-time only assessment that will be made either before the start of the program in fiscal year '08 for companies that participate in that year, or it will be assessed if a company comes later and decides to seek advisory reviews in a subsequent year, because some firms might not have a drug on the market, or they might new drug that they are not actually doing broadcast advertisements until later in the program.
The participation fee is also designed to collect $6.25 million, which will be enough to fund one year of the program if no advertisements were submitted for advisory review so we didn't collect any fees at all, something that we certainly don't expect is actually going to occur.
In order to collect the fee we're going to assess each participating sponsor in an amount equal to that sponsor's advisory review fees in the first year of the program. So going back to my previous example, if a sponsor identifies that they're going to submit five advertisements for advisory review, they'll be assessed $210,000 for the participation fee in addition to the $210,000 in the annual fees that we would be collecting for the actual submissions. So there total bill would be $420,000.
And as you can see, the payment into the reserve fund will be graduated in that way based on the number of advisory review submissions that are identified.
Late participants in the program who join in subsequent years will assessed as much as those who join in fiscal year '08. In addition, the participation fee will capture all ads submitted for advisory review during the first year of participation even if they are identified later in the year. And the participation fee will be fifty percent more if late fees are applied to the advisory reviews, since basically we're taking what somebody had submitted during the first year of the program and doubling it and putting some of that in the reserve.
I'm looking out and seeing all these faces that look totally confused, so I'm sure I'm going to get a lot of questions on this, but that's okay, because it was very interesting trying to develop this system, and it is complicated. But we do think that it will work, and there's a lot of protections to make sure that if something goes wrong, nobody will really be hurt terribly by it.
Anyway, in fiscal year 2012, or if the program ends early, any remaining money that's left in the reserve fund, less expenses needed to close down the program will be refunded to those who have participated.
We do think though that we have created a fair, stable and workable program that will provide an important influx of resources to our review of direct-to-consumer television advertisements, and we'll be able to review these ads in a timely way that will ultimately lead to better quality ads and greater confidence in the ads that everybody sees when they turn on the news every night.
Dr. Mullin: Okay, before we break for lunch let's take any kind of clarifying questions that you may have relating to the direct-to-consumer TV ad proposal or the post-market safety proposal, and if you could just stick with questions that are to clarify either of those proposals, if you have any, come up to one of the microphones and please go ahead and ask.
Ms. Buchholz: My name is Mary Beth Buchholz with BatesNeimand and we represent several patient organizations patient coalitions. My questions are for Jane about DTC, I have have three separate questions.
First of all, are you, through the new user fee, making review mandatory, taking away the voluntary aspect of the program right now?
Second, does this program grandfather the existing DTC already being broadcast, and applied only to newly approved drugs, or is it for all TV DTC going forward?
And third, which may be a question that you can't answer, has the FDA taken a position on banning TV ads, as suggested in the IOM, for newly approved drugs for a certain period of time in order to assess the life cycle?
Dr. Axelrad: I'm going to take your first and third questions together because the answer for both of those is the same. We did not -- we are not addressing or requiring that ads be submitted for review. It is still voluntary whether a company chooses to submit the ads for review, and we did not address the issue of banning direct-to-consumer advertising, or a moratorium. Those are policy issues that can be discussed and debated in another forum.
In connection with the user fee program, basically what we were looking at were proposals that affected the resources that we have to do the work. We were not taking on any broader sort of policy considerations or policy issues, or attempting to change the legal landscape of what we do. So I think that addresses your two questions.
I would say that although we are not requiring people to submit ads for review, if they choose to submit an ad for review, the fee itself is mandatory, so everybody who submits an ad for comment will be assessed a fee. But they still will not be required to submit them.
With regard to grandfathering ads, I think because of what I was just saying and how it works the sponsors will only be assessed fees if they submit at new advertisement, or I suppose if they want to submit an ad that they'd already broadcast to us, we would, you know, assess it a fee. But mostly we expect to see newly created advertisements that have not yet been broadcast coming into the program.
Audience Member: I have some further questions about the DTC ad program. If a company misses on their beginning-of-the-year estimates of the number of ads, and say, they say they're going to do five and they end up wanting to do ten, do you assess fees then or do they just have to go at the end of the queue and have it --
Dr. Axelrad: No, we assess the fees -- we will assess the fees then and there will be a fifty-percent penalty associated with that. So we have a penalty in there as an incentive to get people to accurately estimate what they're going to be submitting.
Audience Member: And the other way if they expect they're going to have a drug approved, say, and it doesn't get approved for them that year so they don't launch their big ad campaign, is there -- and they paid the fees for, say, ten ads, they don't get anything back?
Dr. Alexrad: No, because we're going to -- based on the number of submissions that they estimate they're going to submit, we're going to go out and hire staff to make sure we have the resources to review them, so we don't have the capacity to give the money back or carry it over. They can carry one credit -- sort of credit. We don't like to call it a credit, but they can carry one to the next year if they need to.
Ms. Gustafson: Mary Gustafson, Plasma Protein Therapeutics Association. I have a question on the guidance documents. I assume these will be guidance documents under GGP and Type 1 for comment. I noticed the performance goals seem to address draft guidance documents and one of issues is that draft guidance documents sometimes, even though industry and others comment, they never seem to be final. So are there plans to have final -- performance goals for actually finalizing these guidance documents?
Dr. Jenkins: Well for the pre-market guidances that I referred to, the proposal we put forward said FDA will complete its work on the final version of the guidance within a year of the close of the comment period, so yes we are trying to put metrics around finalizing the guidances.
Ms. Gustafson: Thank you.
Ms. Henderson: Hi Mary.
Ms. Gustafson: Hi.
Ms. Henderson: Similarly for the post-market guidances, yes, of course we will do the GGPs, and similarly in our commitments, we have committed to finalize all of the ones we are committing to a year following the time of the draft. And of course, we only have control over the FDA.
Ms. Gustafson: Thank you. That's good news.
Dr. Mullin: I might add to that that there's a new OMB requirement for OMB review of guidance documents. You're probably aware of that.
Ms. Stiver: Hi. My name's Lili Stiver. I'm with the Drug Safety Institute. My question is quickly to Debbie, and I'm sorry -- I apologize if I missed this in your presentation, but I think, actually, you might have skipped over it. Can I get some more clarification, when you were talking about modernizing the proprietary name review program, there are two points on your slide that discuss public process to explore proprietary name reserves and public release of the POCA tool?
Ms. Henderson: I'm happy to address this. I'll address the last one first because it's very easy. The next to the last one is a little like Jane's trying to describe the DTC program, and so I was hoping I wouldn't have to explain what that means.
The POCA tool is a tool that we use in house. It's a computerized tool through which we run names as just a very preliminary screening tool to see what other names that are out there that might be, you know, sound-alike, lookalike, and that has been a tool that has only been used within the the FDA, and we have -- it's been a rather tangled legal effort to find a way. We've been wanting to make that tool public and available to anyone who wants to use the tool. Primarily, of course, the industry is interested in using the same tool that we use to do that preliminary screening, and we've found a way to do that, and we'll be making that tool available public.
The next to the last one is a little more complicated. When a name comes -- when a proprietary name comes in to be reviewed, we look at it, of course, against all of the existing names to see whether it is confusing based on names that have already been approved. The earlier we do that, so when we are now committing to looking at names, say, in the earlier phases of drug development, the drug will not be approved yet when we say your name is okay. And so then when the next name comes in can we use that name that really isn't -- you get what I'm saying -- it isn't really the name of an approved product yet. It is a product that still is in the development pipeline upon which to compare the newer name that's now come in, and so that is a legal issue and we're going to have a public discussion of the possibility of putting a reserve on a name for a manufacturer who has had their name reviewed and, not really approved, but okayed by the FDA, is it possible then to have that name reserved even though the product has not yet been approved. Can the name be reserved. And so we're going to institute a public process to have a discussion about the possibility of doing that.
Ms. Stiver: And then that name that's on reserve, would it still be proprietary information, or would it --
Ms. Henderson: Those are all good questions. Those are exactly the issues that we need to address.
Ms. Stiver: Okay. Thank you so much.
Ms. Henderson: You're welcome.
Dr. Mullin: Are there any other questions?
Mr. Cavenaugh: Yeah, Dave Cavenaugh, Committee of 10,000. For Jane Alexrad, you mentioned in the course of your discussion of the new program, which I assume will be part of the PDUFA reauthorization language, this DTC program, that it would allow for 27 additional FTE reviewers.
I was just curious what the nominator is, over how many that are there now, and are the ones that are there now at all supported by PDUFA III?
Dr. Axelrad: Right now, we have 41 FTE in the Division of Drug Marketing, Advertising and Communication in CDER, and five FTE in the branch that does direct-to-consumer -- that does advertising in the Center for Biologics, so that's the denominator.
Dr. Mullin: Yes?
Mr. Hannett: I'm sorry, Fred Hannett with the Capitol Alliance. I've got a question regarding adverse events, so I guess it goes to Debbie, and I apologize for not having a citation, but I believe last week, AHRQ issued a proposed, or notice of a proposal where they were going to be establishing an adverse events reporting and tracking system too.
The question is, what is the relationship of what AHRQ is doing versus the PDUFA IV initiatives. Can anyone speak to that, or is the AHRQ proposal just that: a proposal.
Ms. Henderson: I would have to admit to not knowing very much about it other than I've heard it mentioned. If anyone else knows about it -- Ralph do you know anything about it?
Mr. Lillie: It's a good question. There are actually a number of initiatives floating out there, some generated and supported by FDA, some in collaboration with FDA. There's an MIT initiative that's also out there.
I think a lot of these things we're going to have to see how they play out, to tell you the truth. I'm not sure of the exact interrelationship. I don't see it as competitive. I don't see us as losing adverse events. I don't see us as losing information, but exactly how we collaborate with that effort and how that will work out, I really can't -- it remains to be seen.
Mr. Hannett: I appreciate that. I believe the obvious concern in industry would be in terms of duplication, both going to a separate federal government agency and what the interrelationships would be --
Mr. Lillie: Right.
Mr. Hannett: -- or if there was a way of bringing the two together.
Mr. Lillie: And that's exactly our concern, too.
Mr. Hannett: Thank you.
Dr. Mullins: Are there any other questions before we take the break for lunch?
Dr. Axelrad: Theresa, I'd just like to go back to the question before about the denominator, because it's kind of confusing. You can't really compare the 27 FTE we're asking for to the number that are just in the Division of Drug Advertising, the two divisions that do it in CDER and CBER because, as I indicated, it's going to include other resources in the Office of New Drugs and other supportive resources for those that will go in other places.
So I think one way to look at it is that the current level of effort that is being applied to direct-to-consumer broadcast advertisements is about eight FTEs, so basically that sort of includes pieces of people in various locations, and so that's a more direct comparison to the 27 that we're going to be getting under the program.
Dr. Mullin: Okay. Thanks Jane. Anything else before we take a break for lunch. Okay. We're going to reconvene at 12:30 and we have a lot of people who've signed up to speak, so if you want to be back, we'll start promptly at 12:30, and take it from there.
[Break.]
Dr. Mullin: Okay, it’s 12:30, I would like to have everyone take a seat and so we can get going on our afternoon session. We have a number of speakers and we want to make sure everyone has a time to provide their comments and so if you could take a seat that would be really great.
Let me just explain the way that will work. We have quite a few organizations and as I said we’re going to run this session until 4 o’clock and we should have enough time for everyone who has registered to speak, possibly some time if others want to speak as well if we keep to that and basically the way we’re going to do this is we think we’ve budgeted up to ten minutes per presentation and we should be able to do that.
If you have power point slides, hopefully you’ve already given them to the audio visual folks so they can load them, or that they are loaded and good to go when you’re up here.
We’re going to begin with patient perspectives and I’m going to try to keep track of the time. Before our moderator left because he was in a lot of pain, he left me his digital watch so that we can basically keep track and I’ll let you know when you are at eight minutes so that you can begin to close your remarks and then we’ll have to stop it at ten, if we get that far.
Okay, I have a few changes. I’ve got to find my most recent speaker sheet. First we’re going to hear patient advocacy perspectives and the first speaker that we have listed here is Amy Comstock. Amy is a CEO of the Parkinson’s Action Network and Amy could you please come up and make your presentation?
Ms. Comstock: Thank you Theresa and I want to thank you and the FDA for making this opportunity for public comment on PDUFA IV possible. Again, my name is Amy Comstock; I’m the Chief Executive Officer of the Parkinson’s Action Network. I assure you my comments; I will stop before you have to give me the eight-minute warning.
All of our comments really stem from two central thoughts from the patient perspective. First is that time is in no way neutral to a community that struggles with a progressive debilitating disease. Parkinson’s is a chronic progressive disease that in the first few years can be handled very well with medication and by the end in the advanced stages, medications are very difficult. They do not handle the disease well and it is extremely debilitating to the point where one cannot work and often one cannot move.
Second, the Parkinson’s community is very fearful right now that safety concerns and the reauthorization of PDUFA, safety concerns will trump speed in the drug approval process and that ultimately that will slow drugs down in getting to market.
It is virtually unanimous in our community that people with advancing Parkinson’s disease would want to have the opportunity to choose to take a risk with a drug that theoretically might help them in the short term even if there is a chance of liver damage ten years out. With these overall themes in mind we do have the following specific comments on the FDA federal register notice on PDUFA IV. We know that the FDA intends to issue guidance that will “enhance clinical drug development.” While we actually do not have comments on the specific topics chosen or the schedule of guidance development, we do note a complete lack of reference to patient involvement in the development of the guidance.
As many of you may already know the participation rate for participation in clinical trials in the Parkinson’s community is already very low. It is much lower than for many other diseases and actually that low participation rate slows down our progress in clinical trials.
I’m not unrealistic. There’s many explanations for this low participation rate but a lack of trust and design flaws that make the trial participation uncomfortable for the participant can sometimes be the cause. We suggest that it would be quite simple actually, but hugely valuable to include the patient voice, ideally someone who has participated in the clinical trial in the preparation in each of these guidance documents about a trial design.
Second, we can’t help but note that what is missing from FDA’s proposal for PDUFA IV is any discussion particularly again in the area of clinical trial design of transparency of data. When you are dealing with people, patients who take a risk by choice or necessity for the chance of a better future, we should be willing to share as much information as possible about the trial or the process in which they’re about to engage.
We believe that this is important for all aspects of drug development but particularly when safety concerns do arise in clinical trials. At a minimum when there is data in a trial that causes concern that data should be freely shared with the trial participants if not more broadly.
I must tell you that this is really a particularly sensitive issue in the Parkinson’s community. We recently had a Phase II clinical trial that many had looked to as having real promise and that trial was halted as I said during the Phase II for safety concerns. Many in our community disagree with the halting decision and those who do disagree also feel that they don’t have sufficient data, even summaries of the data that justified the halting decision and it has caused a great deal of suspicion and concern in our community so again if we could think about really looking at ways to get around the proprietary information issues, if we are going to ask human beings to put themselves at risk for the greater good.
Third, regarding post market drug safety system, we don’t have specific comments on this proposal except to say that in my first overall theme when I mentioned that there’s concern that safety concerns right now will slow down the speed at which drugs are approved to get to market. If post market drug surveillance is the way to balance that safety efficacy and speed issue then we are all in favor of that.
Fourth, we do support the effort to issue guidance with the goal of reducing medication errors related to look alike and sound alike proprietary names. We support this effort both because, like anyone, we would like to see actual medication errors reduced but also again because we support anything that will bring the patient and caregiver into the process by making information more available and understandable.
Finally we do note that the PDUFA IV document does not include any discussion of fast track accelerator approval and expedited review. As you might expect from my earlier comments we applaud these programs and we hope to see Parkinson therapies continue to make use of them. We therefore strongly suggest that PDUFA IV, in the end, not do anything to weaken these necessary programs. Thank you.
Dr. Mullin: Thank you. Our next speaker is David Fassler. David Fassler is with the Mental Health America.
Mr. Fassler: Thank you. My name is David Fassler. I’m a child and adolescent psychiatrist practicing in Burlington, Vermont. I’m also a clinical professor of psychiatry at the University of Vermont, College of Medicine, and I’m here today as a board member of Mental Health America, a national consumer advocacy organization. Mental Health America which was formally known as the National Mental Health Association is the country’s leading non-profit dedicated to helping all people live mentally, healthier lives. With more than 320 affiliates nationwide, we represent a growing movement of Americans who promote mental wellness for the health and well being of the nation. Nearly a century old, this organization is committed to supporting the development of a health care system that’s based on and responsive to, the latest research, clinician expertise and consumer values.
As an organization we support many of the FDA actions and initiatives which help align the agency with the key recommendations contained in the recent report of the Institute of Medicine. These include strengthening the science supporting and underlying the FDA’s medical product safety system at every stage of the product life cycle, improving communication and information flow among all stakeholders engaged in promoting the safe and appropriate use of medical products and enhancing internal operations and management to ensure implementation of a review analysis consultation and communication system and process needed to strengthen the U.S. drug safety system.
However I’m here today on behalf of Mental Health America to offer a number of specific recommendations for the FDA with respect to the reauthorization of PDUFA, which are aimed at protecting people and families with mental health needs. We hope that our recommendations will help informed decisions to promote transparency and enhance drug safety.
First, we believe that the FDA must retain ultimate authority and control over the allocation of resources within the agency. Such flexibility allows and promotes timely response to the latest research, adverse event reports and public health trends. We also believe the FDA should have the ability to require companies to conduct research on specific aspects of safety or efficacy, even after a medication or device has received initial approval. Scientific knowledge is constantly evolving and the activities and priorities of the FDA should be directed and modified by the most current information, clinical data and research available.
Second, I think I’ll echo one of the recommendations that you just heard from Amy Comstock. We really think that consumers must be at the table in a meaningful way in every stage of the review process. Their experience, perspective and knowledge is valuable and vital from pre-market testing and development through post-market surveillance.
The FDA’s Office of Special Health Issues does an excellent job of serving as a channel through which patient issues and viewpoints can be brought to the attention of FDA medical and regulatory staff. It’s been an extremely valuable experience for consumers with cancer and HIV whose treatment needs are unique, to have this kind of voice in the FDA’s decision making process. We’d suggest that the FDA expand the Office of Special Health Issues to include consumers in the drug review process for other serious and life threatening diseases and we’d recommend that resources be specifically allocated to support these efforts.
Third, we welcome the commitment contained in the proposed reauthorization to expand the review of direct-to-consumer advertisements for pharmaceutical products. While such ads can help inform the public about specific disorders and the availability of treatment, recent research indicates that they often tend to overemphasize benefits while minimizing potential risks and side effects. This is an area which clearly needs more attention and oversight from the FDA.
And finally, we believe the FDA has an obligation to monitor the impact of their actions on public health and access to care and to revisit specific decisions when and if warranted by subsequent data and research findings. We believe that if implemented these recommendations would represent a significant step toward improving health outcomes, especially for the thousands of individuals living with mental illness in our country. I thank you for this opportunity to present the views on behalf of Mental Health America. Thank you.
Dr. Mullin: Thank you, David. Thank you, Jeff Allen with Friends of Cancer Research -- sorry, the founder of Friends of Cancer Research.
Mr. Allen: Thank you. Let me make one clarification. I’m actually the Director of Science Policy for Friends of Cancer Research. I wouldn’t want it to get back to our actual founder, Ellen Sigal that we staged a coup in her absence. On behalf of Friends for Cancer Research I want to thank you all for the opportunity to comment on the proposed recommendations for the reauthorization of the Prescription Drug User Fee Act.
Friends of Cancer Research is a non-profit organization that over the past ten years has pioneered innovative public, private partnerships, organized critical policy forums, educated the public and brought together key communities to develop collaborative strategies in the field of cancer research.
An essential component of accelerating progress for the treatment of all medical conditions is the rigorous and efficient drug review process at the United States Food and Drug Administration. It’s of the utmost importance that we work to improve the process to ensure patient safety, provide access to new therapies and foster the development of innovative new treatments. We support the timely reauthorization of PDUFA and strongly urge Congress to demonstrate their commitment to the future of the health of America through increased federal appropriations for FDA.
PDUFA is a successful program that benefits all stakeholders. It enables FDA to receive vital funds to support their drug review activities. Product sponsors have their drug reviewed more expediently and most importantly, patients receive life saving treatments in a timely manner. The efficiency and expediency that PDUFA introduced to the drug review and approval system has been particularly important for patients with cancer and other life threatening illnesses where the ability to receive new drugs as quickly as possible is literally a matter of life and death.
In discussions about drug safety and the benefit of rest tradeoff it’s useful to remind ourselves that patient’s willingness to accept risk is not static across populations served by the drug review and approval process and this must be reflected in the system.
Cancer is a disease that exists along a continuum from light stage terminal illness to early detection to prevention. Patients suffering from life threatening or seriously debilitating illness are willing to accept greater risk in the treatments available to them than patients who are suffering from less serious conditions. All patients deserve accurate information so that they can work together with their doctors to decide upon the best course of treatment to meet their individual needs.
It’s important to note that PDUFA’s success in eliminating the drug lags in providing new medicine to patients in a more timely manner has been accomplished without compromising safety. In fact since the first authorization of PDUFA only three and a half percent of the approved drugs have been subjected to a safety based withdrawal. This is similar to the ratio of pre-PDUFA safety based withdrawals of 3.1 percent. Obviously no drug is one hundred percent safe, one hundred percent effective in one hundred percent of patients and it’s impossible to know everything about a drug before it is widely used in a large-scale patient population. To approve drugs without sufficient data on safety and efficacy would be irresponsible. Similarly to withhold a drug in order to obtain an unreasonable amount of data could cause countless numbers of patients to suffer due to the lack of access to new treatment.
The FDA is charged with determining the delicate balance between benefits and risks of new drugs from population standpoint before approving them for use. This tremendous responsibility should be accompanied by the resources necessary to do the job. Increasing the regulatory authority of FDA through new legislation should be done with careful consideration and increase to the agency’s authority could result in unintentional consequences such as restricting or slowing access to life saving treatments by patients in need, further increasing the already expanding cost of health care or discouraging future innovation of product development.
Regulatory authority is only effective as the underlying evidence that it generates. An automated and routine approach to dru