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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 drug monitoring is needed to improve the agency’s ability to identify risks of market and new drug products earlier and to evaluate these in the context in the health benefits provided by the product. Addressing the underlying needs of increased personnel, enhance scientific training, advance information technology, identifying new data sources and further integrating emerging science of the overall regulatory process will lead to the systematic approach of safety surveillance. Increased regulator authority will not substitute for a system of routine and automated surveillance in continued chronic under funding will certainly not lead to one.
The recent PDUFA agreement between FDA and industry representatives is a good starting point. As a part of this reauthorization significant new funds from user fees will be applied to post-marketing safety enhancements. We are extremely supportive of these programs and others the FDA has recently announced. Programs designed to enhance communication, identify adverse effects earlier, expand data base interaction, review proprietary names to reduce medication errors will no doubt benefit the public.
Industry user fees alone, however, are not sufficient to fund the growing workload of FDA and position it for success in the 21st century. It is essential that Congress increase appropriations for FDA to address the agency’s underlying needs that I previously mentioned in the form of resources, training, IT, new data sources and advanced science.
The rate of user fee increase has far surpassed the rate of Congressional appropriations for human drug review. This fact raises questions about our elected officials’ commitment to the health of nearly every American.
Protecting Americans and promoting public health will only occur if there are stronger and science based FDA. The agency has committed itself through the development of the Critical Path Initiative to modify the drug development process. During a time of potentially revolutionizing scientific discovery it is crucial to utilize the expertise at the FDA and ensure that the agency play an integral role in emerging science. The central goal of the Critical Path Initiative is to provide tools to identify patients who will most likely respond to particular treatments thereby decreasing the risk to benefit ratio. If that can be accomplished, it will result in new ways to diagnose, treat, cure or prevent disease and allow life saving therapies to reach patients faster while reducing the overall costs to health care in this country.
The PDUFA IV recommendations provide additional support for the Critical Path Initiative but it too is a starting point. We commend the FDA and industry for jointly recognizing the importance of focusing on science. We also recognize the need for all stakeholders to work in partnership and enhance the capabilities of FDA.
Let me conclude by saying that Friends of Cancer Research supports the PDUFA IV agreement and encourages lawmakers to pass before the expiration of PDUFA III. We view the increased user fees in PDUFA as a starting point and urge members of Congress to do their part to ensure FDA has the sustainable resources needed to fulfill its mission. On behalf of the thousands of cancer researchers across the United States working everyday to help the nearly one and a half million Americans diagnosed with cancer every year, I thank you for this opportunity to comment.
Dr. Mullin: Thank you, Jeff. Perry Cohen is going to speak next. Perry is with the Parkinson’s Pipeline Network.
Mr. Cohen: Thank you everybody. My name’s Perry Cohen and I’m here mainly as a patient. I’m 60 years old and I was diagnosed with Parkinson’s disease for 11 years and in March of 2000, I became the patient representative for Parkinson’s. I agree with what’s been said earlier and but I did want to emphasize the role the patient in this process.
I also have a professional role here too. I was a health consultant before I was a patient and I apply my skills to the public health policy issues of management of health care for, I’d say I’ve spent 50 years training for my current job and I started off in this process not being cynical about the process.
I used to think that all we needed was more resources and more information to find a cure but I must say that as I’ve gotten into this, my cynicism has grown and so that I would like to see ways to get around that.
The main thing I want to talk about is innovation because a lot of other issues have been raised and probably be raised again by other patient groups cause I think the patients see this process. If you have a serious illness, time is not neutral and a lot of patients see it the same way. We see the risk/benefit trade-off being different for us then for the general public who may be looking at risks from a different baseline because the certainty of progression in your disease, becoming disabled or put in a nursing home, or dying from some diseases which don’t have treatments now, is the risk that your comparing to the benefits so I think we need to look at innovation as well as some of the flip side of safety and caution is risk and risk is what distinguishes a free society, capitalist society, capitalist economic system from and what makes it work.
When I look at the scientific model for hypothesis testing and the statistical criteria and assumptions that a double blind placebo control studies as the gold standard for new therapies, I think it might be rigorous and precise to a fault as too costly and too unwieldy. Science, as usual, takes fifteen or twenty years to get something from a discovery to a drug on the market or new therapy on the market and precision is different than heavier statistical significance is different than clinical significance. Assumptions about experimental control where all factors are static over one or two year study period needed to wash out placebo effects may not be the actual case. Linear statistical models may miss important implications of non-linear processes and animal models can never be fully predictive of human interactions with medicines and that’s why we do clinical trials, of course. But it’s particularly true when your talking about a brain disease where when you study it you change it, so we think that the key missing ingredient in the development of new therapies is the voice of the patient and that’s my key message. A patient centered system is the core of any change from this model and that would mean things like adaptive trial designs that using basis statistics, now I don’t profess to know a lot about that subject but I think when you’re, I’ve lost my place here.
Let me just go on to say that the funding for FDA should be going to developing these methodologies. I’m not saying that these alternative methodologies are necessarily the best but I think sometime ought to be spent and I commend the FDA on their application of new science and new measurement methods and putting that into the PDUFA act so that we could maybe try out some of these methods that would perhaps work better.
The only other thing that I wanted to mention was in the area of translational research. Transparency is an issue that’s been raised before and transparency and feedback into the process will improve that process and so that science flourishes in an information rich environment. The meetings that are held with the pharmaceutical companies are all held in secret and I think we need to shed some light on the process by making the information needed for public interest, giving the FDA more discretion about releasing that information if it is needed for public interest.
So in closing, I just want to thank you for the opportunity and ask that you consider that expanding the program that the FDA has set up for patient consultants beyond the pilot stage and patient consultants already on the books for cancer and for Parkinson’s and others want to get involved with it to provide a place that’s stable for the patients and look at the laws on conflict of interest and clearances necessary to participate in these meetings so that we can actually have a voice at the table. Thank you.
Dr. Mullin: Thank you, Perry, thank you very much. Steve Gibson is going to present his comments now. Steve is the Vice President of government relations and public affairs at the ALS Association.
Mr. Gibson: Thank you. I think we should have one amendment. I should be part of the patient advocates not the consumer groups, I’m not sure. Thank you for that. My name is Steve Gibson. I’m part of the ALS Association. The ALS Association is the only national not for profit health association dedicated solely to fight ALS, also known as Lou Gehrig’s disease. The ALS Association is one of the world’s largest private sources for funding for ALS specific research having nearly awarded $40 million this past decade.
ALS is a fatal, neurodegenerative disease and it’s always fatal in the average of two to five years after diagnosis therefore people with ALS don’t have time. There currently is only one drug on the market specifically approved to treat ALS, riluzole, which approved in late 1995 has demonstrated only moderate effects prolonging life for just a few months and only in some patients, therefore the Association welcomes any efforts by FDA to examine and speed the innovation process.
The comments we’re providing today are intended as a preliminary assessment for our thoughts on PDUFA. We look forward to working with you and members of Congress on this process as it goes forward. We also believe Congress has an important role in the process simply to act promptly in reauthorizing PDUFA but also to ensure that sufficient government funds are provided to help the agency keep pace.
In recent years there’s been obvious to most observers that FDA has been understaffed and under funded. We believe that the PDUFA plan puts forth last month will provide a much needed increase in staff and resources and help the agency to meet its demands and ensure that patients have timely access. In the event that current mix of industry fees and federal resources are not sufficient we urge Congress to provide additional support through the appropriation process.
We applaud the FDA for including new drug safety initiatives in its PDUFA proposal, including the addition of resource to ensure post-market safety and rapidly identify and even prevent adverse events. The agency’s recent announcement to improve the drug safety system beyond the scope of PDUFA indicates the FDA’s commitment to address the concerns about drug safety.
However while drug safety is an important concern, people with ALS view the issue from a different perspective than most Americans. That’s because people with ALS will die if they do not have access to the latest drugs and biologics that show promise in treating disease for which there is currently no effective treatment. To people with ALS the near ability to access a new drug is itself a matter of drug safety. People with ALS face a greater risk to their lives by not having access to new treatments, therefore we urge FDA and Congress proceed with caution in this area. FDA and Congress must recognize that the practice of medicine is not a one size fits all proposition and the assessment of benefit and risk must be taken into account in the needs of individual patients. To place excessive emphasis on risk without taking due account of drug benefit including the severity of the underlying disease would be a disservice to people with ALS.
As I mentioned before ALS currently only has one treatment option however they hold onto the hope that our nation’s scientists and researchers will develop new treatments for a disease that can slow its progression, improve quality of life and ultimately cure and even prevent the disease from arising. That’s why it’s so critical that PDUFA promote drug development and expedite drug reviews and approvals including for products not specific to ALS, after all people with ALS can benefit from advances in the treatment of other neurological conditions such as Parkinson’s, MS and Alzheimer’s.
We strongly support the timeliness and goals outlined in PDUFA concerning proper viewing and evaluation of investigational drugs. Delays in this area translate into denied access to potential life saving therapies for ALS patients. To withhold a drug in order to obtain an unreasonable amount of data could cause a countless number of patients to suffer due to lack of access to new treatments.
The ALS Association is particularly pleased at the Critical Path Initiative with achieve full time permanent staff and funds in PDUFA. Critical Path will facilitate partnerships between the FDA, the industry and the public that will promote new ideas to advance medical science. It takes advantage of new technologies to ensure the agency employs a 21st century approach to find treatments and cures for ALS. However we are concerned the FDA has not proposed sufficient funding and resources in order for the potential of Critical Path to be fully realized but we are pleased that new resources are provided. We hope the agency and Congress will work with us and concerned stakeholders to salvage a funding mechanism to support Critical Path.
In conclusion, we encourage rapid consideration and adoption of the new PDUFA. We hope that this will be the beginning of the opportunity to comment on this important initiative and to work with our fellow stakeholders in the final approval. Thank you.
Dr. Mullin: Thank you very much Steven. We’re going to change to our consumer groups now and first consumer advocate we have is Kim Witczak. Actually, Kim is a patient advocate speaking for herself.
Ms. Witczak: Hi. Thanks for having me here. My name’s Kim Witczak and I’m from Minneapolis, Minnesota. I’m here today to represent the voices of families who live everyday with the consequences of the current drug safety system. Unfortunately I know first hand what it’s like to lose someone. On August 6, 2003, I became a widow. My husband of almost ten years died of Zoloft induced suicide at age 37. Woody was not depressed nor did he have a history of depression or any other mental illness. What he was given Zoloft from his general physician for an insomnia diagnosis and took his life five weeks later.
Woody had just started his dream job as Vice President of sales with a start up company and was having difficulty sleeping as most of us with nerves do. He went to his doctor and he went home with a three week sample pack. I was out of the country the first three weeks when he was on the drug. When I returned from my trip I found Woody on the floor with his hands around his head like a vice telling me to help him. He didn’t know what was happening. He felt like his head was outside his body looking in. Never once did I question the drug. Why would I? It was FDA approved, heavily advertised as safe and effective and it was given out by Woody’s doctor who he had gone to and trusted for years.
From the beginning something didn’t add up with Woody’s death so my brother-in-law and I started researching the only thing that had made Woody change in this short period of time and that was Zoloft. Our journey for the truth has led us to the FDA, HHS, Congress and the courts. In fact this is my 23rd trip out here. In our battle for Woody we were able to get confidential internal Pfizer and other drug company and FDA documents made public that the suicide risk was known since the late 80’s and kept from the public. I used to think that the FDA when it gave its stamp of approval was under the highest standards. I quickly realized this isn’t always the case.
I was also shocked to learn that the drug industry through PDUFA paid a portion of the FDA budget to approve its drugs. The very nature of the industry paying fees to the regulator in which it’s supposed to regulate seems like conflicts of interest from the get go. With PDUFA we lost the idea that the FDA had a watchdog role, instead it created new marching orders. Ideally this is someone exists however to be given the reality of the current federal budget it’s something that we’re going to have to live with. Why not take the user fees that are collected and put into a general treasury kitty in which Congress appropriates like other budgets, like Representative Henchy has proposed. This would keep the drug company influence out of the picture.
With that being said I’d like to offer my perspective on some changes proposed and didn’t propose. While I’m happy to see that post-market safety is going to be a part of it, it seems right now to be lip service. On the drug approval side there are tangible, measurable requirements and a much larger budget to do their job but what about the post-market side? We need to have specifics that ensure the drug safety staff has the ability to do their job and not be trumped by politics, conflicting interest or senior staff who want to avoid the embarrassment because they approved the drug in the first place.
I fully support the Dodd-Grassley Proposal that separates post-market safety from the new office of drug approvals. There has to be more money appropriated to post-market safety. We need to increase the staff that not only reviews the post-market studies and adverse reports, but also maybe training some to act like more true investigators that proactively look for potential problems before they kill.
In the case of the anti-depressants, it’s literally the same people who approve the drugs back in the late 80s and early 90s who are now overseeing the drug safety reviews. They continue to defend their decisions for approval despite mounting evidence over the years. Most people don’t realize it was David Graham was one of the first within the FDA back in 1990 that didn’t think that Eli Lilly addressed the suicide concern, and just Tuesday he mentioned in the key tech hearings that he thinks the antipsychotics will be next.
As part of this post-market safety analysis consumers have to be part of the equation. Since most drugs get approved after being tested on limited numbers of people in clinical trials with true clinical trial exists in the real world when millions get put on a drug. One idea is to revamp the Medwatch Program. It has a lot of potential and most Americans don’t even know that it exists. One idea is to include on all direct-to-consumer ads and communications a tag that directs the public to report side effects to the FDA through the Medwatch Program. Another possibility is to allocate some of the funds to create a public awareness campaign that promotes the FDA Medwatch Program. This would be a separate FDA initiative from the DTC tag. The FDA could set up a specific call center that takes these calls and is trained on information seeking questions. Think of it like a claims center with an insurance company.
But in order to do it more successfully you obviously have to have the technology and the systems in place. More money needs to be allocated to improve technology now and not in creating a five-year plan. The technology exists today so we have to use it. The drug companies do. The days of faxes, scans and manually having to review the boxes of files should be over. The fees could pay for this technology. Don’t let the industry use your lack of technology to their advantage. These systems ultimately will help simplify, expedite the approval process, help in post-marketing analysis and aid you in the ability to do key word searches in Medwatch and other databases which ultimately will lead to a stronger FDA.
We all know DTC advertising is here to stay. I believe DTC advertising has greatly influenced the large numbers of people taking the drugs that they don’t necessarily need and throwing them into potential risk. From the outside it looks like you’re being proactive in getting additional funds. However that amount you’re planning to collect is a drop in the bucket for the drug companies. That’s barely the cost of a small national TV and print buy for one drug. It’s still voluntary and it should be mandatory or at least have key messaging approved.
I had the opportunity to speak at the DTC hearing that the FDA had in November 2005 and I believe at minimum DTC advertising has to be held at a higher standard. It’s not the same as advertising cars or soap or fast food. I spent my entire career working in various ad agencies around the country and I can tell you the fact that it takes 30 to 45 days to review ads is unrealistic given schedules and clients own internal routing needs. The process needs…
Dr. Mullin: Kim, two more minutes.
Ms. Witczak: Okay. A process needs to be put in place to allow for ads to be reviewed. I’d also like to make a comment on the FDA on conflicts of interests on advisory boards. In December at the FDA hearing on antidepressants, the consumer rep who sat on the panel had one of the highest effected company stock. How can I as the public trust that she is going to be able to look out for my interests?
I would also like to address the issue of off label use. Obviously there’s nothing you can do with the doctors, but maybe when you know the FDA knows that the off label uses aren’t being done it can demand further safety studies, take a proactive stance. After the ’91 hearing on Prozac, the FDA determined that more studies were needed, they were never done and the FDA never followed up. It’s clear the FDA needs more money to do their job. Ideally this money would have no ties. Earlier this week I heard a great out of the box thinking that would bring in additional funds for the FDA. It was the one cent on every prescription that was sold. I know that I would personally have no problem with one minute, or no, one second, sorry. I’m getting a little nervous on the time, with paying one additional penny to ensure that the drugs I’m about to take are safe. I’m sure most Americans wouldn’t either.
In conclusion I came here today in hopes that Woody’s story and the lessons it holds would help reach meaningful change. As you debate over the merits of PDUFA IV I want you to remember Woody, for his story represents countless of Americans who have personally paid the price for past FDA failures. This has real life consequences. Our lives, not statistics are at stake. Someone once said statistics are human stories without the tears. Please don’t forget the horror, grief and ocean of tears that I’ve shed and many others. We have a historic opportunity to work together to restore the FDA back to the gold standard it once was. Thank you.
Dr. Mullin: Thank you, Kim. Our next speaker is consumer advocate Bill Vaughn, with Consumers Union.
Mr. Vaughn: Thank you all very much for the opportunity for Consumers Union, publisher of Consumer Reports to comment on the fourth extension of PDUFA. As there’s some very difficult speakers to follow on Parkinson’s and Lou Gehrig’s and Kim, we strongly endorse Kim’s statement and make my statement a little bit shorter here, I think, today.
For the record we believe that your duties are so essential for the health and safety of the American public that we asked Congress to have them fully funded out of the general treasury but just like when I was a teenager and would ask my Dad for something, he’d often say, Yeah, and people in hell want ice water too. Given the hell of the federal budget that we’re in, we guess we need a user fee system in which case we’d like to see some of the strings that come with it perhaps broken. We support Congressman Maurice Hinchey’s bill, and the Commissioner this morning was very calm and eloquent in saying that the user fee system does not buy the agency and I’m glad he said that and I’m glad he believes it. There is a perception. The Institute of Medicine talked about it, the Union of Concerned Scientists got about a thousand people back on a poll, a physician scientist, colleagues of you all and if you read the comments that those doctor scientists made, many of them are feeling if not bought, pressured and I know every group has disgruntled workers. If my boss asked me to test one more toaster I’m going to scream, I think, but these comments are very impassioned and they’re scary to read and that’s what we have to deal with and it would be good to break these bounds.
It is good that the continuing resolution and the 2008 budget request single out the FDA for increases, but those amounts do not make up for years of resource erosion or allow the FDA to do a job that a gold standard agency should be doing. As consumers we want fast approvals and I see nothing in this PDUFA language or in Kennedy-Enzi that would slow up approvals. We also want safety and I’m picking up that there’s some tension or that’s it an either/or, that it’s either approval or it’s safety. What we want is an agency that can walk and chew gum at the same time, do both and that everybody is in the same boat and we would all gain from a better safety system. Imagine how much Merck research could be done if they weren’t spending billions of dollars on lawyers and in court cases, if the Vioxx issue had been resolved earlier but clearly more resources are needed, not through apropes then through user fees that give new emphasis to post approval safety and the new agreement does call for $29 million there and thankfully removes the time limit on when those funds can be used and that’s a start but we think it’s woefully inadequate.
For example the ILM report is a little fuzzy but it was asking for $100 to $200 million more and so basically we urge the FDA and since it probably is too late for you all, we urge the Congress to start over, to put this deal on hold and start over, not just because we need more money but when you look at the tone of what the user fees go for in speeding approvals they’re very detailed, date specific. They march along like with mathematical precision and on the post approval safety side they’re frankly pretty fuzzy, pretty academic and kind of bland.
The industry keeps getting 90 percent of the applications decided within a certain number of months and meetings within two weeks. The post- approval safety side we get sentences like, “potential activities in this area might include integration of certain proposed recommendations made by IOM.” We get a sentence like a public workshop could identify best practices in this emerging field ultimately developing a document that addresses epidemiology best practices.
As someone once said, “Where’s the beef?” We don’t see that much beef on the post approval side and in the sense of urgency, the February 7th JAMA article on Drysol that says about 2,000 people dying unnecessarily each year for the use of this medicine. Is this an issue then before the FDA for a year? At that rate there’s two people; two fellow citizens will have died during the course of this meeting from the use of this drug. We need to look at these issues more urgently.
So as consumers we’d like to see some tough deliverables with specific guidelines, deadlines, just like PhRMA gets and while the things you list are good, we would hope for more things like x number of clinical trials and IRB’s be audited each year for the quality of the work. How many more key tech kind of clinical trials are out there? Each year we’d like a certain number of commonly off labeled used drugs looked at, not to interfere in any way with the doctors prescribing but look at them to bring some science to the most commonly off labeled uses.
Set a date certain for IT modernization that will ensure that electronic filing of everything that comes before you. The language in the PDUFA agreement clearly shows the inadequacy of the agreement; uses phrases like “would accelerate the movement” rather than achieve computer modernization.
This is a chance to get into the 2st century and it should be seized. We hope you set a date certain that you’ll be able to use CMS’s wonderful database for big epidemiological studies and start some of those studies. We’re hopeful for other things like more aggressive follow up on AERs, faster diversification of the clinical trial population which I think in the document says FY2010. Spend money to develop a stable, if you will, of non-conflicted advisory committee members, find out why so many of those Phase IV trials are so slow and push on the companies that aren’t delivering, ensure that, I think the Parkinson’s gentleman mentioned this, that all scientific opinions and safety concerns from FDA funded staff are made public and easily available during advisory committee processes and address the unapproved drug problem that Congressman Markey keeps talking about.
On generics, switching subjects a bit, we appreciate the budget effort to reduce the backlog. We hope the funds could be adjusted in the future to assist in the implementation of legislation like Waxman-Schumer, if that’s enacted because dealing with biogenerics will be very revenue and resource intensive. We support pre-clearance of television and frankly all other advertisement for prescription drugs and that user fee program and finally I’d just conclude that we hope the FDA will support Congressional language requiring that when we consider PDUFA V in 2012, that consumer and patients get to participate in the real negotiations, get to sit at the adult table, if you will.
We thank you for this meeting. It’s good to see you guys. It’s always fun here, but I’d trade you ten hours of consultation for one hour of real negotiation and I hope that can happen in the next PDUFA and on that I thank you very much.
Dr. Mullin: Thank you, Bill. Our next speaker is Judith Cahill. Judith is the Executive Director of the Academy for Managed Care Pharmacy.
Ms. Cahill: Thank you. On behalf of the Academy of Managed Care Pharmacy, I’m delighted to be here today and to have the opportunity to share with you some of the views that the Academy has on behalf of PDUFA reform.
First of all let me explain to you what the Academy is, we are a professional society of individual pharmacists who have chosen to practice their profession through the use of managed care principles. We have over 5,000 members nationwide; most of them come from health plans whose names you would recognize from pharmacy benefit management companies and from pharmaceutical manufacturers who are concerned about managed care pharmacy and the way that it delivers on the pharmacy benefit for Americans today.
We totally support the renewal of PDUFA given the realities of the federal budget situation such as it is. We recognize that the agency would not be able to continue doing the things that it does today if it were not for the user fee funds. We agree with the Consumers Union that we would prefer not to see user fee funds being tapped into but to think that that agency could be fully funded through appropriated funds is probably not living in the real world today.
We do believe that those funds are necessary so that the agency can fulfill its obligation to promote and protect the public health through its timely review of new drugs and biologics and through the monitoring of the appropriate marketing of those items. We believe that it is the PDUFA user fee is essential for the drug review, but I would like to spend my time today with you focusing on two aspects of the four that were mentioned and that is the post-market surveillance and the direct-to-consumer advertising.
We do know that FDA approval of a drug does not mean that a drug is risk free. Indeed, a drug that is approved by FDA is approved only for appropriate uses where it is deemed to be safe and efficacious. Even when it is used in those appropriate circumstances it can have side effects for patients that can have deleterious effects and we do know from the FDA’s own data that it can take several years for problems associated with the use of an approved drug to actually materialize and that really underlies our concern about the post-market surveillance. We believe the post-market drug surveillance system needs to have more teeth in it. We agree with the recommendations that the agency has made but we do not believe that they go far enough. We believe that the agency should be in a position to mandate Phase IV studies that it believes need to be done in order to assure the safety of a product through its entire life cycle. We believe that the completion rate of the post-market studies that are requested now is abysmal.
As of September 30, 2006, there were over 1,200 studies that have been requested by the agency, 71 percent of those have yet to be begun. Now we recognize that in that 71 percent are companies that are towing the line and are trying to work to design studies that will be responsive to the commitments that are being asked by the agency, but we also believe that in that 71 percent are our several companies that have just paid lip service to the request by the agency. We believe that the agency should have the authority to manage those studies.
We also look to see that the agency itself has said that it does take several years, up to eight years, to actually see problems associated with the drugs. Therefore we’re very much in league with the agency’s request to remove the time restrictions for post-market studying. We believe that both the agency and the manufacturer have a responsibility to the user public for the safety of the drug throughout its entire life cycle and that does not stop at a two-year period or a three-year period post approval.
Therefore we believe that the agency needs to have sufficient funding to be able to put real teeth into the requests it makes that is, to be able to mandate those studies and to have enforcement opportunity. Currently the agency can do no less then withdraw a drug from the market. There is no opportunity for the agency to impose the fines, to restrict advertising or to impose other penalties that may be less than withdrawal of a product from market.
We’ve heard from some very eloquent people this afternoon that there’s need for these products and we don’t want to see them withdrawn if they can indeed be handed over to patients who have a real need for them. However, we do believe that it is the obligation of both the agency and the manufacturer to assure the public that there is safety in that product for its entire life cycle.
I’d like to turn my attention now to the direct consumer advertising area. Again we agree with the agency in their recommendation that they have additional funding for this function. I must explain to you that the Academy supports direct-to-consumer advertising of medications as long as it is done in a way to raise the awareness with regard to a disease and its symptoms and to alternative treatment options. We discourage the use of direct-to-consumer advertising with regard to specific drug products.
We believe that direct-to-consumer advertising can form a useful service for the American public if indeed it is used to raise awareness of patients to encourage constructive dialogue between patients and their providers and to examine alternative treatment options. We believe that that direct-to-consumer advertising needs to be fair. It needs to be not misleading and it needs to do a reasonable job of stating the potential risks that are involved with the use of the product as well as the benefits.
We believe that the agency needs significant funding in order to exercise its monitoring of direct-to-consumer advertising.
We champion the recommendation that has been made for a separate user fee for that function but we don’t believe that that goes far enough. We believe that the agency should be given the authority to mandate prior approval of all advertising, be it television, be it radio, be it printed matter and in the same we recognize that we would be talking about significantly higher dollars but we do believe that because of the fee, patient demand that can be generated with the use of direct-to-consumer advertising that there is an obligation on the part of the agency to act with dispatch in pre-approving what is put before the American public in the way of claims for risks and benefits with regard to specific products.
I believe the bottom line that we have come to today and I’ve heard from almost each of the speakers that has come forward today is that there needs to be sufficient funding for this agency to be able to do the important work that it is supposed to do and the Academy stands ready to champion that.
We are part of the FDA Alliance. This is a group that was begun about a year ago. It is bipartisan in nature. It now has approximately 100 organizations that are its members and it’s dedicated to no one particular area of agency activity. Not particularly prescription drugs, not particularly the safety of the foods system and the supply in this country, but rather to assure that there is work being done on Capitol Hill to encourage appropriate funding for this vital function for the American public and I would encourage anyone in this room that has an interest in making sure that the agency is adequately funded to look into the FDA Alliance. You can find it on the web at its website and I would ask for any organization that is not a part of this that feels strongly that the agency needs better funding to do its important work that they would become members of the FDA Alliance. Thank you for the time today.
Dr. Mullin: Thank you, Judy. Now we will hear from Brian Meyer, American Society of Health System Pharmacists.
Mr. Meyer: Good afternoon. My name is Brian Meyer and I’m the Director of Government Affairs at the American Society of Health System Pharmacists. ASHP represents over 30,000 pharmacists and pharmacy technicians who practice in a variety of health system settings including inpatient, outpatient, home care and long term care settings. I appreciate the opportunity to present the views of ASHP on the agency’s recommendations for PDUFA IV.
At the outset, ASHP has broad policy in support of FDA’s public health mission and believes that the agency should be appropriated ample funds to conduct that mission. However, we recognize the reliance on user fees is unlikely to change in the foreseeable future. While ASHP is pleased that the PDUFA program continues to support FDA’s mission, we believe the next reauthorization must go much further. As PDUFA has allowed faster drug approvals, manufacturers must bear some of the responsibility to support, to provide support for drug safety initiatives.
I’ll provide some brief comments in three areas of the agency’s proposed recommendations. These include pre-market risk assessment, post-marketing surveillance and direct-to-consumer advertising.
In the area of pre-market risk assessment the agency’s recommendations highlight the need to improve the availability of information during this phase of a product’s life cycle. However, ASHP would urge the agency to also establish clear guidance and policy regarding manufacturer development of restricted drug distribution systems. ASHP recommends that PDUFA establish new research to determine how well existing and new restricted drug distribution systems are achieving their goals. Moreover ASHP member’s experiences indicate the need for PDUFA to mandate that drug manufacturers and the FDA partner with professional organizations in conducting this research. The Society would also suggest that PDUFA authorize the establishment of a new advisory committee tasked with crafting recommendations to improve restricted drug distribution systems and those programs. This committee would analyze current FDA standards and recommend new policy in several key areas relating to restricted drug distribution systems. These include feasibility of standardizing basic elements of all these programs ensuring timely access to drugs for patients, eliminating continuity of care problems and permitting exceptions from various restricted drug distribution program registration rules for those practitioners that meet predetermined standards and requirements.
In the post-marketing area, ASHP supports the agency’s recommendation to eliminate the statutory restrictions so that PDUFA fees could be used to assess safety issues independent of a product’s approval date and allow the agency to review the drug’s safety in whatever time frame risks arise using all available resources. We’re also pleased to see a recommended initiative to conduct research on maximizing the public health benefits associated with collecting and reporting adverse events throughout a product’s life cycle. We also support the development of guidance on epidemiology best practices to aid and evaluating drug safety. Additionally we support access to population based data to utilize signal detection as part of improved post marketing surveillance.
With respect to measures to reduce medication errors related to look-alike and sound-alike names, we support the recommended pilot program to explore a different paradigm for proprietary name review. The agency recommends publishing three guidance documents in this area including naming, labeling and packaging. We urge the inclusion of pharmacists as part of this pilot and the agency’s consultation in developing this guidance. In addition we recommend that FDA tap the expertise of human factor scientists who can provide that needed perspective.
In the area of direct-to-consumer advertising, ASHP has long advocated for FDA to develop research to evaluate the medication used safety implications of FDA policies and industry marketing practices related to DTC advertising of prescription medicines.
We believe that the recommendations included in PDUFA IV of this area fall short. ASHP’s policy supports a delay in direct-to-consumer promotion until post-marketing data are collected and assessed. ASHP suggests that in combination with this delay the agency commission research on the impact of these advertisements on the appropriateness of a medication’s use.
Finally FDA feels that dedicated funds should be used to research innovations in health care practice that may improve the safety of the medication use system and the life cycle of a drug product. Researching this critical element may solve a significant portion of the drug safety problem. Thanks for the opportunity to present these comments.
Dr. Mullin: Thank you very much. Now we’re going to turn to some perspectives from industry and Alan Goldhammer is Deputy Vice President for Regulatory Affairs at PhRMA and he’s going to present.
Mr. Goldhammer: Thank you very much for having us here today to give thoughts of the Pharmaceutical Research and Manufacturers of America on this important proposal from the agency.
The passage of the 1992 PDUFA bill brought about tangible results in a very short period of time. At that time drug reviews were averaging over 30 months per NDA and there was a backlog of pending reviews at the agency. The additional resources provided the agency eliminated the backlog and allowed FDA to complete reviews of priority applications in six months and standard applications in 12 months. This added predictability to the drug review process but more importantly it benefited patients. Important new therapies for life-threatening diseases were approved in a timely manner providing widespread access.
At the time PDUFA was originally passed it was not clear whether the program would succeed or not, plus the legislation contained a five year sunset provision. In retrospect this has been a good thing. It provides the necessary time to gauge the effectiveness of the program but also allows stakeholders to reflect on what can be further done within the confines of user fees to protect and promote the public health, the central mission of the FDA.
In PDUFA II, the program was enhanced by increasing FDA resources in return for improved interactions during the drug development process. PDUFA III addressed FDA’s needs for sound financial footing in increased resources that could be directed towards drug safety. Both of these reauthorizations also directed funding for its information technology infrastructure so that both FDA and industry could realize the benefits of an electronic regulatory submission system.
It’s important to stress that throughout the PDUFA programs of the past 15 years, the exacting standards the Food and Drug Administration and the way they evaluate new drug applications has not been altered. What has been altered is the level of resources available for the FDA to perform its critical function of reviewing the safety and effectiveness of potentially life saving medications. With more resources being provided by PDUFA, FDA has been able to complete its rigorous reviews more quickly and efficiently. The outcome of this review however is not affected at all by PDUFA funding and may or may not, which may or may not be a drug approval at the end of the review cycle. That decision is FDA’s and FDA’s only and is based on information submitted in the application.
The agency’s PDUFA IV proposal contains important new provisions and resources to enhance and modernize the FDA drug safety program. It will add an additional new user fee program to give FDA additional resources to review and provide advisory opinions on direct-to-consumer television advertisements. It will improve drug development and provide more stable financing for the program.
Although the industry-funded part of the drug review process will increase during the PDUFA IV period, patients will be well served by a more predictable review process in assurance that the excellent drug safety office within the agency will be enhanced and modernized. PhRMA believes that the substantial new funding provided to enhance and modernize the drug safety system which would be nearly $150 million dollars over the next five years, will continue to assure that FDA’s pre and post-market safety assessment system is the world’s gold standard.
We believe that this PDUFA agreement substantially addresses all relevant recommendations of the IOM drug safety report that could be addressed through PDUFA. These additional resources will be used by FDA to reduce its reliance on spontaneous reporting of adverse events and increase the use of modernized techniques and resources such as epidemiological studies and large medical databases to identify risks more quickly and accurately. The FDA’s PDUFA proposal also provides funds to allow FDA to develop guidance on best epidemiology practices that will serve as a base for agency, academia and industry use. This guidance is intended to serve the public’s interest by assuring the studies reporting drug associated safety signals, do so based on defined minimum scientific standards.
FDA and industry also need a process to identify risk management and risk communication tools that are effective and work. Industry will benefit by having a list of risk management tools that work simplifying the development of drug specific risk management plans. This PDUFA agreement provides the resources to accomplish this. Significant resources are spent by companies late in the drug’s life cycle for monitoring adverse events. It’s rare that significant new safety issues are identified this late and such resources could be better allocated towards other drug safety activities. FDA will also conduct research during PDUFA IV to determine the best way to maximize the public health benefit associated with the collecting and reporting of such adverse events.
A key piece of patient safety initiative contained in this proposal is the allocation of resources to improve the trade name review process. Trade names are reviewed within the FDA drug safety office to help ensure that such new names cannot be confused with existing trade names in an effort to reduce potential medication errors. The FDA will now have additional resources to review trade names during drug development and provide industry with guidance on good naming practices. This will improve the predictability of the trade name review process.
The FDA proposal also includes a new user fee program for the review of direct-to-consumer television advertisements. In 2005 PhRMA issued a set of voluntary guiding principles regarding direct-to-consumer advertising. In those guiding principles PhRMA member companies committed to submit all new DTC television ads to FDA prior to public dissemination to ensure that FDA suggestions could be addressed before the ad was seen widely by the public. The proposed new user fees would ensure FDA has the resources to review such advertisements, voluntarily submitted to the agency in accordance with our guiding principles thus demonstrating PhRMA’s commitment to those principles.
This PDUFA proposal also continues forward with suggested improvements to the drug review process. FDA will implement good review management principles were formulated during PDUFA III. The agency will communicate to sponsors a timeline for discussing labeling and post-marketing commitments in advance of the action date. This will improve the predictability of the drug review process and lead to more meaningful post-market studies that are appropriate for the new drug. Funding is allocated for the purpose of expediting drug development. This will permit FDA staff to directly be involved in external activities such as partnerships and consortia that are generating data and information that will create new paradigms for drug development. In return FDA commits to develop draft guidance in areas related to safety assessment, clinical trial design and the use of biomarkers. In addition FDA will participate in workshops and other public meetings to explore new approaches to a structured model for benefit risk assessment. The results of these interactions will be used to assess whether pilots of such new approaches can be conducted during PDUFA IV. Collectively these will lead to new paradigms for drug development, leading to earlier patient access of important therapies.
Finally, there are a number of proposed technical amendments for financing the PDUFA program over the next five years. It’s PhRMA’s hope that collectively these will provide the sound financial footing needed to continue keeping FDA’s drug and biological review program strong.
Dr. Mullin: Thank you, Alan. Our next speaker is Mary Gustafson. Mary is with Plasma Protein Therapeutics Association.
Ms. Ellis: I actually am not Mary Gustafson. I’m Bridgett Ellis from the Plasma Protein Therapeutics Association, PPTA. PPTA is pleased to provide these comments on the Food and Drug Administration’s public meeting regarding the proposed recommendations for the reauthorization of PDUFA for the process of human drug application review for fiscal years 2008 through 2012.
PPTA is the international trade association and standard setting organization for the world’s major producers of plasma derived and recombinant analog therapies. Our members provide 60 percent of the world’s needs for source plasma and protein therapies. These include clotting therapies for individuals with bleeding disorders, immunoglobulins to treat a complex of diseases and persons with immune deficiencies. Therapies for individuals who have Alpha one antitrypsin deficiency, which typically manifests as adult onset emphysema and substantially limits life expectancy and albumen which is used in emergency room settings to treat individuals with shock, trauma, burns and other conditions. PPTA members are committed to assuring the safety and availability of these medically needed life sustaining therapies.
PPTA appreciates the opportunity to comment of FDA’s proposed recommendations. PPTA presented at the previous PDUFA public meeting held in November 2005, submitted written comments to the docket in December 2005 and met with FDA representatives in May of 2006 to discuss the reauthorization of PDUFA. PPTA member companies, including those not subject to user fees, are regulated by the Center for Biologics and Evaluation and Research, CBER. The products produced by our member companies are reviewed by the Office of Blood Research and Review. In these previous communications, PPTA stated that overall the companies are pleased with CBER’s performance regarding PDUFA. Without the development of this user fee program many life saving therapies would not have come to fruition. Because of the success of the user fee program, PPTA supports reauthorization of PDUFA. At the same time PPTA is interested in containing costs of the program while ensuring that FDA’s important programs, whether user fee funded or not, remain viable.
To improve this essential program, PPTA communicated initiatives that should be implemented. We are pleased to see that some of the proposed recommendations included in PDUFA IV are priorities PPTA presented, for instance, the withdrawal of programs such as the continuous market application pilot programs, if the overall benefits of the program did not justify their costs to FDA.
Two, revising the time line during the drug review process to include earlier discussion of labeling and negotiation of post market Phase IV commitments to alleviate some of the detrimental last minute decisions that can occur right before a drug is approved.
Three, improvements to the IT infrastructure that would help improve transparency and predictability of the human drug review process, additionally PPTA is supportive of fund allocation for the development of guidance documents particularly for clinical trial design expectations.
PPTA member companies produce therapies that are often indicated for small patient populations. Allocation of PDUFA funds to develop guidance under good guidance practices allows industry input into licensing criteria standards including clinical trial design rather than having those standards developed on an ad hock basis during the application review process.
Despite the positive proposed recommendations included in PDUFA IV, PPTA remains concerned about the increase in user fees towards post market surveillance and the possible expansion beyond the peri-approval period included under PDUFA III. PPTA previously advocated that if PDUFA IV included an expanded post market surveillance program the program should be developed on an interactive basis between FDA, industry, consumers and other interested parties.
PPTA is pleased at FDA’s recommendations include plans for transparency in the process and opportunities for recommendations, include for transparency in the process and opportunities for input via participating in public workshops and commenting on published documents. PPTA’s unease with the expansion of post market surveillance programs supported by user fees is that it presents certain conflicts that may be perceived in a public health drug safety monitoring program that is underwritten by industry. PPTA members support the use of PDUFA user fees for post-market studies and monitoring during the peri-approval period as included in PDUFA III. However, FDA should receive public funds through Congressional appropriations to undertake the comprehensive effort to modernize and transform its post market safety system.
Finally, PPTA remains alarmed by the erosion of FDA’s and particular CBER’s funding outside of the user fee programs. CBER operates uniquely under both PDUFA and the medical device user fee program. In addition CBER maintains a significant number of non user fee programs; therefore, it is of great importance to our member companies that user fees in both programs be used appropriately including tracking and accountability, while non user fee programs continue to receive adequate funds. CBER cannot perform all essential regulatory functions without sufficient funding. CBER plays an important role in the lives of many individuals who rely on plasma protein therapies, manufactured by PPTA members. CBER must be provided the necessary funding to administer programs appropriately to assure the availability of these life saving therapies to those who desperately need them.
In summary, PPTA thanks FDA for holding this public meeting and allowing us the opportunity to speak on behalf of members. PPTA member companies have supported PDUFA since its inception. The open process during PDUFA IV gave PPTA and its member companies a voice in shaping the FDA recommendations that will directly affect our industry. We believe the inclusion of all affected industry as well as patients and other stakeholders is vital to the user fee program and commend FDA for this open process. Should you have any questions regarding these comments please contact the Association. Thank you.
Dr. Mullin: Thank you, Bridgett. Our next speaker is John Kamp. John is the Executive Director of the Coalition for Healthcare Communication.
Mr. Kamp: I had some slides. Can they come up? Thank you very much for inviting us to speak here today and we’ll talk quickly. Just a quick note on who the Coalition is. We’re companies and trade associations that are in the business of medical publishing and also advertising, public relations and other things for PhRMA companies. We believe in the first amendment right, most importantly for all citizens, but also for the companies that speak on these issues and we’re proud to say that we think that self regulation whenever possible, almost always trumps government regulation and we’re delighted to work on those processes.
We wanted to start by reminding you of our most important statement and that is PDUFA works. We agree with virtually everyone who spoke here today that it’s of a very important system that helps patient and industry as well as FDA do its job and do its job well and enables new medicines, improve quality of life, prevention of disease and medical advances of all types.
Our major points today are really, I’ll go through them quickly and then we’ll talk about each one of them in some more detail. First of all we must say that DTC advertising, the existing system actually works for citizens in FDA. To a certain extent the counter point, not stated on my slide here is that if it’s not broke, don’t fix it and for the most part, the system is not broken in any way. We do suggest that new objective review standards would reduce the time it took both the industry and the FDA to do DTC review burdens and we suggested some clear distinctions between professional advertising and DTC advertising that actually help.
Should we, I can see it well enough to see which one we’re on here. We’re on major points. Well maybe, I’m not and now I’m on the third of the bullet points here. Put on my own glasses here and we can probably make this do.
We think we need some better distinctions between consumer advertising regulation and DTC advertising. We also suggest that there be limited uses of the DTC review funds that are in the existing PDUFA recommendations. We also ask all of those involved with this to pay very close attention to the first amendment on some of these issues. There’s not only important lessons to be learned there but we don’t want the courts to overturn any of this and we remind us all that the FDA jurisdiction on DTC advertising on marketing generally has been under assault from other organizations.
First of all, just to remind you of our most important statement that not only does PDUFA work with DTC works, patient and care givers and others, are improved by this process, but we notice particularly and FDA research is some of the very best on this, that it stimulates conversations between doctors and healthcare providers and leads to all kinds of diagnosis that may not otherwise happen, treatment of those and therefore it advances the public health. We also want to remind everyone that the PhRMA principles that are now less than two years old work quite well. They clearly have led to better risk information, prescribers are now educated routinely first before DTCs happens. We see fewer ED ads on prime time TV. The use of reminder ads has been specifically limited and especially in DTC, and of course pre-clearance which is part of one of the reasons that we’re here today, has happened.
The PhRMA principles also work for the FDA and they work for the FDA partially because now the FDA has seen virtually all DTC TV ads, but also notice that the warning letters on DTC ads essentially have stopped. They’ve been significantly reduced since the time of just the announcement of these principles by the PhRMA companies, virtually no DTC warning letters about TV and radio and other mass media ads since mid 2005 and also I think we see that both in the industry and elsewhere that there are very few consumer complaints now about DTC advertising or at least many fewer than before.
Meanwhile we suggest that there ought to be some things, should we back out of that? The work for FDA, meanwhile we suggested some clear guidance from FDA would make the whole process work better and faster. We think that some more objective and predictable standards in the DDMAC unit, especially for DTC where you respect a difference between consumer and professional audience and more reliance on social science would actually make the process of review much faster both at FDA and inside the industry.
We suggest also that there be brief summary reform. The FDA has been talking about this for some time. It’s time to issue some final guidance on the brief summary, avoid these complicated messages. If we developed a very serious, straightforward, standard process, it would make the review faster and more predictable for all. Most importantly, I notice that Bob Temple is not here, but he was the one who first claimed the phrase that the brief summary is like the holy Roman Empire, not holy, Roman or an empire, or at least not brief nor a summary. I think it is time for us to just blow that away and do what Bob has suggested and move on in that area.
We suggest that the new PDUFA standards may preclude even the need for as many of 27 of additional staff, not necessarily all of them reviewers and that process we suggest also that the FDA avoid calls for mandatory reviews continuing the existing pre-clearance process, which is essentially voluntary. There is a first amendment problem if we make them mandatory among other processes and in other ways it may clog the process unnecessarily. Also again, clear and consistent standards would make the whole process work better.
We also suggest that the proposed system safeguards may be better; made more specific than they are in the current plan, limit revenue use from the PDUFA fees for specified purposes, that we avoid particularly a mission creep inside of DDMAC and of personnel redeployment. I say that as a former head of a similar kind of a unit and in a different agency. I don’t want to accuse anybody of doing anything wrong, but since I did some of this myself as a federal employee, I feel that I can warn others not to emulate my own process.
We also suggest that the FDA remain very flexible in this regard. We’re skeptical of the need for as many as 27 new people and that FDA make sure that it keeps its options open to reduce that number if possible. We also want people to pay attention to the first amendment in all of this process and we feel it necessary to remind people that the public record, the FDA has to have a clear public record for all speech regulation that it does. It has the burden of proof on all four of the so called four prongs of the Central Hudson Standard of the U.S. Supreme Court and must articulate the need for the rules and processes prove that the procedures work, consider narrower alternatives and use speech restrictions as a very last resort.
Meanwhile the FDA must protect its marketing jurisdiction. We’re concerned that in DTC advertising and other places in its marketing jurisdiction, there seem to be a lot of FDA want-to-be’s out there to regulate here, particularly state laws, attorney generals in the states. We think that the FDA would be -- is doing the right thing in participating in many of these state cases. We urge them to continue that and to resist those actions and private actions by plaintiff’s attorneys, especially in plaintiff class action cases on failure to warn and other false advertising cases that threatened to disrupt the DTC advertising jurisdiction of the FDA. We’re also a little concerned that even inside our own house, the HHSIG’s office is doing more aggressive failure to warn and false claims act jurisdictions and we think the FDA should essentially take back that jurisdiction.
In summary, quickly, start with clear objectives on this PDUFA program, proceed carefully, separate professional and consumer DTC standards, follow first amendment mandates, resist the attacks on the jurisdiction of the FDA by others. Thank you very much. If you would like a copy of these slides or have any other information, my information is up there and I’d be glad to answer any of your questions. Thank you very much.
Dr. Mullin: Thank you, John. Our next speaker is Alan Kirchenbaum. Alan is with Hyman, Phelps and McNamara. He’s presenting on behalf of the Council on Radionuclides and Radiopharmaceuticals.
Mr. Kirchenbaum: My name is Alan Kirchenbaum. I’m a principle in the law firm of Hyman, Phelps and McNamara here in Washington and I’m appearing here today on behalf of the Council on Radionuclides and Radiopharmaceuticals or to make things simpler, CORAR. CORAR is an association of companies that manufacture and market radiopharmaceuticals that are used in diagnostic procedures and also for therapeutic purposes.
I’d like to take a few minutes to focus on the user fee issue that is quite narrow but critical to a very important type of diagnostic imaging drug and that is positron emission tomography drugs or PET drugs. PET drugs raise unique issues under the user fee act. In order to explain why, I’d like to give you some background on PET drugs.
PET drugs are produced by tagging or labeling a substrate compound with a positron emitting isotope which is produced in cyclotrons. Cyclotrons are devices that accelerate protons or deuterons to the high energies needed for nuclear reaction to occur and for nuclear particles to be released. Once injected the isotope travels through a patient’s bloodstream and is distributed in certain tissues. Using a PET camera that detects the nuclear particles emitted, nuclear physicians produce computerized images of biochemical processes and tissue structures within the body.
Physicians use these images to diagnose, stage and monitor diseases like epilepsy, certain cardiac diseases, dementias and cancer. Because the radioactive half lives of PET drugs extend only up to a few hours, they have to be used soon after they’re prepared, therefore PET drugs are prepared by PET drug facilities only as needed and in close proximity to the medical facilities in which they are used. This distinguishes PET drugs from other diagnostic and therapeutic drugs which typically have long shelf lives and therefore can be manufactured at centralized facilities and distributed over long distances for commercial use.
PET drugs have had an unusual regulatory history which I don’t have time to explain in detail here, but suffice it to say that pursuant to a provision of the FDA Modernization Act of 1997, there’s currently a moratorium on FDA’s regulation of PET drugs as new drugs. Therefore NDAs are not yet required in order to market these drugs, but they will be required once the moratorium has ended which will likely be in two to three years.
PET drugs raise user fee problems that are unique among pharmaceuticals and that obviously weren’t contemplated by Congress when it enacted PDUFA. Because of the short half lives of PET drugs, a commercial manufacturer that supplies PET drugs nationally or even regionally requires multiple, small cyclotron facilities located throughout the U.S. or the region. If such a manufacturer were to submit an NDA, each of these facilities would have to be identified in the NDA as a manufacturing establishment and the company could be subject to enormous establishment fees each year, for example one PET drug manufacturer operates 44 cyclotron facilities nationwide. If these were used to manufacture and supply a particular PET drug under an NDA, this company would have to pay over $13 million dollars every year in establishment fees and that’s based on this years establishment fee rate. This is an obvious and serious problem. Annual revenues for some PET drugs wouldn’t even pay for the $13 million dollars in annual establishment fees in this example, much less recover the cost of development, production, marketing or provide a profit. The market for PET drugs is miniscule compared to the market for many therapeutic drugs and yet absent relief, some PET drugs will be burdened with much higher fees than multi-billion dollar drugs like Lipitor.
When the moratorium ends, no commercial PET manufacturer will be able to stay in business under these conditions and patient access to these innovative life-saving diagnostics will be severely diminished. How can this problem be resolved? CORAR proposed an administrative solution in a citizen petition that was submitted to the FDA in August of 2005 and we’re awaiting a response from the agency.
However, we believe that a legislative solution is the surest way to resolve the issue for all PET producers. We’re proposing that PDUFA be amended so that establishment fees would be limited to one per NDA for commercial PET manufacturers.
In addition many PET drugs are produced by not for profit academic medical centers that have one cyclotron for use within the same institution. Our additional proposal is to exempt these facilities from all establishment fees where the PET center is operated by or affiliated with a medical center where it has only one cyclotron and where the PET drugs produced are for use within the medical center.
Nine years ago in FBAMA, Congress mandated a special regulatory framework to accommodate the unique characteristics and the unique distribution of PET drugs. Since PET drug NDAs were not required then the issue of user fees didn’t need to be addressed in PDUFA III. Now however with the end of moratorium approaching this is the time to resolve the problem.
On behalf of CORAR, I’d like to thank the agency for the opportunity to bring this issue to your attention and to provide input into the reauthorization process and we’ll be submitting written comments as well. Thank you.
Dr. Mullin: Thank you, Alan. Our next speaker is Alison Lawton. Alison is a Senior Vice President for Regulatory Affairs and Corporate Quality Systems at Genzyme Corporation presenting on behalf of the Biotechnology Industry Organization.
Ms. Lawton: Thank you. On behalf of BIO I’d like to thank FDA for the opportunity to comment today and for the sake of time I’m going to keep my comments short, but I do want to make note that we will be submitting full comments to the docket and there is a copy of our full comments outside on the table in the front.
BIO, or the Biotechnology Industry Organization represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the U.S. and 31 other nations. BIO members are involved in the research and development of health care, agricultural, industrial and environmental biotechnology products. Leveraging recent advances in genomics, proteomics and bio-informatics, biotechnology researchers are leading the development of novel therapies to treat unmet medical needs in areas such as Alzheimer’s, diabetes, cancer, cardiovascular disease and many other devastating illnesses.
A strong FDA is critical to the continued innovation of BIO member companies and creating the next generation of biotechnology medicines. BIO supports the PDUFA IV recommendations and timely enactment. We are also urging Congress not to complicate and possibly delay the enactment of PDUFA by encumbering the legislation with complex and controversial issues that are not related directly to the PDUFA program.
As you’ve heard during today by many speakers the PDUFA program itself has been a success and has provided FDA with additive, consistent, multi-year resources which has led to over 1,100 new medicines being approved with reduced review times and providing patients and doctors with earlier access to breakthrough treatments.
BIO endorses the PDUFA IV proposals because they underscore our commitment to patient well being and safety by supplementing the agency’s resources to enhance and modernize the drug safety system in the United States. While considering improvements to the FDA safety evaluation system, BIO believes the following principles should be taken into account.
First, in the United States the FDA is and should remain the government reviewer of benefits and risks in determining whether and how to approve the new regulated products whether and under what conditions to keep them on the market. The FDA scientific knowledge and expertise that’s essential for the evaluation of safety and efficacy of medicinal products and FDA must have sufficient resources to complete this mission. In addition FDA’s current organizational structure which deals with drug and biologic safety pre and post approval in an integrated way is appropriate for the comprehensive and systematic evaluation of safety throughout the life cycle of medicines.
Second, all drugs and biologics carry both benefits and risks that should be carefully weighed by patients and their doctors. The balance between the benefits of treatment and the risks of potential side effects will differ based on many factors including the nature of the treatment and the condition in each patient’s unique medical profile. Efforts to improve safe use of medicine should support and inform medical decisions made by these patients and their physicians rather than limit the ability of physicians to prescribe a particular medicine to a particular patient.
Third, patients and physicians need timely, accurate and relevant information about the benefits and risks of drug or biologics so that they can make well informed choices about therapy. FDA assessments in communication of emerging information regarding a treatment benefit and risk both before and after approval provides a needed integrated system of medical product evaluation. Safety information, collection assessment, communication and regulatory action must be informed by the best available scientific data and expert advice.
Finally, the most beneficial policies and actions with respect to drug safety are those that continue to enhance patient health and that promote innovation and the development of novel medicines. The public and private sectors including biotechnology companies on the leading edge of scientific advances and innovation in biomedical science and bio-informatics, both the public and private sector together should work collaboratively to harness these advancements to enhance and modernize a system of drug and biologic evaluation.
BIO believes the negotiated PDUFA IV reauthorization proposals are fully consistent with these principles and should be implemented. I’m just going to click through these. I think you heard this morning from the presentations from the FDA a very good overview of all the different PDUFA IV proposed enhancements and I’m not going to spend time going through them again, only I would like to say that all the proposed PDUFA IV initiatives will enhance the drug safety evaluation and monitoring of drugs and biologics and these together with the initiatives that the FDA announced in response to the IOM report allow FDA to establish a modern, comprehensive, life cycle approach to drug safety based on the 21st century information technologies, biomedical advances and efficient risk management strategies and again the next slide I’m going to jump because you heard this morning the need for additional money to ensure the base for PDUFA.
While we applaud the new recommendations in PDUFA IV, BIO notes that PDUFA fees are intended to be additive to a sound base of appropriations for FDA’s core activities. However, BIO is concerned like many others that FDA has become over reliant on these user fees to meet the core mission of the human drug program.
For instance in 2005, appropriations funded 150 reviewers less than in 1992. In 2005, user fees funded more than half the cost of human drug review compared to seven percent at the start of the program. Unless appropriations increase substantially more than they have done over the last ten years, user fees could actually account for more than two thirds of the cost of human drug review by the end of PDUFA IV. BIO is concerned that the FDA’s over reliance on industry fees creates an unseemingly misperception that FDA’s beholden to the industry it regulates. In the long term this perception is not in the best interest of patients, the biopharmaceutical innovators or the FDA. The fee increases proposed under PDUFA IV are important, they’re necessary for FDA to implement the new proposals but BIO believes that FDA also needs increased appropriations to continue its mission of protecting patients as it faces a revolutionary new era of scientific evaluation and advancement.
BIO is a founding member of the Coalition for a Stronger FDA, a group of trade associations, patient groups, consumer advocates and individual companies whose goal is to ensure a strong, consistent, public commitment to resources for the FDA. BIO and the Coalition for a Stronger FDA will continue to work with the Administration and Congress to seek needed increases in appropriations for human drug review activities at FDA over the next five years.
So, in summary, it’s important that Congress complete the reauthorization of PDUFA in a timely manner well in advance of the September 30th expiration date in order to avoid the initiation of a reduction of the FDA workforce which it would slow down in regulatory reviews and reduce patient access to new therapies. BIO believes that the PDUFA program has been highly successful and is a direct contributor to increased patient access to life saving and breakthrough therapies. The proposed enhancements under PDUFA IV would provide FDA with tools and resources to modernize the post-market surveillance system, evaluate more efficiently each products unique benefit and risks and continue to support the timely development and availability of needed new medicines to patients. Thank you.
Dr. Mullin: Okay, thank you, Alison. Our next speaker is Lili Ann Stiver who’s the Managing Director of the Drug Safety Institute presenting for the Drug Safety Institute.
Ms. Stiver: Well, good afternoon and as introduced my name is Lili Stiver and I’m the Managing Director for Canadian Regulatory Affairs at the Drug Safety Institute and as well I’m a registered Canadian pharmacist. I was formally a patient safety specialist with Health Canada and participated in the development of Health Canada’s guidance for industry on drug naming review as it pertains to look alike and sound alike naming.
Today I’m speaking to you on behalf of Mr. Jerry Phillips who was formally the acting Director of the Division of Medication Errors and Technical Support at the FDA’s Office of Drug Safety and is currently President of the Drug Safety Institute, a subsidiary of Brand Institute. For our background, the Drug Safety Institute, or DSI works as a consultant to industry in the area of proprietary name safety research. DSI appreciates the opportunity to offer comments on this important subject and will focus comments specifically on PDUFA IV proposals as they relate to the prevention of medication errors due to sound alike and look alike proprietary names.
The first set of comments pertains to FDA’s proposal to publish three guidances to industry that will address firstly the contents of a complete proprietary name submission document, secondly, good naming, labeling and packaging practices and third, best practices on a proprietary name evaluation. These three guidance documents are essential to the industry, the public and the agency in establishing good naming practices and minimizing medication errors and patient harm.
We’re pleased that the agency is committed to publishing these three guidance documents which have been in the drafting stage at the FDA for a number of years. However, we would encourage consideration of placing a definitive timeline of 24 months to the publication of the final guidance documents. This would be somewhat similar to what was done in PDUFA III for the risk management guidance documents. These guidances are especially important for the successful implementation of the proposed pilot program that shifts responsibility for testing of proposed proprietary names from FDA to the industry. Without these guidances in place it will be difficult to implement a successful pilot program. In addition, we encourage the agency to consider expanding the scope of these three guidance documents to include all FDA regulated product proprietary names including vaccines, blood products, devices, veterinary drugs and over the counter drugs. As well, we propose that the agency include guidance about proprietary names under which distributors are re-packer’s market approved products.
The second set of comments pertains to the performance goals for reviewing proprietary names, proposed to be within 180 days for INDs and 90 days for NDAs. Considering that the agency’s current average name review time as part of both INDs and NDAs is 90 to 120 days, we would encourage the agency to target a performance goal of 90 days for completing name reviews of both INDs and NDAs and in accordance with the proposed phase in percentage of submissions subject to this completion goal of 50 percent in year one and 90 percent in year four of the program. We do however request clarification on how the agency will determine that it has completed 50 to 90 percent of its workload and for example in year one of PDUFA IV, would the agency include those applications for IND, NDA or MDA, ANDA that were not covered under PDUFA IV and the applications received during that year and we’re interested in knowing how the current backlog of work will be assimilated into the PDUFA IV review process.
In addition we would encourage the agency to adopt this 90-day performance goal as a timeline for not only the review time for the agency but also notification of the applicant as to the outcome of this review, measured from the time the request is received by FDA from the applicant.
The third and final set of comments pertains to the FDA proposal to develop and implement a pilot program that shifts the risk assessment and testing responsibility of a proposed proprietary name from FDA to the industry. Again we commend the FDA for shifting this responsibility to industry as suggested by the 1999 Institute of Medicine Report, To Err is Human: Building a Safer Health System and this is also more consistent with the traditional approach of FDA reviewing data submitted to the agency. We do suggest that the FDA for the timeline of this implementation of the pilot program to coincide with the publication of the final guidance documents which we recommend would be 24 months after PDUFA IV is implemented.
We also suggest that this pilot program be open to both INDs and NDAs and that the agency consider an incentive such as perhaps shorter review times to get companies to participate. In addition we suggest that the pilot be open to all pharmaceutical companies and consulting companies who routinely perform these risk assessments and would include companies such as the Drug Safety Institute which has been routinely submitting these types of reports to the agency over the past 14 years.
So in conclusion, I’d like to thank the agency for the opportunity to present comments on behalf of the Drug Safety Institute today and we look forward to working with the agency and the pharmaceutical industry in reducing medication errors due to sound alike and look alike proprietary names. Thank you.
Dr. Mullin: Thank you, Lili. Our next speaker is Anthony Wisniewski. Anthony’s the Executive Director of U.S. Chamber of Commerce.
Mr. Wisniewski: Members and representatives of the FDA, I am pleased and honored to be here today. Thank you for your kind invitation. By way of introduction, I’m a life sciences attorney serving as the head of Health Care Policy for the United States Chamber of Commerce where my responsibilities include managing the Chamber’s diverse health policy portfolio and primary responsibility for health policy issues pending before the U.S. Congress and federal agencies. Prior to joining the Chamber, I served as the head of public policy for biotechnology company, MedImmune and prior to that worked in the life sciences industry on behalf of an industry trade association as well as focusing on corporate transactions and government affairs while in private legal practice. I also currently serve as a gubernatorial appointee to the board of the Maryland Technology Development Corporation, a public-private entity that is a national leader in providing seed stage venture capital funding to emerging biotechnology companies.
The Chamber applauds the historic successes of PDUFA. PDUFA’s programs have dramatically improved the drug approval process remedying the significant drug lag of the 1990’s. However, these accomplishments in the pre-market product review process have also made PDUFA an attractive vehicle for increasing user fees to fund other programs such as post-market safety surveillance and most recently direct-to-consumer advertising. Generally speaking we believe that the PDUFA IV proposal will ensure that FDA maintains the necessary tools for conducting timely yet thorough reviews for new drugs.
Given some incidents of advertised popular products that have been recalled in the past five years, insuring drug safety has become paramount, improving post-market drug safety and its funding must be a fundamental priority. However, there must be a balance between safety and access without this balance consumer access to critical new treatments will be delayed.
This chicken and egg issue begs the question of how stringent can the approval process afford to be before it hinders the entrepreneurial discovery and the innovation of new medicines. Onerous regulations could eventually frustrate a biotech’s ability to attract venture capital funding likewise, established innovator companies may not be able to prevent a higher cost of bringing and maintaining drugs on the market without passing added cost on to the consumer.
The Chamber believes that the FDA’s and PDUFA stakeholder’s assertion is correct providing guidance to the industry on clinical trial design will improve the development of new drugs. Likewise the Chamber also agrees that focusing efforts on useful trials and decreasing less useful experimentation will reduce R&D times and total costs of bringing a new drug to market all of which should lower drug prices for the consumer.
The Chamber also supports collecting user fees to promote scientific research collaborations designed to clarify regulatory pathways for new technologies and potential new biomarkers for drug safety and effectiveness. However, in this area of the proposal we would like to provide added encouragement that Critical Path projects receive adequate user fees and perhaps appropriations funding to help accelerate new drug development. Critical Path Programs are personalized medicine and pre-market focus vehicles designed to address drug safety yet these programs potentially offset the cost of compliance with the inclusion of additional post-market regulatory requirements.
Utilizing PDUFA’s user fees to more clearly fund these products can decrease the cost of clinical trials, expedite development of new medicines, reduce the number of adverse events and related litigation costs and provide greater access to consumers at an ostensibly lower cost.
In October 2006, the CBO released its report R&D in the Pharmaceutical Industry. This report finds that the drug industry spends more on R&D relative to its sales revenue than almost any other industry in the entire country. Based on the results of several independent studies, the report asserts that industry’s real spending on drug R&D has increased between three fold and six fold over the past 25 years. However, CBO goes on to say that in spite of increases in R&D that there has been little change in the number of innovative new drugs approved for use each year. Greater research challenges, more technological complexities in drug development and greater specificity in disease targets all contribute to increased R&D expenditures as well as higher clinical trial failure rates. These failures contribute to increasing R&D cost per new product, especially when those failures occur further down the clinical trial process.
Under the current clinical trial system many products are failing to reach the market because they cannot be proved safe or effective or because they could not be manufactured at a consistently high quality. The Chamber agrees with FDA that a large part of the blame falls upon the scientific tools needed to develop new medicines that are trailing the rapid advances in new medicine discovery. This inefficient pre-market process delays consumer access to new medicines and ultimately drives up market prices.
FDA’s development of the Critical Path Initiative in March 2004 focuses on incorporating modernized process oriented scientific tools. These tools, we believe, have the potential to evaluate safety and efficacy of new medicines expeditiously with greater certainty and at lower costs and with better information.
Biomarkers are particularly interesting scientific tools that can be used to prevent, detect and treat a wide range of diseases ranging from cancer to depression. Biomarker technology could save time and money in R&D, shortened clinical trial times while using fewer patients and expedite FDA marketing approval. We are pleased to see that the Biomarkers Consortium led by the National Institutes of Health Foundation and FDA is collaborating with private industry groups to finance biomarker research.
The Critical Path Institute is involved in similar process oriented projects but does not accept funding from biopharmaceutical companies. Instead the Institute accomplishes its work by being a catalyst for coalitions and stakeholders to work together. We view the Institute’s fast path program as coinciding directly with the Chamber’s priority of lowering employer health care costs through, among other things, reduced R&D expenses, particularly relevant fast track projects include cancer biomarkers and cardiovascular genomics project.
Of course, there is already precedent for the successes of fast path projects in promoting drug safety and lowering the cost of health care. In the National Warforin Study for the Institute is helping provide vital information to the FDA so they can develop drug labeling that will instruct physicians and patients with a certain genomic makeup should start with either a higher or lower dose of cardiovascular disease medication such as potentially life saving blood thinners.
In fact the AEI-Brookings Joint Center studies concluded this project will save lives; reduce the health care spending by an estimated $1.1 billion dollars annually.
We further support the role the Institute plays in analyzing generic drugs such as warforin. These fast path projects may receive broad support as a means to reduce the time and expense of employing aging clinical trial and R&D processes that take up to 15 years to bring a product to marketing approval.
The Critical Path Institute provides scientific credibility and neutrality to the drug development process and applying user fees to fund the Institute’s programs will appeal to legislative overseers. Further, these Critical Path Programs demonstrate FDA’s commitment to reducing biopharmaceutical R&D costs while promoting safety and consumer access to new medicines.
FDA should also support adequate funding for its Office of Generics as demonstrated through popular discount generic drug programs, large retail stores. Generic drugs offer additional choices in drug therapies and enhance competition in the marketplace ultimately making drugs more affordable to employers and consumers. To address this concern a generic PDUFA program should be further discussed. A public, private collaborative solution to funding the review and approval of generic drugs complete with the deliverables and benchmarks of a PDUFA program is the preferred method. Given that the medical device industry also pays user fees through their own MDUFMA, it seems appropriate to perhaps consider a generic PDUFA program.
In conclusion the U.S. Chamber of Commerce applauds the terms of PDUFA for a proposal and we call upon FDA to give that a consideration to ensuring that Critical Path projects receive adequate funding to accelerate new drug development. It is critical that consumers have optimal access to safe and lower cost innovative medicines. We also support further discussion of the creation of a new user fee program for the generic drug industry in order to accelerate the delivery and cost-effective alternative drug therapies to consumers and employers. Thank you very much for your time.
Dr. Mullin: Okay. Thank you, Anthony. We’re almost at 2:45. Do we have other speakers who wanted, who haven’t signed up, who didn’t register, but want to talk about the PDUFA IV recommendations and have any comments on that?
If not, then we’re going to take a break earlier than expected because we’re ahead of where we thought we might be at this point in the afternoon. Let’s take a break, then, break until three and then we’ll see if we have, are David Cavenaugh, Andrew Sperling here? So we can proceed at three maybe just to go on with other comments, okay, and take a break. All right. Let’s convene again at three.
[Break.]
Dr. Mullin: If folks could have a seat, then we can get started on our general comments section, our last session of our public meeting today. And I hope the folks that are on our list here, I know some of them at least are here already, and hopefully everyone is here who wanted to speak in this last session.
Our first speaker is David Cavenaugh. David is with the Committee of 10,000, and he will be with us in a moment.
Mr. Cavenaugh: Thank you. The Committee of 10,000 considers the Prescription Drug User Fee Act contrary to protection of the public health. It is bad policy introduced at a historical time when many Americans are clamoring for drugs to combat the growing AIDS epidemic.
For those whose goal is the accelerated approval of AIDS drugs, it provided a format for expedited approvals. For those whose goal is less FDA regulation and increased industry influence and control, however, it has been the perfect vehicle for compromising the very mission of the Food and Drug Administration.
With the adoption of PDUFA, Congress became the agent for this destruction. No longer would FDA function as the watchdog of our citizens' safety. After passage of PDUFA, they became the paid consultants of the pharmaceutical industry, the technocrats of fast track.
At bottom, PDUFA turned control of the Food and Drug Administration's finances over to the pharmaceutical industry, protest not withstanding. Dr. Sidney Wolf of Public Citizen has said it succinctly recently, quote “the public is getting the kind of FDA that the industry is paying for them to get.”
The biggest unintended consequence of the change in the source of funding is the relative poverty into which other regularly appropriated FDA programs have comparatively sunk. This is why MDUFA was passed several years ago to allow the Center for Devices and Radiological Health to boost its device applications review process.
However, the worst damage is in the FDA programs in the Center for Drug Evaluation and Review itself because other programs have atrophied under the reign of PDUFA.
PDUFA ensured the phase IV post-market surveillance studies stood no chance of being mandated or adequately funded. The FDA does not currently have the authority to require phase IV post-market studies. They can ask, and they frequently do ask, however there exists no direct enforcement vehicle for ensuring compliance by drug manufacturers. The agency is wholly dependent on the science generated by those who stand to significantly profit from the approval of a given drug, biologic or device. Industry-driven science has wholly replaced good independent FDA-driven research rooted in the public health, not in the profits of large pharmaceuticals.
How can the agency tasked to regulate the pharmaceutical industry simultaneously be dependent on that very industry for its budget and the lion's share of its science. Increasingly, there's on image of Boeing approaching FAA to pay for receiving its airworthiness certificate on its latest airliner. It doesn't fit. I wouldn't ride in that plane.
It is nothing less than a prescription for disaster. We in the hemophiliac community, the canaries in the coal mine, are the early warning system for this nation's blood supply, have already suffered through two nightmares, HCV and HIV. Both were, in part, driven by conflict of interest and the complete lack of post-market surveillance. For us acceptable safety margins can only be attained in the context of a fiercely independent Food and Drug Administration fully funded, generating its own science, and tracking drugs, biologics and devices already in the market pipeline.
Our organization represents persons with hemophilia who were infected with HIV and hepatitis C in the '70s and '80s when the United States blood supply was contaminated with these viruses. Industry has paid $650 million to our families in recognition of their failure to rapidly begin a standard program to screen potentially infected donors, and their failure to use adequate available processes in the manufacture of blood products to eliminate such viruses.
FDA's lack of oversight in this period, when entire lots of factor concentrates suspected of being infected were nevertheless approved for sale, was unconscionable. Moreover FDA allowed industry to depleted existing stocks of potentially infected product for sale and infusion by members of our families before using newly processed product free of infection.
In recognition of these shortcomings by its regulatory agency, the federal government paid another $650 million to our families. One point three billion dollars brought back none of our children.
Our organization's name derives from estimates that our community was approximately 20,000 strong in 1980. Approximately one half contracted HIV. Even more contracted HCV, hepatitis. Few such individuals are still with us.
In the 1980s and early '90s, the AIDS community of which we count ourselves a member, was active in efforts to encourage FDA to create a fast track for AIDS drug review. However, we're cut different from the majority of groups calling for fast-track AIDS drugs because of our call for post-market surveillance as a critical component of any initiative to expedite the approval process.
Given the AIDS blood epidemic, we in hemophilia intimately understood the need for serious tracking of approved drugs, especially drugs approved on a fast track. Considering the years since the advent of the virus on our shores in the 1980s, and the little done in research or drug development at that time, there was a crying need for FDA-approved medications for a population that to this point merely had had a death sentence over its head. However, we certainly never supported fast track becoming the new methodology for all drugs.
When AZT was found effective under Protocol 019 in 1988, the door began to open. Only six years later, a combination of therapies was available that increased the lifespan and quality of life for those afflicted with HIV/AIDS.
But FDA continued to use fast track with little post-market surveillance, and recipients of many such approved medications were thankful and became natural protectors of the fast-track process.
Unfortunately, in the same time period, with the influx of a new conservative majority in Congress, the idea of speeding drug reviews by requiring applicants to pay for their review was made part of their platform, and in the name of the same fast review as the AIDS community had requested, it became law. Republican governments since that time have routinely reauthorized the process, which has, over fifteen fiscal years, allowed the need for appropriated funds for FDA new drug review to atrophy completely.
The FDA still relies on promises. When a drug is approved, the developer is told of the conditions for approval, for example, manufacturing parameters as well as dosing limitations.
When trial data or other information suggest the potential for harmful effects not seen in the required pre-approval clinical trials, the developer is asked to do post-market surveillance studies. If it not agreed, approval would be denied, so of course all agree or promise to spend the additional funds to conduct large-scale, carefully designed phase IV trials with a large enough end and and a long enough duration to identify any less prevalent harmful effects.
FDA reports annually on how many of these promised studies have been even started. As you've heard earlier today, the average is one third or less.
The current situation is a circus. Only in recent years have efforts begun in Congress as well as FDA to restructure the agency to get back to its job of regulating.
For our part, we oppose PDUFA and will work to see that these proposals included terminating it and finding dollars to put new drug approval back into the FDA's annual appropriations.
Thank you.
Dr. Mullin: Okay, thank you David. Our next speaker is Andrew Sperling, director of the legislative advocacy National Alliance on Mental Illness.
Mr. Sperling: Thank you. I know the hour's late and I know all of you have been up there all day, so I'll be as brief as I possibly can.
I'm Andrew Sperling and I'm director of legislative advocacy at NAMI, the National Alliance on Mental Illness. NAMI is the largest patient advocacy organization in the field of psychiatric medicine with 210,000 members and 12,000 affiliates in all fifty states. We represent people with severe mental illness, schizophrenia, bipolar disorder, major depression and severe anxiety disorders, and their families.
At NAMI, we have always placed the highest value on scientific advance and new treatments. The last twenty years have seen a little revolution in effective treatments for severe mental illness, and have really made the promise of recovery available for more patients and consumers than we ever thought possible. But we're not where we need to be, not by far.
Many of the treatments, as effective as they are, are still only palliative for illness such as schizophrenia and bipolar disorder. NAMI believes we need a new scientific revolution to reach toward a cure for these dread diseases.
The public health burden associated with untreated mental illness is enormous to our society, estimated as high as $80 to $85 billion in terms of lost productivity, lost lives, homelessness, criminalization -- burden on the criminal justice system, and effective treatments can help relieve that burden on our society.
NAMI has a strong interest in this PDUFA agreement, and we support it. We believe this PDUFA agreement can bring the FDA toward where it needs to be, a well-resourced organization with modern information technology systems that really meets five -- six of the important goals articulated in this agreement.
Number one, an FDA that engages in effective pre-market review.
Number two, an FDA that fosters expedited drug development.
Number three, an FDA that is making rapid progress toward fully automated drug review systems.
Number four, an FDA with a transformed post-market drug safety system in place. It's critical that the resources are there to address the increase in volume of adverse events reports, and the resources to examine post-market safety beyond the current three year window.
Number five, we need an FDA with full funding and staffing for the Critical Path Initiative. The reference to Critical Path in PDUFA IV is something that NAMI strongly supports. It's a first step. More is needed for that gulf that exists there between the laboratory and bringing products to market so the new products can reach people that need need them.
A few final observations.
Number one, NAMI believes and agrees, I think, with the testimony, I believe, offered from many of the witnesses today that there's wide agreement that FDA has been hampered by a lack of staff and a lack of funds. This is in part due to the infringement on overall discretionary spending at the federal level.
We've seen it in other areas of public health, certainly with the NIH that went through a doubling between 1997 and 2002, and since 2002 has seen those levels -- that funding for NIH level off to the point where it's not keeping pace with the cost of doing research. We don't want to see FDA end up in a situation where those appropriated funds remain flat, but for the time being, given the imposition of what are called PAYGO rules at the federal level it's unlikely that that Congressional appropriation is going to go up substantially in the next few years, which is why this PDUFA agreement becomes all the more important to make sure FDA's resourced in the way it needs to be.
Second, NAMI would observe that PDUFA has succeeded in expediting the drug review process. What was once a process that took three to four years has been reduced to less than a year in most cases. That is why NAMI supports this PDUFA IV agreement.
NAMI would also observe that patients understand, NAMI members understand that there always inherent risks with every drug. Nothing is going to be 100-percent safe and effective. What patients want, what NAMI members want, and our family members want is the ability to have access to a variety of treatment options, the full array of treatment options, and a clear understanding of the risks and benefits associated with each of those, and to make the decision in consultation with their physician.
Finally, NAMI would observe that delays in the reauthorization process of this PDUFA agreement could be catastrophic and derail many current drug reviews underway. NAMI's concerned about the impact failure to rapidly reauthorize PDUFA in Congress could have on the morale of the staff of the agency knowing in just a few months that we could have actual RIFs put in place. The process of reduction in force is not the way to go, and Congress needs to rapidly and expeditiously reauthorize and pass this PDUFA IV agreement.
Thank you very much.
Dr. Mullin: Thank you Andrew. Our next speaker Ellen Liversidge. Am I saying that right? Good. The Alliance for Human Research Protection.
Ms. Liversidge: Good afternoon. I'm glad there's still an audience here. My name is Ellen Liversidge from Silver Spring, Maryland. I'm a member of the Alliance for Human Research Protection, and I'm also the mother of beautiful son, Rob, who died on October 5, 2002, two years after being put on Zyprexa at the suggestion of Maryland Medicaid. He gained 100 pounds, fell into a coma and died of profound hyperglycemia. I also represent many friends who have lost their children to psychotropic drugs who live all around the country and are unable to be here today.
On behalf of my friends and myself, I would like to come right to the point. We do not approve the FDA taking a dime of pharmaceutical money to do any drug safety activities. We see this possibility as that of letting the fox into the hen house. There are always strings attached to money and there are already too many strings attached to the money PhRMA currently gives to the FDA for drug approval activities.
The money and the regulatory power that goes with it for improvement of FDA's practically defunct drug safety activities must come from Congress. Since the Democrats took over, there are finally already two bills in the works for this, the Grassley-Dodd-Mikulski and Bingaman bill and the Kennedy-Enzi bill.
In addition, various Congressional committees are examining the work of the FDA and its relationship to PhRMA. Representative Dingle's Committee on Energy and Commerce met about this just the other day, and talked to Dr. David Graham.
I see the scheme of taking PhRMA money to help with drug safety as a smoke screen -- a way to say to Congress, “See, we are already busy working on this, and trying to do what the Institute of Medicine said we should be doing.” And I do not think it should fly.
The material handed out by the FDA about this possibility stated that various consumer groups thought it was a good idea. I would be very interested to know what consumer groups these were. No one asked me. No one asked your harshest constituency, the families of the dead.
The Institute of Medicine report was correct. Drug safety at the FDA has nowhere to go but up. I know this first hand. I learned why my son died from Public Citizen. Just as I learned that in 2001 one of your colleagues and Dr. Doris Zwami [ph] from Duke studied you MedWatch for Zyprexa and found 23 deaths. I found that Japan and the UK required warning labels on Zyprexa in spring of 2002. The FDA did nothing. I earnestly filled out a MedWatch report about my son's death. I got no response.
Excuse me.
In the spring of 2003, I was able to get a front-page story in the Baltimore Sun about the dangers of Zyprexa. Right after that there front-page stories in the Wall Street Journal and the New York times. There was no response from the FDA, only a remark that you were looking at all the atypicals to see if there might be a problem. However, I did hear that you were embarrassed that these stories were coming out and I did hear that Lilly was worried.
Finally, instead of immediately acting on Zyprexa, at the end of 2003, you told all of the atypical antipsychotics to place a warning. Two of them had hardly been out on the market. In taking this terribly belated action, the proven lethal nature of Zyprexa was hidden in amongst the rest.
To finish the Zyprexa lack of action, other than a black box for dementia, an off-label use for all atypicals, you have done nothing.
Twenty-six thousand plaintiffs have settled with Lilly with more to come. You have done nothing. Two million children are taking off-label atypical antipsychotics. The FDA has not said a word.
And finally, revealing stories in the New York Times that came out in December, written by Alex Berenson, show that Lilly knew before the drug even came out in 1996 that the drug had lethal side effects -- diabetes, hyperglycemia and death. Nothing happened.
I would say that drug safety at the FDA based on this little sample of one drug is a dead letter. It is not a letter that should be read by PhRMA. The FDA must remember that it is the regulator, not the friend of PhRMA. It must remember that people like my friends and myself are still waiting for justice. So far there is no justice.
I urge you to drop this idea and wait for Congress to take its rightful actions, actions that were not taken during a Republican-led Congress. Nothing happened when the Republicans led Congress.
Senator Grassley put a bill into the Senate Health Committee and it sat in a drawer. Never came out of committee. It's looking a little better now. And I think we need to trust in Congress and not trust in PhRMA. Sorry.
Thank you.
Dr. Mullin: Thank you Ellen. Our next speaker is Diana Zuckerman. Is Diana here? I might be too early. She might think that we're having this session a little bit later. Wilson Decamp. Wilson, do you want to come provide your remarks?
Mr. Decamp: Thank you. I'll try to be very brief. I'm a former review chemist and team leader at FDA. I'm from Leesburg, Virginia, so I'm relatively local, and shortly after my retirement from FDA, I was diagnosed with Parkinson's disease.
I'd like to direct your attention and your recollection to the comments of Amy Comstock earlier this afternoon. She mentioned a product that had been terminated in phase II trial, that they have great concern about at PAN. I'm familiar with the details of that, having heard it at the PAN forum earlier this week. I also heard there of one particular event that occurred just recently when a patient in a clinical trial of this product died and was autopsied, and the brain tissue from that autopsy showed for the first time evidence of neuronal regrowth in the area of the brain that produces dopamine. In other words, this is the first indication of any sort of the possibility that dopamine-producing neurons could regenerate.
Now why am I mentioning this. As a reviewer at FDA, I knew perfectly well that the major concerns during the investigational stage were safety. Whether the -- despite the comments today, I think the FDA has been very appropriate in their concerns with safety. A single report of a risk in an IND can result on the IND being placed on clinical hold. However, I know of no regulation that requires the reporting of an event that may alter the agency's perception of the potential for a drug -- for the curative potential for that drug.
In a case such of this, should there not be a regulatory requirement, a procedural requirement that a company immediately advise FDA of events that may alter the FDA assumption of a priority for that particular product.
So having said that, I will thank you for your attention. Thank you very much.
Dr. Mullin: Thank you Wilson. Do we have any other people here who'd like to make comments about, you know, PDUFA IV, or other aspects of PDUFA, and, or FDA more generally? I think there's only one person who we had registered who isn't here, so I think that that pretty much would then otherwise, if not, conclude our meeting. And just in terms of closing, I want to thank you all for coming to this meeting and staying here with us, and listening to the input that we've received from all of our stakeholders and the comments that we've gotten. Thank you for reviewing the proposed recommendations that we had published in the Federal Register, listening to our presentations this morning, and providing us with your very thoughtful comments and your concerns about the program. We've had a number of people here from my office and other parts of FDA who've been taking notes to make sure we've captured everything that we've heard. Our next steps on this include waiting for our docket to close. The docket for written comments will remain open for another week, so you could submit written comments if you want to do that, up through next Friday, February 23rd. Following that, we will take the comments that we heard today and those written comments and we will be summarizing them, analyzing what we have heard to understand what impact it would have, and how they might affect the proposed regulations that we would want to take forward. FDA would basically review that information, have discussions, and take that forward to the Secretary and department, and from there the department will determine how they want to proceed, taking it forward to Congress, and that will then be our more formal and official recommendations for PDUFA IV that would go to Congress. And we would try to finish our process here by, you know, end of February, beginning of March, in that time frame in order to be in the spirit and keep -- do our part to help facilitate timely discussion of this, and timely reauthorization.
So thank you so much for your comments, and for coming here today.
[Whereupon, at 3:30 p.m. the hearing adjourned.]