> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> PUBLIC MEETING:
>
> PRESCRIPTION DRUG USER FEE ACT
>
> (PDUFA)
>
> 9:07 a.m. to 2:36 p.m.
>
> Friday, December 7, 2001
>
> Hyatt Regency
>
> Bethesda, Maryland
>
> **C O N T E N T S**
>
> [Page]{.underline}
>
> [Introduction]{.underline}
>
> **Mark Barnett**, Moderator 4
>
> [Opening]{.underline}
>
> **Linda Suydam**, Senior Associate
>
> Commissioner, FDA 9
>
> [Panel I - Public Health]{.underline}
>
> **Kathy Zoon**, Director
>
> Center for Biologics Evaluation and
>
> Research, FDA 15
>
> **Travis Plunkett**, Legislative Director
>
> Consumer Federation of America 20
>
> **Susan Winckler**, Director, Policy and
>
> Legislation American Pharmaceutical
>
> Association (APhA) 27
>
> **Amy Allina**, National Women\'s Health
>
> Network 37
>
> **Richard Levinson**, Associate Director
>
> of Policy American Public Health
>
> Association 44
>
> [Panel II - Post Market]{.underline}
>
> **Janet Woodcock**, Director
>
> Center for Drug Evaluation and
>
> Research, FDA 61
>
> **Robert Griffin**, Associate Medical
>
> Director Blue Cross/Blue Shield of
>
> Vermont 71
>
> **Diana Zuckerman**, President, National
>
> Center for Policy Research for Women
>
> and Families 82
>
> **Jeff Bloom**, Patient and Consumer Coalition 93
>
> **Judy Cahill**, Academy of Managed Care
>
> Pharmacy 104
>
> [Panel III - Finance]{.underline}
>
> **Theresa Mullin**, Associate Commissioner
>
> Office of Planning, FDA 140
>
> [Panel III - Finance]{.underline} (Continued)
>
> **Mary Rouleau**, Deputy Legislative
>
> Director, UAW 147
>
> **Sharon Levine**, Associate Medical
>
> Director Permanente Medical Group
>
> (RxHealthValue) 156
>
> **Diane Dorman**, Senior Director of
>
> Public Policy National Organization
>
> for Rare Disorders 166
>
> **Mike Warner**, Biotechnology Industry
>
> Organization 175
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> \[9:07 a.m.\]
>
> **Introduction**
>
> MR. BARNETT: I want to welcome you to this public meeting on the
> Prescription Drug User Fee Act, or PDUFA as we have come to call it. I
> am Mark Barnett with the FDA, and I will be serving as your moderator
> today.
>
> As we all know, PDUFA authorizes the FDA to collect fees from
> manufacturers to help offset the cost of reviewing applications for
> new drugs and biologics, and you know that PDUFA is scheduled to
> expire September of 2002. Well before that happens, the FDA wants to
> take into account the views of its various stakeholders, that is, the
> people and the organizations that are going to be affected by this
> legislation. Of course, that includes manufacturers, health
> professionals, provide organizations, patients, and consumer groups,
> and, of course, that is what this meeting is all about.
>
> Actually, this meeting is a continuation of a meeting we had last
> September, a similar meeting, and they have one thing in common, and
> that is that this is a listening meeting for the FDA. We are here to
> hear your views about PDUFA.
>
> The difference between last year\'s meeting and this one is that this
> year we are in a position to be a little more specific in presenting
> to you both the successes we have experienced with PDUFA and some of
> the new challenges that we are going to be facing in the future. So
> what we need from you is, in a sense, your perspective on PDUFA, how
> you think it has worked so far, what you would recommend for the
> future, your reactions to the program, how you think we should deal
> with some of the new challenges you are going to be hearing about, and
> whether PDUFA, in fact, has fulfilled your expectations for the
> legislation, and if not, why not.
>
> We are going to elicit that information through a series of three
> panel sessions, each of them with several speakers. Each panel is
> going to include a range of perspectives. There will be the FDA,
> patients, consumer protection groups, health professionals, and
> provider organizations. In each of the panels, we are going to have
> the FDA speaker lead off and give some perspective on the agency\'s
> experience and assessment of the issues that are being faced by that
> panel, and then we will hear from the various panel members.
>
> Since we want to hear from as broad a spectrum of stakeholders as
> possible and not just the panelists, we are going to open the floor
> after each panel to an open discussion in which people from the
> audience can comment on what they heard during that panel, and the
> ground rule is that we will limit those comments and questions to what
> it was that the panel was discussion. If you have questions or
> comments on PDUFA not covered by the panels, we will leave time for
> that at the end.
>
> When it comes to questions and comments from the audience, I wanted to
> mention that we cannot give you FDA positions on a given issue
> because, in fact, we are in the process of formulating those
> positions. So, if you ask us about that sort of thing, that should not
> be a great drawback because, in fact, this meeting is not for you to
> hear from us, but from us to hear from you.
>
> As you know from the Federal Register notice, the panels were asked to
> consider three questions.
>
> The first panel is going to consider public health outcome; that is,
> has PDUFA supported the FDA\'s mission to protect and promote the
> public health and what in the program should be retained and changed
> as we think about the future.
>
> The second panel is going to be talking about the post-market
> question; that is, should PDUFA permit user fee funds to be used to
> monitor the safety of a new drug or a biologic after it is approved.
>
> The third panel is going to talk about funding; that is, how can the
> FDA ensure that PDUFA goals are being met during an era when the
> continues to be a funding shortfall, if the funding shortfall
> continues, what is to be done about it, how do we set review
> priorities, and if so, how do we do it, should there be flexibility in
> setting up user fees in order to cover whatever increased costs we
> encounter.
>
> At the close of the last panel, in addition to hearing from the
> audience about the issues of that panel, we are going to also hear
> from a few individuals or organizations who have signed up in advance
> to make comments, and at that point, I will also open it to the floor
> for PDUFA questions not covered by the panel.
>
> So we have a full program today, and in order to make sure that
> everybody gets a chance to speak, including members of the audience, I
> am going to limit each of the speakers to 10 minutes. When there are 2
> minutes to go, I will give an oral warning, and then we will cut it
> off at the 10-minute mark. I think everybody understands that in
> advance.
>
> One of the things that everybody is reminded at a meeting like this is
> what is going to happen with the information. I mean, you are hearing
> it, but are you really listening, and are you going to do anything
> about, and the answer to that is yes. The FDA takes these meetings
> seriously, and we will, in fact, consider everything we hear today as
> we formulate a position.
>
> In thinking about listening, I saw a cartoon in this week\'s New
> Yorker last night. A man is on a couch, a book in his lap, and the TV
> is on. His wife is sitting next to him, apparently trying to get his
> attention. In the caption, he says, \"Of course, I am listening. I am
> in a state of heightened alert,\" so a sign of the times. But we are
> listening, and that is the message.
>
> On that positive note, let me introduce Dr. Linda Suydam, FDA\'s
> senior associate commissioner for Communications and Constituent
> Relations.
>
> Dr. Suydam is going to give us a general overview of the PDUFA
> program, how it works, what it is supposed to accomplish, and what we
> have learned over the past year in implementing PDUFA as we prepare
> for reauthorization. She is going to give us an overview of the steps
> that the FDA is going to take between now and next September as
> Congress considers reauthorizing PDUFA.
>
> Linda?
>
> **Opening**
>
> DR. SUYDAM: Thank you, Mark.
>
> First of all, thank you and welcome to all of you. We really
> appreciate this opportunity to meet with people and hear about your
> views related to the Prescription Drug User Fee program.
>
> Our consultation with stakeholders is, in fact, critical to the work
> that the FDA does. Even prior to the passage of FDAMA, we worked very
> hard to make sure that we heard from people across the spectrum of all
> of the groups that have actually an interest in FDA. It is central to
> our public health mission, and it is really essential to meeting the
> goals of the agency.
>
> FDA is no different than any other large organization in that getting
> results means that we need to keep thinking differently. We need to
> reexamine what we are doing, how we are doing it, and making sure that
> we are meeting all of the needs that we need to meet as an
> organization.
>
> In our case, that means we have a lot of change in what we do.
> Products we regulate continue to become more complex. There are
> scientific advancements and uncertainties. Always, there is new
> knowledge, new expectations, and new standards. Obviously, there are
> altered national priorities, and I think after September 11th, it is
> very clear that our priorities have changed. All of a sudden,
> \"bioterrorism,\" \"counterterrorism,\" and \"antiterrorism\" have
> become words that the FDA needs to know and act on and be a part of,
> and the programs we have in that area did not exist in any great
> extent prior to September 11th.
>
> PDUFA has evolved as well as the agency. Ten years ago, PDUFA was
> established, and the promise of it was to assure timeliness and to
> assure access of patients to new products.
>
> Recently, the goal for PDUFA has been stability, and 10 years from
> now, who knows what that goal will be? But we certainly how that,
> today, we can begin to capture what are some of the future needs for
> the PDUFA program.
>
> As Mark said, we have 10 months remaining before the PDUFA program
> expires, and that is really scary to a lot of us in the agency because
> there is a lot to be done. As you can see, we had our first public
> meeting in September. We have had ongoing discussions with
> stakeholders. We had three smaller meetings in the last couple of
> months. We hope this will be our final public meeting today. We are
> looking at developing options and formulating positions. Obviously, we
> have to have draft legislative language. There have to be hearings in
> both the House and Senate. There needs to be markup and amendments,
> floor debates, and conference. We need to go through the entire
> legislative process, and the President needs to sign the bill by
> October 1st of 2002.
>
> In prior years, we always had a carryover of money. This year, we will
> not, and so the program is in such precarious financial shape that we
> must have it reauthorized by October 1st of 2002.
>
> Let me talk a little bit about what we heard at the public meeting in
> September of 2000. I think there was some general agreement that
> resources are key to the performance of this program, and we have
> proven that when we are well-resourced, we can do the job. We can do
> what is expected of us and meet the goals, but we also discovered that
> our non-PDUFA responsibilities are vital. We have had a difficult time
> in the last 10 years in budgets, and as a result, our non-PDUFA
> responsibilities are not as robust or healthy as they should be.
>
> There were also divergent opinions expressed. Many people felt that
> the appropriation of the fees could, in fact, provide some conflict to
> the agency, could perhaps make us more biased than we would be, and
> that, in fact, Congress ought to be appropriating the dollars to fully
> fund the FDA.
>
> There was also some debate on performance goals and what they meant,
> and those performance goals relate to accountability, predictability,
> and establishing goals. The problems with performance goals is
> sometimes they were met and perhaps that wasn\'t exactly what needed
> to be done. So we are dealing with the performance goals as an issue.
>
> Finally, should there be fees for other safety functions, for
> functions that are related to pre-market review, such as post-market
> surveillance and advertising?
>
> As Mark said, today\'s meeting is going to focus on three topics.
>
> Public health. Has PDUFA supported FDA\'s public health mission, and
> what are you ideas for changes or enhancements to that mission and to
> the program?
>
> Post-market safety. Should fees be used to monitor safety after new
> drugs and biologics are approved? We want your thoughts on that.
>
> Funding. How can FDA ensure that this program remains viable when
> funds are clearly short? What suggestions do you have for how we can
> maintain the viability of this program?
>
> So, today, let\'s draw on our experiences with PDUFA I and II, and
> let\'s look at the new knowledge we have gained in science, medicine,
> and public health, and then work on the best way we can apply our
> resources to the common good. Together, as a group, we can help shape
> PDUFA III.
>
> Public health outcomes have been tremendous. The real question is can
> we keep that going. Post-market safety is more significant than it was
> in the last 10 years. Can it be addressed more directly? PDUFA is a
> financially fragile program. Can we add assurances for its financial
> viability in the future?
>
> Thank you.
>
> MR. BARNETT: Thank you, Linda.
>
> **Panel I - Public Health**
>
> MR. BARNETT: Let me now ask Panel I to come up and sit over here at
> the other table.
>
> While they do that, let me give you a little housekeeping hint. There
> is a message board outside the room, over at the far end of the room,
> which you will see up on an easel. So you can look for messages up
> there.
>
> \[Pause.\]
>
> MR. BARNETT: If this is right, in addition to Dr. Zoon who is going to
> be our FDA representative, we have Travis Plunkett who is legislative
> director for the Consumer Federation of America, Susan Winckler who is
> director of Police and Legislation for the American Pharmaceutical
> Association, Amy Allina who is with the National Women\'s Health
> Network, and Richard Levinson who is associate director for policy of
> the American Public Health Association.
>
> So let\'s lead off with Dr. Zoon.
>
> DR. ZOON: Good morning. It is a pleasure to have an opportunity to
> participate in this panel that is going to address the public health
> benefits and outcomes of PDUFA. This is obviously an area of great
> importance to all of us, and, certainly, the FDA is very much engaged
> in our assessments of this.
>
> The PDUFA program, or the Prescription Drug User Fee program, was
> initiated with two primary goals in mind, one, to reduce the time
> required for FDA review of new drug and biological product
> applications and to, thereby, enable patients to have earlier access
> to therapies and vaccines. This program provided additive resources to
> the FDA, review staff, and systems, particularly information systems,
> that have allowed us to expedite reviews of important new products.
>
> When we talked about the success of PDUFA, we often go on to talk
> about meeting our performance goals of the program and the resulting
> reductions in the average time to approval for new drugs and
> biologicals. Today, I would like to say more about the drugs and
> biologics that we have been referring to because these are really the
> outcome that provide to the public the treatments and the vaccines to
> improve the health of our country.
>
> These products touch patients across a wide spectrum of diseases,
> everything from cancer to infectious diseases. Some have helped to
> expand the options available to the medical community in treating
> patients that they serve. Others have provided therapies that have
> literally saved lives.
>
> To date, 712 products have been approved under the Prescription Drug
> User Fee program. 198 are considered significant therapeutic
> advancements and have undergone priority review. They include 30
> products for cancer, 37 products for AIDS, 29 products to fight
> infections, and 47 products to treat cardiovascular diseases.
> Ninety-five of the priority product approvals were used for new
> treatments. These are what we call often \"new molecular entities\"
> for conditions ranging from rheumatoid arthritis to sepsis.
>
> With the priority review under the Prescription Drug User Fee Act,
> literally thousands of cancer patients have had earlier access to new
> cancer treatments. This, in turn, extended many cancer patients\'
> lives or improved the quality of their life.
>
> One example is a new biologic for the treatment of breast cancer,
> Herceptin, which was approved by the FDA in less than 5 months. This
> drug too 18 months to be approved in Europe. There was an estimated
> 10,000 American patients with advanced breast cancer who received this
> new treatment during the time that FDA might have still been reviewing
> the application, had it not been for the improvements made with
> additional funds under PDUFA. This added about 2,300 years of life to
> the population who had access to this new treatment following its
> marketing approval in May of 1998. This is a significant impact on
> women with breast cancer.
>
> Other life-saving therapies were also reviewed in less time than
> comparable drugs prior to PDUFA. Earlier access to a new drug for
> congestive heart failure is estimated to have prevented up to 2,800
> deaths. With other new treatments, the earlier approval has helped
> thousands of patients to avoid significant sickness and
> hospitalization. For example, earlier access to new treatment for
> osteoporosis is estimated to have prevented as many as 3,000 fractures
> among women who received this drug following its approval in the
> United States.
>
> Many reviews of important products with pediatric indications have
> also benefitted from the resources provided from PDUFA. The faster
> review and earlier approval of a new vaccine, Prevnar, for
> life-threatening infections in children allowed earlier access of this
> vaccine and prevented an estimated 14,000 cases of serious infections
> in infants and young children.
>
> Other important approvals of pediatric medicines include the first
> inhaled corticosteroid for children with asthma, a new treatment for
> newborn infants with respiratory failure, that helps increase the
> oxygen in blood and reduces the need for heart-lung bypass.
>
> Recently, a new recombinant activated protein C has been approved for
> the reduction of mortality in patients with severe sepsis and who are
> at high risk of death, and a new breakthrough treatment for children
> with rheumatoid arthritis and a Pegylated Interferon for hepatitis C.
>
> In summary, we think the additive resources of PDUFA have played an
> important role in helping FDA achieve its goal of increasing patient
> access to safe and effective new medicines. It has made a very big
> difference in the lives of many patients.
>
> With all of these many important parts of the program, the impact, I
> believe, has been very significant on public health. While we have
> been, and continue to be, supportive of this PDUFA program, one must
> look at the challenges, and some of those will be discussed later with
> respect to the post-marketing and the financial issues, but, all in
> all, this program has been an important part of our program and, we
> believe, has had a major public health benefit.
>
> Looking at the FDA\'s program, probably one of our significant
> challenges has been during the time while we have had additive
> resources to PDUFA. In fact, until this year, we had not received
> cost-of-living for the agency to our base activities, and this has put
> a lot of stress on our non-PDUFA programs. And that raises a concern
> from a public health point of view that I think we need to address.
>
> In closing, I would just like to say, we look forward to the
> reauthorization of PDUFA, and we would very much like to hear your
> views on this program. We have two main questions for you today: one,
> in your view, has PDUFA supported FDA\'s mission to protect and to
> promote the public health; and, two, as we consider the potential
> shape of a PDUFA III, what should be retained or changed to enhance
> the program and to ensure a good public health outcome.
>
> Thank you.
>
> MR. BARNETT: Thank you.
>
> I am going to call on the panelists in the same order they are on the
> agenda. So our next speaker will be Travis Plunkett from the Consumer
> Federation of America.
>
> MR. PLUNKETT: Good morning. Thank you, Dr. Zoon, and thanks to the FDA
> for holding this public meeting.
>
> My name is Travis Plunkett, and I am the legislative director with the
> Consumer Federation of America. CFA has worked with the Patient and
> Consumer Coalition regarding renewal of PDUFA in 1997 and will be
> working hard with the FDA and the Patient and Consumer Coalition on
> Capitol Hill regarding reauthorization next year.
>
> I want to start by thanking the FDA for your consistent efforts over
> the last year to reach out to the public, to patients, to consumers,
> about reauthorization of PDUFA next year. You have done an excellent
> job, and we very much appreciate the opportunity to offer our
> comments.
>
> To the first question, has PDUFA supported the FDA\'s mission to
> protect and promote the public health, well, if success is measured by
> the goals mandated in the \'97 act, the answer is a resounding yes.
> The time for approval of new drugs declined from a median of slightly
> less than 2 years in 1992 to less than 1 year in 2000. It is now at
> about 15 months. A higher percentage of applications are now being
> approved as well.
>
> Clearly, there are very important public health benefits\--and Dr.
> Zoon has outlined some of them\--to be gained from faster approval of
> certain new drugs. These include medications that treat serious and
> life-threatening conditions, drugs that provide relief for patients
> with illness or disability refractory to existing therapies, or drugs
> that are less toxic than currently available, but the success of drug
> review and approval should not be measured by speeding approval rates
> alone. That is the major flaw of the \'97 act.
>
> The FDA\'s responsibility under law is obviously to ensure that new
> drugs and devices are safe and effective. If success is measured by a
> more balanced assessment where you weigh the advantages and the
> disadvantages of faster new drug approval, such as the negative public
> health effects of drugs that have harmed or killed Americans and have
> subsequently been withdrawn from the market, there is definitely cause
> for concern or at least further investigation. And if success is
> measured by the draining effect of PDUFA on the FDA\'s ability to
> achieve the rest of its public health mission, a fact that the FDA has
> openly acknowledged and we are going to hear a lot about today, then
> one can only deduce that PDUFA has not provided a net benefit to the
> public health.
>
> Now, the flip side of some of the public health successes that Dr.
> Zoon pointed out is that there has been a going number of recalls and
> warnings related to newly approved drugs, and this has reinforced our
> concern that PDUFA, by providing user fees from a regulated industry
> to the regulator, represents a potential conflict of interest.
>
> The agency has attempted to demonstrate, primarily talking about the
> withdrawal rate of drugs, that there is no relationship between faster
> approval times and more frequent recalls. Twelve prescription drugs
> have been pulled from the U.S. market in the last 4 years for safety
> reasons, by far the most such actions taken in any comparable period.
> Only three of these withdrawn drugs were approved before PDUFA took
> effect in 1993. The most recent withdrawal was the anti-cholesterol
> drug, Bakol, which is implicated in 31 deaths.
>
> Now, according to a Pulitzer Prize-winning investigation by the Los
> Angeles Times, more than 22 million Americans took the drugs that were
> withdrawn prior to Bakol, and I would submit that this is the proper
> way to evaluate public health. It is not what the approval or
> disapproval rate is. It is how many people were affected, what they
> were exposed to, how dangerous the drugs were, and how important
> initially the drugs were for public health; that is, did they provide
> breakthrough therapies, did they provide life-saving potential, or
> were they \"me, toos,\" were they just copies of drugs that are
> already in the market.
>
> To the second question, what should be retained or changed to enhance
> this program, we have a number of suggestions in the written comments
> that I have left for the FDA and should be available on the
> information table.
>
> The best way to ensure the timely approval of safe drugs is to
> adequately fund the FDA from general revenues. Adherence to this
> principle would be the surest way to remove the worrisome potential
> for conflict of interest that arises when dedicated income streams
> flow to the regulator from the regulated.
>
> Congress should also provide additional appropriations for the public
> health functions that are suffering, including post-marketing
> surveillance of drug safety, adverse-event reporting, generic drug
> approval, direct-to-consumer advertising, and food safety.
>
> Secondly, regulated interests should not be allowed to inappropriately
> influence FDA functions through the use of new user fees. This is a
> topic of a lot of conversation right now.
>
> If an unwillingness on Congress\' part to appropriate adequate funds
> leads Congress to consider the expansion of new user fees, it is
> absolutely essential that there be a firewall between these user fees
> and the dispersement of these user fees in the performance by the FDA
> of its mandated responsibilities.
>
> At the State level, utility commissions and insurance departments
> often assess regulated businesses for the cost of oversight. Although
> conflicts of interest sometimes occur at these agencies, this approach
> gives the regulated industry far less control over the priorities of
> the agency in the manner in which success or failure is measured than
> a dedicated funding stream like PDUFA user fees.
>
> Third, the PDUFA performance goals really need to be overhauled. There
> is absolutely nothing wrong with a Federal agency using performance
> goals as an internal management tool to achieve its public health
> goals, to hold its employees accountable to measurable standards, and
> to better serve the public. That is very good. However, the
> performance goals in PDUFA II have become far more than a management
> tool. They have given a regulated industry inappropriate and
> potentially dangerous control over the functions of the regulator.
>
> I lay out in my written comments three principles for overhauling
> these performance goals.
>
> First, public health should be paramount. Medical officers and
> scientists, not one-size-fits-all deadlines that are rigidly
> interpreted, should determine the speed of new drug approval.
>
> Secondly, the FDA has to be given meaningful flexibility to implement
> these performance goals. One way to do that is to write into the
> statute an override clause that says that any scientist or medical
> officer with the power to make this decision can slow down the
> approval process if public health concerns exist, without facing
> censure by the agency.
>
> The third principle for overhauling performance goals should allow for
> greater differentiation within the standard and priority review
> categories. This would allow the agency to put the approval of drugs
> that are not breakthrough or life-saving therapies on the back burner
> if conditions warrant; for instance, if a national emergency arises,
> as we have now.
>
> So, in conclusion, thank you very much, again, for reaching out to the
> public so well on this issue, and I look forward to working with all
> of you to get a good statute on the books next year that protects the
> American people.
>
> MR. BARNETT: Thank you.
>
> Before we go on, let me ask whether the FDA panelists have a comment,
> a brief comment to make on Mr. Plunkett\'s remarks. Anyone?
>
> DR. SUYDAM: No.
>
> MR. BARNETT: All right. Let\'s go on, then, to Susan Winckler.
>
> MS. WINCKLER: Good morning. As we noted, I am Susan Winckler. I am a
> pharmacist and an attorney with the American Pharmaceutical
> Association, which is a group founded in 1852 that represents
> pharmacists in all practice settings.
>
> With that, our members, pharmacists, rely on a credible drug review
> process by the FDA, and this morning, as part of this panel, I will
> talk about whether the PDUFA program has supported the agency\'s
> mission to protect the public health and how PDUFA could be enhanced.
>
> If we talk about a public health goal in one context, I think we can
> argue that PDUFA has helped meet that goal, and that is by promptly
> and efficiently reviewing clinical research. Through that new drug
> review process, the agency reviews and, when appropriate, approves
> those new and beneficial therapies.
>
> Prescription drugs can be a valuable tool in the prevention and
> management of chronic illness and disease when they are used
> correctly, and pharmacists certainly look to the FDA to ensure that
> new medications are only brought to the market upon completion of a
> comprehensive high-quality review.
>
> Obviously, the revenue generated by the PDUFA program has allowed the
> agency to increase staffing levels and enhance the resources allocated
> to the application process for human drug and biologic products.
>
> You have the statistics before you, and the assessment of those
> statistics is that the increased level of resources has clearly
> improved the time required for agency decision. However, it appears
> that we have a problem in that due to an increase in the number of new
> drug applications, the increasingly stringent annual review goals from
> PDUFA and funding levels that were lower than anticipated, it has been
> increasingly difficult for the agency to achieve a prompt review of
> new drugs.
>
> It is evident that the amount of revenue generated by PDUFA fees is
> not adequate for the agency to maintain its shortened review times and
> meet the increasingly stringent performance goals. Importantly, fees
> alone are not the answer and should not be perceived as the answer
> here. They are a very important portion, but we also have to look to
> sufficient appropriations, and I think that has been lost in some of
> the discussions with PDUFA and understanding that we need accompanying
> appropriations as well.
>
> It is unacceptable that funding for a program as important as our drug
> review process was insufficient to keep pace with mandatory
> across-the-board pay increases. Additional appropriations must be
> provided to the agency to properly fund vital health programs.
>
> While the PDUFA program has helped the agency meet its mission to
> promptly and efficiently review clinical applications, it appears that
> current levels of funding are not adequate for the FDA to sustain
> these gains and continue to approve drugs efficiently without
> compromising review quality and safety.
>
> Speaking to the issue of how we could enhance PDUFA\--because it is
> working at some point, but we obviously need to deal with the
> appropriations question\--there is also something beyond the new drug
> review process that should be addressed.
>
> The agency\'s work does not end when the drug applications are
> approved. The agency is also responsible for monitoring drug
> performance after approval. The PDUFA program could be enhanced if it
> was expanded to fund other activities related to the overview of
> direct-to-consumer advertising and post-marketing surveillance. Both
> activities are crucial to the agency\'s mission to protect the public
> health by ensuring that drugs are safe and effective.
>
> The PDUFA program does not currently provide funding for the review of
> direct-to-consumer advertising. Oversight of DTC activities should be
> added to the PDUFA-funded scope of work. The prevalence of DTC
> advertising is obvious to any of us watching television or reading
> magazines. A recent survey by the Kaiser Family Foundation found that
> 91 percent of all Americans had seen or heard a DTC advertisement for
> a prescription drug, but the benefits and potential risk of this
> expansion are not so readily observable.
>
> We hope that consumers are retaining adequate information from a DTC
> ad, including a clear understanding of the drugs\' risks and benefits,
> but I do not believe we know that.
>
> Are DTC ads increasing consumer and health professional dialogue? Has
> the explosion of DTC advertising yielded improvement in medication
> use, either through improved compliance or by stimulating consumers to
> seek medical care for untreated conditions? Or, by contrast, has the
> DTC explosion yielded an increase in the casualness with which our
> society treats medication, that there is a tablet to treat everything
> and all I must do is ask my doctor to get it? These questions must be
> answered.
>
> The agency is pursuing an initiative to survey physician and patient
> attitudes toward DTC promotion of prescription drugs. APhA strongly
> recommends that the agency expand that survey beyond physicians to
> include pharmacists and other members of the health care team.
>
> We appreciate the agency\'s efforts to examine the effects of DTC
> advertising on both the public and health care practitioners. An
> assessment of the impact of DTC advertising on medication use,
> including prescribing and patient compliance, is essential. Adding
> such activity to PDUFA-funded activities would be helpful in making
> sure that when we have a drug that is reviewed and subsequently comes
> on the market, we know the impact of this activity known as
> direct-to-consumer advertising.
>
> Post-market monitoring activities are also not funded by the PDUFA
> program. APhA supports the expansion of PDUFA-funded activity to
> include enhancements in post-marketing surveillance. Close monitoring
> of newly approved products is crucial to the agency\'s mission to
> protect the public health.
>
> The reality is that some problems and benefits of products will not be
> discovered in pre-approval clinical trials. Medication use in real
> life is far different from the controlled environment of a clinical
> trial, with the concurrent use of other medications, over-the-counter
> products, and dietary supplements, as well as personal activities.
> These all impact how medications work.
>
> Identifying the risks and benefits of medication use in real life will
> likely not benefit from a slower review time. Only assessment of the
> extensive use of the medication in real life in the real market will
> identify those problems.
>
> Rigorous post-marketing surveillance and early detection of potential
> problems is particularly important as the number of new molecular
> entities first introduced in the U.S. has increased substantially with
> the PDUFA activity.
>
> According to the Tufts University Center for the Study of Drug
> Development, 80 percent of new molecular entities received FDA
> approval within their first year of introduction on the world market
> between 1996 and 1998, compared to only 43 percent in the previous
> 4-year period.
>
> While the FDA approval of new molecular entities brings new drug
> therapies to the U.S. first, it also brings the agency an added
> responsibility because significant adverse events will likely be first
> detected here, if we are looking for them.
>
> Providing the agency the resources to closely monitor newly approved
> drug products during the first few years the product is marketed could
> help identify potential problems before serious widespread patient
> harm occurs. We have heard discussion of the withdrawal of products in
> the recent years, and most of that withdrawal had to do with the real
> use and whether the health care system was managing these products
> correctly, did we know enough about the products to make sure that
> they were used correctly and that the risk in them was minimized and
> the benefit maximized.
>
> What we have here in our post-marketing surveillance and the
> withdrawal of those products is that patients lost access to a number
> of valuable medications because the health care system failed to
> appropriately manage risk. I think the FDA can help the health care
> system here, manage that identifiable risk and keep these products on
> the market, but we have to have more information in order to do that.
>
> This reality creates an opportunity for pharmacists and the FDA to
> work together, focused on the profession\'s goal, to help patients
> make medications work. There are two problems in the important
> function of post-marketing surveillance at the agency.
>
> First, FDA does not receive a sufficient number of adverse drug
> reports, far fewer than what we would expect compared to published
> reports regarding the amount of morbidity and mortality associated
> with drug use. We should work with the agency to promote swift
> reporting of all adverse events to the FDA, but simply increasing
> reporting will not fix the situation.
>
> The current reporting system is insufficient as a strategy to identify
> adverse effects and problems with appropriate prescribing and use of
> pharmaceuticals. FDA\'s current system for identifying unknown adverse
> effects of prescription drugs suffers from a lack of resources to
> analyze and respond to reports received by the agencies.
>
> Use of PDUFA funds to improve this activity is vital to maintain the
> integrity of our drug review system, a system that relies on
> surveillance to identify, analyze, and communicate adverse events of
> products that are identified in real-life use.
>
> Pharmacists can help with this, and we would like to work with the
> agency to use a promising mechanism to identify the problems, what
> happens once we get through the review process and bring these
> products to the market.
>
> An additional component of post-marketing surveillance would a new
> system for higher-risk prescription medications. Developing a
> standardized process to work with medicines or devices demanding
> special attention helps manage risks and optimize medication use. An
> enhanced risk management system should be developed through a
> cooperative effort among stakeholders, including patients,
> prescribers, manufacturers, and pharmacists. A system could use a
> standardized process to work with those high-risk medications.
>
> Health professionals would know that a drug in the high-risk category
> bears special or unusual risks that require close monitoring, and a
> common system would allow pharmacists and prescribers to build these
> services into their practices.
>
> I think the comment of the previous speaker in talking about, perhaps,
> a firewall between the fees and any expansion of activity may warrant
> more comment and may be the way to move forward with this. There
> certainly is a need for more activity to occur within the agency
> through additional appropriations and additional user fees, and
> discussion of those firewalls may be a way to move that forward.
>
> I do appreciate the opportunity to present the views of the Nation\'s
> pharmacists, and let me express our support for the PDUFA program and
> its ability to support the FDA\'s mission to promote and protect the
> public health.
>
> Managing the risk of the powerful technology we call medications is
> not, however, simply a function of the approval process. The risk must
> be managed when consumers use these products in real life. Pharmacists
> are essential to that management, and we look forward to continuing to
> work with the agency, consumers, and other health care professionals.
>
> Thanks.
>
> MR. BARNETT: Thank you.
>
> Amy Allina.
>
> MS. ALLINA: Thank you.
>
> I am Amy Allina, the program director of the National Women\'s Health
> Network, and I would also like to start by thanking the FDA for
> inviting me to speak today and also for all that you have done over
> the last year to reach out to consumer advocates and hear our thoughts
> about the PDUFA program.
>
> The network has spoken at past meetings about PDUFA and has raised
> serious concerns about the program. Our greatest concerns about it
> relate to the ways in which we believe it has affected FDA\'s
> relationship to the drug companies the agency is responsible for
> regulating. We think that by establishing the user fee system and the
> PDUFA performance goals which were created in consultation with the
> industry, the Congress has undermined the agency\'s independence and
> the public\'s confidence in the quality of consumer protection that
> the FDA provides.
>
> We are a member of two coalitions which share these concerns. One is
> the Patient and Consumer Coalition, previously mentioned, and also
> Prevention First, a coalition of independent health organizations.
>
> This panel has been asked to address the question, has PDUFA supported
> FDA\'s mission to protect and promote public health. The network
> believes the answer to this question is no. In fact, we be believe
> that, on balance, PDUFA has detracted from FDA\'s ability to fulfill
> its mission to protect and promote public health.
>
> While we do not dismiss the contribution made by faster approval of
> those drugs which have represented genuine advances for patients and
> consumers, some of which were mentioned by Dr. Zoon, over the last
> several years we believe this contribution has been outweighed by the
> other effects of PDUFA.
>
> Today, 4 years after the current PDUFA program was put in place, there
> is clear evidence that it has led to a reconfiguration of FDA\'s
> priorities and reallocation of its resources, to the detriment of the
> public health.
>
> In the years since enactment of PDUFA, FDA\'s resources for functions
> outside of drug review have been reduced. This has impeded the
> agency\'s ability to meet its consumer protection responsibilities.
> The non-PDUFA programs which have been hurt include health fraud
> investigation, plant inspection, post-marketing surveillance of drug
> safety, oversight of drug advertising, among others.
>
> As FDA has acknowledged in some of the previous meetings we have had,
> critical new drug safety work is not getting needed funding. FDA\'s
> non-PDUFA programs have absorbed inflationary costs and cuts to fund
> PDUFA, and FDA has been forced to reduce its work force and budget for
> programs other than drug review to meet the requirements set by PDUFA.
>
> In addition to the drain of financial resources resulting from the
> need to meet statutory spending requirements for drug review, the
> faster approval of drugs itself has increased the work burden on other
> parts of the agency without providing any more resources to meet the
> new demands. With more drugs being approved and more drugs being
> introduced first in the United States, as Susan noted, there are more
> drug safety problems to be managed after approval, but the parts of
> FDA responsible for managing post-approval drug safety have lost, not
> gained, staff and resources.
>
> At the same time, other changes have taken place, which have also
> increased the workload of non-PDUFA programs. In the area of drug
> advertising, for example, spending on direct-to-consumer ads has
> skyrocketed in recent years, climbing from less than 800 million in
> 1996 to almost 2.5 billion in 2000. Yet, the FDA staff responsible for
> oversight of drug advertising and promotion has not been able to grow
> at anything like that pace.
>
> As the Congress gets ready to consider reauthorization of the PDUFA
> program, it is critical that lawmakers review the impact this program
> has had on the public health and recommit themselves to providing the
> FDA with adequate funds to allow the agency to fulfill its mission of
> protecting and promoting public health.
>
> In addition to addressing the lack of adequate funds for the public
> health protection functions of the FDA, the network also believes
> there is a need for Congress to help the agency rebalance its
> priorities, which have been skewed inappropriately toward faster drug
> review by the performance goals established in PDUFA.
>
> We believe it is time to consider establishing performance goals for
> the agency with respect to its functions protecting and promoting
> public health. Setting performance goals in, for example, the areas of
> Phase IV study completion and oversight of drug advertising would help
> ensure that these critical functions of the agency are not undercut by
> the need to meet drug review goals. Such public health goals could
> include a standard for the agency to have taken action against a
> percentage of companies that failed to conduct required post-approval
> safety studies or a standard for the agency to review all
> direct-to-consumer advertisements for compliance and take action
> against violations within a set time period after the ad has been
> aired or published.
>
> It is not even clear to us that the FDA could tell the public today
> how many of the post-approval safety studies that it has required as a
> condition of approval over the last 3 years have even been started.
>
> All too often, once companies have received FDA\'s approval to market
> a drug, they fail to follow through with the Phase IV studies that FDA
> directs them to conduct, and we believe that if the agency had to meet
> a performance goal of taking action against companies that fail to
> conduct this required research, enforcement of approval conditions
> would improve.
>
> With respect to review of direct-to-consumer advertisements, the
> agency reports that it is keeping up with timely review, but in at
> least one case, it took several months for the agency to respond to a
> complaint about an ad which was eventually found to violate required
> standards of accuracy and balance. This delay meant that by the time
> the company was notified that FDA has found a problem with the
> advertisement, it had been running for several months and it had been
> seen by hundreds of thousands of consumers. Requiring that ads be
> reviewed within a specific time frame soon after being aired or
> published would improve accountability and encourage timely action in
> this area as well.
>
> Similar performance goals for other consumer protection and public
> health promotion functions of the agency could be established. We do
> continue to be concerned about the inflexibility of the current drug
> review performance goals and also about the process by which they were
> established, but we would like to work with the FDA to create public
> health protection performance goals that have appropriate flexibility
> and input from consumers and public health experts.
>
> I want to end by reiterating three points. First, Congress\' decision
> to fund FDA\'s drug review through user fees has undercut the
> agency\'s autonomy from industry and undermined the agency\'s ability
> to fulfill its mission of protecting and promoting public health.
> Second, the fiscal demands of faster drug review and the establishment
> of performance goals for that review have drained resources from
> critical public health functions of the agency and have
> inappropriately skewed FDA\'s priorities toward faster drug review at
> the expense of their ability to safeguard the public health.
>
> Finally, in reauthorizing PDUFA, we would like to see Congress address
> these problems by recommitting itself to funding FDA at levels that
> make it possible for the agency to fulfill its public health
> protection functions and also by directing the agency to establish
> public health performance goals in consultation with public health
> experts and consumers, so that faster drug review no longer trumps all
> other functions of the agency.
>
> Thank you.
>
> MR. BARNETT: Thank you.
>
> Richard Levinson.
>
> MR. LEVINSON: Thank you.
>
> My name is Richard Levinson. I am the associate executive director of
> the American Public Health Association. We are the world\'s largest
> association of public health professionals, 55,000 members and 76
> different disciplines that make up the public health family.
>
> As the last speaker on the panel, I am going to refer you to my
> published remarks for details. I am just going to highlight the
> agreements and disagreements that I have with not only what the
> previous panelists have said, but what has been said over the years
> about the PDUFA process.
>
> First of all, I do congratulate the FDA for staying within the
> parameters of the PDUFA process. They have met the goals, almost
> without exception. They have brought to the market a number of very
> critical products for health and human safety. We know with the
> tremendous expansion in the biotech industry that many more products
> are on the market, and, hopefully, this expedited review process will
> also make them available to the public in a timely fashion.
>
> We believe that they have given appropriate emphasis to drugs of high
> priority dealing with serious chronic illnesses and with untreatable
> illnesses, and we congratulate them also for that.
>
> Like almost everybody else who has looked at this process, we have
> great concern, however, about the PDUFA process, even though we
> support its renewal and continuance.
>
> First of all, the standards. We think that the 2002 standards cannot
> be used as a floor or basis for the development of further standards.
> We think that they may already be too compressed, that they may be
> putting, despite additional staff and other resources\--and I am just
> talking about pre-market review of drugs and biologicals that may
> already be putting too great a stress on the process of review in the
> FDA, and this may be\--I am not saying it is, but may be related to
> the increased rate of drug recalls.
>
> We are also concerned not only about the number of recalls, but the
> quality of some of them. We think that several drugs might not have
> been approved had there been additional leisure to go into greater
> depth about their possible side effects.
>
> We think that the solution to forming better standards is certainly
> broadening the input of those who can comment on the drug review
> process. Public members, consumer members are absolutely essential,
> but they are necessary, not sufficient.
>
> I think that there is a cadre of expertise in the world independent of
> both the drug industry and the Government that can comment
> intelligently about the relationship between the volume of drug review
> process and its outcome, and we think that such people, either on a
> consultant basis or as a member of various review panels, should be
> permitted and encouraged to comment about future PDUFA regulations.
>
> Second, we are concerned, as almost everybody else is, about what is
> covered by PDUFA, and you have heard a great deal and should hear a
> great deal more about post-marketing surveillance for adverse drug
> reactions, that it is certainly not adequate if there are 2 million
> hospitalizations every year for adverse drug reactions and 100,000
> deaths. And that is probably a conservative figure.
>
> We feel that this is very definitely, of course, an FDA function, but
> it should be much more adequately supported, and we think that user
> fees are an appropriate way to support this.
>
> We are also very much concerned in this era of self-medication and
> self-management of health conditions, and we totally support this. We
> think this is a very good trend, but several dangers creep in at
> inadequate regulation of over-the-counter drugs and of generics as
> well as direct-to-consumer advertising. You have read about some of
> the horrors of that process. It certainly needs to be regulated very
> vigorously.
>
> We would also point out that we in the American Public Health
> Association are also concerned about other FDA functions which need to
> be made far more adequate. There are many of them. Of particular
> concern to us is their role in food safety. Certainly, the food
> supply, which is increasingly important, from overseas is a major open
> target for bioterrorists, and the FDA simply is not adequately
> monitoring imported foods. I will not go into that. That is not the
> purpose of this panel, but just to say that there are many other FDA
> functions that need additional function, and, hopefully, sources of
> this funding will be found.
>
> I think that the idea of user fees to fund FDA functions is not
> inappropriate. I share everybody else\'s concern about inappropriate
> industry influence in this process and about conflict of interest. I
> believe that it has been fairly well prevented, and it can be
> prevented further by appropriate legislation and by vigilance on the
> part of FDA staff.
>
> I do not believe that the fear alone of improper influence should stop
> the use of user funds. I think the use of these user funds should be
> expanded.
>
> Furthermore, I feel that the way in which they are used needs to be
> more flexible. You are going to hear more in other panels about the
> rigidities imposed with one-third from new products and one-third from
> establishments and one-third from existing products, and the \'97
> appropriation plus inflation as the basis for future appropriations. I
> think these things are inappropriate and artificial. The FDA should be
> given more leeway not only in terms of the use of the funds, but,
> also, of course, in the establishment and use of standards of
> performance.
>
> I think that a great deal has been said, and I guess this gets into
> epistemology, if I understand the meaning of that term, about what is
> public health and what is not public health. What is said to be public
> health is a function such as post-marketing surveillance and
> direct-to-consumer advertising. On the other hand, what is said to be
> not public health is the support of review of new drug applications
> and applications for new biologicals.
>
> I am very much interested in philosophy, and epistemology, this
> distinction totally evades me. I think that everything that FDA does
> is part of public health. We consider it a public health agency. I am
> delighted to know that FDA also considers itself basically a public
> health agency, and I cannot make distinctions about what is and what
> is not public health. It is all public health.
>
> Does this mean that Congress should support all of FDA\'s function?
> Yes, this would be very desirable. We in the real world know this will
> never happen. So the use of user fees from people who profit very
> grandly from the sale of drugs and other products is not an
> unreasonable way to support this function with adequate protections.
>
> If the Congress is failing to support the rest of FDA functions\--and
> I think there is adequate evidence that it is failing to do so\--then
> it is the responsibility of people on this panel, people in the
> audience, people in the community who support the FDA function to
> lobby, or at least advocate where you are not allowed to lobby, to
> Congress that the support should be more adequate, and the failure for
> FDA to achieve this support is as much a fault of ours as it is of
> anything that they might do.
>
> I think this concludes my remarks, and as I said, I did want to
> highlight mostly my differences and support. My written comments will
> have more details about the APHA position.
>
> MR. BARNETT: Thank you.
>
> Now it is time to go to questions from the audience, or comments,
> rather. We would ask you to come up to the microphone in the middle,
> tell us who you are, where you are from, and then give us your
> comments. Remember, they are supposed to be focused on the subject of
> this particular panel which was public health. If you have other
> issues that you want talk about, we will save those for later.
>
> DR. WOODCOCK: Mark, when you are ready, could I make a comment?
>
> MR. BARNETT: Oh, yes. Go ahead.
>
> DR. WOODCOCK: A number of the speakers on the panel alluded to the
> loss of support in other programs that FDA has, and there was a wide
> range of comments, all the way to the foods program, the lack of
> robust program in those areas and what is the relationship to the user
> fee program.
>
> I just want to correct any misconception people have that the user fee
> program caused this other problem. It may be that perhaps people felt
> the FDA was getting a lot of money from the user fee program and
> didn\'t require any money, but FDA lost \$50 million every year in the
> cost of living for a decade, and our budget is only \$1.2 billion or
> something like that.
>
> Is that right, Linda?
>
> DR. SUYDAM: Yes. It is \$1.2 billion.
>
> DR. WOODCOCK: So that is a very large percentage in real dollars that
> was lost.
>
> At the same time, user fee money was added to the Prescription Drug
> User Fee program, but whether there is a cause-and-effect
> relationship, the loss in these programs is a problem we have had in
> funding, say to take a neutral topic, health fraud. Our health fraud
> program has shrunk dramatically. Parts of the device program,
> radiologic health, say, has shrunk dramatically. I don\'t think these
> are really a function that people were moved over to the user fee
> program. It was a function of FDA had lost the support, the funds that
> we had available to actually have those people on board or fund those
> programs, just so that is clear.
>
> Now, the user fee program may, in fact, remain more robust, the
> appropriated side, than some of the other programs, but by no means is
> it a cause-and-effect relationship. I just wanted to make that clear.
>
> MR. BARNETT: Thanks.
>
> Come on up to the mike if anyone has a comment.
>
> FLOOR QUESTION: I am Reginald Ryan with Script World Pharmaceutical
> News.
>
> Last year, a number of consumer groups actually opposed the
> reauthorization of PDUFA. I don\'t know whether Consumer Federation of
> America was one of them. I believe the Women\'s Health Network was. Is
> that still the position of the consumer groups, to your knowledge?
>
> MR. PLUNKETT: We are going to oppose reauthorization in its current
> form.
>
> We, just like everyone else on the panel, do acknowledge political
> reality. I spend a good part of my time on Capitol Hill. So, unless
> President Bush decides very shortly to put me on the short list for
> those who might become commissioner, I probably won\'t have the power
> to impose my will on Congress or the administration. So we will deal
> with the political realities when we have to, but the concerns that
> the consumer and the patient groups have laid out are that in its
> current form we don\'t think it should be renewed.
>
> MR. BARNETT: Yes.
>
> FLOOR QUESTION: Good morning. My name is Chris Heeley, and I am the
> executive director for the Plasma Protein Therapeutics Association.
> PPTA represents the major products of plasma-derived and recombinant
> analog protein therapies to treat a number of rare disorders,
> including life-threatening conditions such as hemophilia and primary
> immune deficiency diseases, as well as many others.
>
> Given the comments of the panel, I would just ask that as the day goes
> by, please don\'t forget the many, many rare disorders and rare
> conditions that are out there that stand to benefit directly from the
> benefits of PDUFA. Many of these patient groups already are subject to
> health surveillance by CDC, such as the hemophilia community and
> others, and they really stand to benefit by making sure that there is
> timely review, a quick review of product and process improvement,
> safety improvements for the products that they take.
>
> So, again, just to comment, please don\'t forget those many rare
> disorders that are out there that really have benefitted greatly from
> PDUFA.
>
> Thanks.
>
> FLOOR QUESTION: Good morning. I am Jay Lee from the National Center
> for Policy Research for Women and Families.
>
> I just wanted to thank the panel for their comments today. I noticed
> that some of you had expressed some concerns about direct-to-consumer
> advertising, and I was just wondering whether there were any
> obstacles, legal or otherwise, that would prevent the FDA from
> requiring a review of these advertisements before they are released
> into the media.
>
> MR. BARNETT: Comments from the panel on that?
>
> MS. ALLINA: Well, probably, it would be better if FDA responded. They
> have certainly told us that they think there are obstacles to that.
>
> DR. WOODCOCK: There are certain strictures that we have in our ability
> to regulate speech, basically, and we are able to look at these ads.
> For the broadcast ads, we have a voluntary program for the voluntary
> submission of direct-to-consumer broadcast ads before they are put on
> the air.
>
> Ann Wine can actually explain. Ann Wine is in our Office of Chief
> Counsel, and she can explain the legal framework.
>
> MS. WINE: As some of you, I am sure, are aware, FDA has been looking
> at issues related to direct-to-consumer advertising, both the policy
> issues and the legal issues, for many years, and continues to do so. I
> think there could be, certainly, an entire day\'s worth of discussion
> about both the policy and legal issues related to direct-to-consumer
> advertising.
>
> I think what people are focusing on today is what is the relationship
> between whatever review of direct-to-consumer advertising FDA does and
> the user fee program and whatever the best approach is to whatever,
> either voluntary or required, actions are taken to make sure that the
> advertising is both appropriate, and I think what the consumer groups
> are saying is to make those ads beneficial and not detrimental to the
> public health.
>
> How to make sure that there is appropriate funding for this program is
> the question that is being addressed today, and I am not just trying
> to completely avoid the issue here. What I am saying is these are
> complicated issues from a policy and legal perspective, and maybe
> there is agreement that there needs to be an adequate program in
> place. If there is agreement on that point, then the question is how
> do you fund it, and should user fees help to fund that program.
>
> I think at least some of the panelists have been clear on their
> position. If other people have different positions on that point, I
> think that the agency folks would certainly like to hear.
>
> MR. BARNETT: Thanks.
>
> Any comments? Yes.
>
> MS. ALLINA: I wanted to just respond to Dr. Woodcock\'s earlier
> clarification about the relationship of reduction of other areas
> outside of drug review. Really, I am reiterating a point that I made
> in my comments, but I wanted to clarify myself that I was quoting from
> a presentation done by the FDA at our previous meeting in which they
> said that FDA\'s non-PDUFA programs have absorbed inflationary costs
> and cuts to fund PDUFA.
>
> MS. MULLIN: I am Theresa Mullin, and let me say from the planning shop
> perspective that that may be de facto what has happened, but I think
> it is different. That is not the same as saying this is the fault of
> the PDUFA program.
>
> What it reflects is an interaction of what might be viewed as a
> reasonable provision under other circumstances, other budgetary
> circumstances of spending only an inflation-adjusted amount from the
> prior year if you don\'t make any assumptions about what the overall
> appropriation is going to be, but what we have experienced is very
> limited growth of our appropriation overall, and, certainly, in the
> Center for Drugs, actually flat to declining appropriations over the
> past 5 years. You put that together with earmarks of that money for
> other things, and then you put in this otherwise what appears to be
> reasonable inflation-adjusted spending from appropriations on PDUFA.
> The intersection of those things is what I think we are dealing with.
>
> I think it is helpful to keep those concepts separate. I think many of
> you have talked about those as sort of separate things.
>
> DR. WOODCOCK: Amy, I apologize because I recognize that, but it is a
> little more complicated than simply that PDUFA sucked up all the
> money. The fact is we didn\'t get money, and we had to keep our
> programs going. So I am completely neutral about where the money comes
> from in the sense of if we are going to operate a program, it has to
> be funded. That is a basic business principle is that you got to have
> resources, and so I just think it is easy to say, well, the PDUFA
> program caused all that, but by no means is that the story is what I
> was saying.
>
> MR. PLUNKETT: I am afraid this might be an argument over a distinction
> without a real difference.
>
> DR. WOODCOCK: I don\'t think we are arguing. We are just trying to
> clarify what happened.
>
> MR. PLUNKETT: A discussion.
>
> DR. WOODCOCK: Yes.
>
> MR. PLUNKETT: I don\'t think any of the folks who have raised concerns
> have not acknowledged that the backdrop to all of this is that
> Congress has not adequately funded the agency, and then if you have
> these mandated cost-of-living adjustments, then that drains a greater
> and greater proportion of the agency\'s resources.
>
> MS. ALLINA: And also that it is an interaction as well between
> appropriations and performance goals. As you said, if you have to keep
> your programs operating and you have performance goals for faster drug
> review and not for anything else, that is going to skew the decisions.
>
> MR. BARNETT: Anyone else in the audience want to come up and join in?
>
> \[No response.\]
>
> MR. BARNETT: If that is the case, I think it is time for our break. My
> watch says 15 after. Let\'s be back at 25 after.
>
> \[Recess taken at 10:17 until 10:34 a.m.\]
>
> **Panel II - Post Market**
>
> MR. BARNETT: Can I ask the second panel to convene up here on the
> platform.
>
> \[Pause.\]
>
> MR. BARNETT: Lets\'s get underway, then, with our second panel, and
> the focus here, remember, is post-market issues as they relate to
> PDUFA.
>
> Our FDA speaker is Dr. Janet Woodcock, who is director of the Center
> for Drug Evaluation and Research.
>
> Dr. Woodcock?
>
> DR. WOODCOCK: Thank you.
>
> I am just going to talk about the post-marketing program and what it
> is and what it can and can\'t do as a basis for, then, our panelists\'
> comments.
>
> Post-marketing surveillance is required, as Susan Winckler already
> alluded to in the prior panel, because when we approve a drug or a
> vaccine, we don\'t know everything about it. I would really like to
> reiterate that it isn\'t a function of the fact that we didn\'t spend
> time reviewing it. It is that we really haven\'t seen everything that
> is going to happen with a drug or biologic in the clinical trials, and
> unexpected findings often emerge after widespread use. It is kind of
> expected that unexpected findings will emerge because this routinely
> happens.
>
> Why is this? Well, there are rare side effects that you just don\'t
> see unless a lot of people are exposed to the drug or the biologic.
>
> Once the drug or biologic is approved, it is going to be used in
> different populations or different circumstances than actually it was
> when the drug was studied in the clinical trials, and this is simply a
> reality we have to face. We don\'t see every kind of circumstance in
> the clinical trials. We don\'t see the off-label use that is often
> seen.
>
> The other thing that happens is that certain interactions occur. As
> Susan said very eloquently, it is drugs, dietary supplements, other
> substances that people may be taking over the counter. We can\'t
> predict every kind of interaction that might occur. So, in other
> words, we learn things, good and bad things about drugs after they are
> approved, and so that knowledge needs to be captured and disseminated
> to the public and health professionals to maintain the risk-benefit
> ratio of drugs.
>
> Unfortunately, our drug and biologic surveillance system is severely
> challenged, but this is not new news. I have in my files a report to
> Senator Kennedy in 1980\--and by my count, that is almost 25 years
> ago\--that called for a reform of the system. It called for increasing
> the resources. It called for creation of new structures and so forth
> put into place, and, unfortunately, none of that happened, and the
> system that we are talking about today is the same kind of system that
> was the subject of that report in 1980.
>
> There have been numerous studies in the medical literature and the
> public health literature since that time and editorials calling for
> improved surveillance, and, yet, this hasn\'t changed very much.
>
> There have also been called for additional oversight even. Some
> commentators, as many of you probably know, become so frustrated they
> have asked for a new agency to be formed to oversee drug safety
> problems.
>
> In addition, there has been a growth actually of the reports that we
> have to deal with, and I will get into that a little bit later.
>
> What kind of system do we have? What are we talking about here? Well,
> the foundation of our surveillance for FDA for drug and biologics, we
> call spontaneous reports, voluntary reporting by health professionals.
>
> If they report to a manufacturer, then the manufacturer must report to
> the FDA. That is mandatory. The MedWatch program is the voluntary
> piece where health professionals can report directly to the FDA. That
> is what we have.
>
> These reports pour into the agency, but they are strictly voluntary in
> the case of the health care system, and then we have to make sense of
> them at our end.
>
> We made a major effort in the mid to late 1990\'s to
> modernize\--actually have a database, and we have achieved that. We
> call that our AERS system, our adverse-event reporting system. It is a
> computer database and electronic reporting system that keeps all of
> this information there and allows our safety evaluators to analyze the
> database. That was a successful innovation that is continuing, but
> that doesn\'t create a new system. That is simply a database to
> support the spontaneous reporting system in a modern fashion.
>
> When we get all of these reports, though, we may not know what to make
> of them. For example, say a report is people have been in motor
> vehicle accidents. Well, we don\'t know. Is it because the drug is
> impairing driving performance, or is that because people
> happen\--every day, on my way to work, I see somebody in a motor
> vehicle accident. So we have to do further analysis, and the way we do
> that is try to work with linked databases in the health care system
> and get other data that can allow us to make sense of we are getting
> spontaneously reported to us.
>
> Unfortunately, the funding for that has had to be cut over the years.
> It is severely limited, and this is truly a shame because now, with
> managed care and so forth, there are lots of these linked databases
> out there, and there are lots of way to discover what is happening out
> there in the real world to people as they take these drugs.
>
> We also lack enough staff, safety evaluators, epidemiologists, and
> other scientific staff that are needed to analyze this data pouring in
> and making sense of it .
>
> In addition, since 1980, of course, our system has become more
> stressed. There have been increases in the number of drugs and
> biologics approved, and I call this the gift that keeps on giving
> because, when we approve a drug or a biologic, we don\'t get just the
> reports next year. We continue to get the reports all through the life
> cycle of the drug, and then it may go on generic and it may raise new
> issues and so forth.
>
> In addition, as already been alluded to by another panelists, the user
> fee program has probably doubled our rate of being first in the world.
> Why is that important? Well, it is important because when you are
> first no other population has been exposed before. As I earlier told
> you, we find out these things when large numbers of people are exposed
> out in the real world.
>
> Back in the \'80s when drugs were first approved in Europe or other
> countries, those populations would be exposed. We look back in our
> files and we can see drugs where the Europeans had a problem with that
> drug and we were still reviewing it in our long review process, and it
> was pulled off the application before it even got on the U.S. market.
>
> You heard from Kathy about the benefits of getting many of these drugs
> to our patients earlier. On the other hand, we have to recognize that
> that brings a cost in terms of additional risk from uncertainty about
> certain side effects.
>
> In addition, there has been a dramatic increase since 1980, if you use
> that as the bench mark, in drug utilization, and that has stressed our
> system.
>
> Let me just show you a couple slides of numbers. This just shows from
> \'92 to 2000, the number of dispensed prescriptions. This is just the
> outpatient world, 3 billion. We are up to 3 billion prescriptions in
> 2000.
>
> This is the number of reports of different kinds that are coming into
> this system I have described to you, this adverse-event reporting
> system. The yellow bars are the serious unexpected adverse events.
> They are serious. In other words, people do report their headaches and
> upset stomachs to us from drugs, but what we are really concerned
> about here from a public health impact is the serious ones. You can
> see we get almost 100,000 of those in \'00. Unexpected means that
> health care professional, that manufacturer didn\'t think that was on
> the label or thought it was of greater severity than was described.
> These are things we have to jump on. That is 100,000.
>
> In addition, you can see the overall reports are very high, and, yet,
> the direct reports, the purple boxes, that we get directly from the
> health care professionals is very limited. We know we could increase
> that dramatically by promoting the system, but I think we only have
> three people working on the MedWatch program.
>
> In addition, I think another thing that we forget about, because you
> tend not to take the long view here, is that public expectations have
> really changed for the FDA and our programs. In the past, when there
> were not so many drugs, the risk management was really felt to be by
> the medical community, the health care provider would know everything
> about the drug, decide if it is right for that patient, have access to
> all of the information, and apply it in the prescribing situation, but
> now there are too many drugs and the health care system is too
> stressed. Really, the public and Congress expect\--and we ourselves at
> FDA expect ourselves to take an active role, to make sure that health
> provider is informed, make sure that information is out there before
> people who need it. So that has changed and also stressed our system
> because it is very difficult in the current environment for us to do
> this.
>
> In addition, another stressor or change is the recognition, which we
> have recognized for a long time, of medical errors. Pharmaceuticals
> are prominent in medical errors. The Institute of Medicine thought
> maybe there are 50- to 100,000 hospital-based fatalities per year due
> to errors. The data show that medications are involved in about a
> quarter of these at least.
>
> We have a small post-marketing program at FDA aimed at preventing
> errors in the use of products. Some of this is just structural, is the
> product packaged right, is it labeled in a way that won\'t be mixed up
> with another medication during an emergency situation or on a
> prescription, but others is the whole risk management, do the
> providers have the risk information they need to make logical
> decisions for patients about risk.
>
> We have instituted formal risk management programs for some products
> in the last 5 years where it was becoming clear from the reports
> coming in that prescribers were not logically taking this into
> account. They were giving teratogens to women of child-bearing age,
> for example, without doing a pregnancy test.
>
> MR. BARNETT: Two more minutes.
>
> DR. WOODCOCK: I\'m sorry. I\'m done.
>
> How does this relate to the user fee program?
>
> MR. BARNETT: You are done with that slide, you mean.
>
> \[Laughter.\]
>
> DR. WOODCOCK: How does this relate to the user fee program, though? I
> have just sort of laid out what our post-marketing program is and what
> the status of it is right now. Well, as I already said, we think the
> rapid pre-market review process has to be predicated on the fact that
> there is a robust post-marketing surveillance. We cannot just have one
> side of the program and not have the other side of the program.
>
> \"U.S. first in the world\" means our population is placed at greater
> risk because we are going to discover these new adverse events in our
> population. The speed then becomes important. We want to discover them
> fast and get that information out. So we limit the number of people
> who might be exposed to those.
>
> Effective drugs, as was already alluded to by the past panel, may be
> removed from the market if the risk management of them is not done
> properly. So it isn\'t that useful to speed the availability of drugs
> if then they become unavailable.
>
> Public confidence, as you have already heard, in the drug regulatory
> system must be maintained, and part of that is the confidence that
> there is a robust safety net for adverse events.
>
> So this relates to the questions that we have for this panel, which
> are supposed to be up here, but I think you have them.
>
> Thank you.
>
> MR. BARNETT: Thanks very much.
>
> Let me pause now to introduce the non-FDA members of the panel, and,
> again, I will ask each person to just raise their hand so the folks
> out there know who I am talking about.
>
> Robert Griffin is associate medical director for Blue Cross/Blue
> Shield of Vermont. Diana Zuckerman is president of the National Center
> for Policy Research for Women and Families. Jeff Bloom is with Patient
> and Consumer Coalition. Judy Cahill is executive director of the
> Academy of Managed Care Pharmacy.
>
> Again, I will call on the speakers in the same order that they appear
> on the agenda. So we will start with Dr. Griffin, please.
>
> DR. GRIFFIN: Thank you.
>
> Good morning. I am Dr. Bob Griffin. As noted, I am from the Vermont
> health plan for Blue Cross/Blue Shield. However, actually, today I am
> representing the National Blue Cross/Blue Shield Association which
> represents the 44 independent locally owned Blue Cross/Blue Shield
> plans that provide coverage to 81.5 million members. That is
> approximately one in four Americans.
>
> Blue Cross/Blue Shield plans have extensive experience in providing
> prescription drug coverage to American consumers through a variety of
> our products.
>
> I would like to thank you for the opportunity to appear before the
> Food and Drug Administration at today\'s public meeting on the PDUFA
> act.
>
> I am here to address the specific question posed in the Federal
> Register notice for today\'s meeting, and that is, should PDUFA allow
> the use of the user fee funding to monitor safety after new drug or
> biologic approval. Our short answer is yes, we certainly think so, but
> let me summarize the association\'s recommendations on PDUFA.
>
> We believe that an integral part of delivering new drug therapies to
> physicians and consumers is assuring consumer safety after the drug
> has penetrated the market. By funding only the pre-market review of
> new drugs, PDUFA speeds access to new therapies, but that does not
> provide the FDA with the necessary resources to conduct critical
> post-market surveillance activities that keep patients safe.
>
> In addition, the association believes that the flow of new drugs to
> market must be accompanied by health outcomes information that allows
> consumers to make value-driven decisions.
>
> We also support continued increases in Federal appropriations for the
> FDA to provide resources for agency programs that impact public
> health.
>
> To ensure consumer safety at each stage of the drug product life
> cycle, we specifically recommend expanding PDUFA\'s definition of
> \"user fee-funded activities\" to include post-marketing surveillance
> of adverse events and the monitoring of the risk and benefit
> information and the direct-to-consumer, or DTC, advertising,
> supporting FDA initiatives to require manufacturers to provide
> information that allows evaluation of the benefits, costs, and risks
> of new drugs compared to the benefits, costs, and risks of drugs
> already on the market, and increasing Federal appropriations for the
> FDA to provide resources for agency programs that impact public
> health.
>
> Thanks to PDUFA, more new drugs are coming to the market faster than
> ever. However, resources for important activities that ensure these
> new products are safe and effective for consumers have not kept pace
> with resources for drug review. PDUFA provides funding only for tasks
> that lead up to a decision on whether to approve or deny a new drug
> application. Post-marketing regulatory activities that are critical
> for all new drugs, such as tracking and responding to reports of
> adverse drug reactions and monitoring drugs advertisements for
> compliance with agency regulations, are not covered by user fees.
> Thus, these vital consumer safety responsibilities must be paid for
> out of congressional appropriations and may be at risk if the volume
> of new drug requests siphons funds from other FDA activities and
> Congress fails to sustain the increased funding granted this year.
>
> Last week, Congress and the President signed a record budget for the
> FDA for fiscal year 2002. This represents the first increase in
> appropriations for drug reviews since 1992. The Blue Cross/Blue Shield
> association applauds Congress and the administration for their
> recognition of the agency\'s role in protecting public health. We are
> encouraged that appropriations measures also enables the agency to
> meet the statutory triggers for collection and use of PDUFA fees
> without diverting resources from other key agency programs.
>
> However, as noted, there is ongoing need for funding for critical
> agency responsibilities. Despite the welcome infusion of appropriated
> money fro fiscal year 2002, Congress must commit to long-term funding
> for the FDA.
>
> I would like to discuss our specific recommendations. First, we
> recommend that Congress amend PDUFA to include post-marketing
> monitoring of adverse drug events as a user fee-funded activity. This
> will give FDA the resources to speed consumer access to new therapies
> and conduct critical post-market surveillance that keeps patients
> safe.
>
> Not all of the drug\'s potential side effects and interactions can be
> known at the time of market entry. Indeed, these events manifest
> themselves gradually as the drug is accepted into clinical practice
> and is used by an expanding patient population for the first time.
>
> Currently, the FDA relies on voluntary reporting of drug adverse
> events by consumers and health care professionals. As more and more
> new products enter the market under PDUFA, the volume of adverse event
> reports has grown substantially.
>
> According to CDER 2000, the FDA received 246,000 reports of
> drug-related adverse events in calendar year 2002. The GAO in its
> report, \"Major Management Challenges and Program Risks,\" released in
> January 2001, stated the FDA estimates, however, that it receives
> reports for only 1 percent to 10 percent of the serious adverse
> events.
>
> As the FDA recognized in announcing this meeting the agency lacks
> sufficient resources to adequately monitor reports of adverse events
> and conduct timely safety interventions. The FDA also noted that the
> current system for detecting adverse drug and biologic events does not
> provide sufficient data on the actual incidence of problems.
>
> When Blue Cross/Blue Shield association last testified on this issue
> before the FDA in September 2000, we cited the withdrawal of several
> drugs as examples of the need for PDUFA funding for post-market
> surveillance. Since that time, two more drugs have been withdrawn from
> the market for safety reasons, Lotronex for irritable bowel syndrome
> and Bakol, a cholesterol-lowering drug. This further illustrates our
> point.
>
> We believe Congress should provide specific funds and require FDA to
> develop and implement a comprehensive protocol to monitor adverse
> reactions related to new drugs entering the market. The association
> supports a proactive role for the FDA in collecting adverse event
> data. We understand that the FDA\'s 2002 budget request approved last
> week included \$10 billion to monitor marketed products and safeguard
> patients against adverse events associated with the use of drugs,
> biologics, and medical devices. However, there is ongoing need for
> funding of this critical task.
>
> Congress must commit to long-term funding for post-market surveillance
> of drugs. This cannot just be a one-time event.
>
> The association also believes that consumers faced with a barrage of
> advertisements for new drugs entering the market must receive clear
> and understandable information about the benefits and risks. As such,
> we recommend that Congress also amend PDUFA to include monitoring of
> DTC advertising as a user fee-funded activity. We further recommend
> that Congress require the FDA to establish criteria for the level and
> type of information that consumers without a medical background need
> to make informed choices concerning advertised drugs. As more new
> drugs reach the market faster under PDUFA, they are marketed directly
> to consumers.
>
> Recent surveys raised questions about the effectiveness of DTC
> advertising in communicating the important information about drugs. A
> survey released last month by the Kaiser Family Foundation found that
> nearly a third of adults have talked to their doctors about a drug
> they saw advertised, and 44 percent of those who talked to the doctor
> received a prescription for the drug that they asked about. This means
> that one in eight Americans have received a specific prescription in
> response to seeing a drug ad.
>
> However, when asked for a self-assessment of how much they learned
> from viewing a specific ad, most responded, about 70 percent, said
> they had learned little or nothing more about their health condition,
> and a majority, 59 percent, said they knew littler or nothing more
> about the drug.
>
> In addition, according to the 1998 Scott Levin study, most physicians
> are also skeptical of the quality and the objectivity of the
> information presented in the ads. By expanding the definition of user
> fee-funded activities to include this critical regulatory requirement,
> Congress will help ensure that consumers have more complete, accurate,
> and understandable information about the risks and benefits associated
> with prescription drugs.
>
> Our second recommendation that the FDA review PDUFA\'s role in
> ensuring that the rapid flow of new drugs to market is accompanied by
> information that allows consumers, physicians, and health plans to
> make value-driven prescription drug decisions. Specifically, Blue
> Cross/Blue Shield association recommends that the FDA support
> initiatives to require manufacturers to provide information that
> allows a comparison of benefits, costs, and risks of new drugs that
> replace existing therapies.
>
> Some of the drugs that reach the market faster under PDUFA will truly
> be breakthrough processes, offering treatments where no effective
> treatment currently exists. These drugs are likely to be the treatment
> of choice by physicians and their patients and will bring valuable
> benefits to consumers.
>
> Other newly introduced drugs will simply substitute newer, more
> expensive drug treatments for existing cost-effective agents. Because
> the marketplace is becoming more and more competitive with many
> therapeutic classes, relative cost-effectiveness information is
> becoming more important.
>
> For example, consumers, clinicians, Government and private payers need
> more information about the relative value of various asthma treatments
> in terms of symptom-free days, decrease in work loss, and any decrease
> in the emergency room use or inpatient services. Quality-of-life data
> is also an important determinant of value. By supporting initiatives
> to require manufacturers to provide information that allows a
> comparison of benefits, costs, and risks of new drugs that replace
> existing therapies, the FDA will help to ensure that Americans have
> continued access to breakthrough medical treatments and the right
> information to make informed choices about their own medical
> treatment.
>
> Given the critical consumer safety functions the FDA performs with
> respect to new drugs and under many other important agency programs,
> sustained increased congressional appropriations are necessary. The
> association\'s final recommendation calls on Congress to match the
> 2002 fiscal year appropriations level each year going forward adjusted
> for inflation.
>
> We look forward to working with the agency, the pharmaceutical
> industry, and other stakeholders on this initiative to achieve the
> goal of a fully funded FDA that has the resources to carry out its
> public health and safety mission.
>
> In conclusion, the Blue Cross/Blue Shield association is very
> concerned that accelerated drug reviews under PDUFA have not in the
> past been accompanied by comparable funding for consumer safety
> initiatives. We believe that as user fees speed new therapies to
> consumers, there is a comparable need to ensure that these drugs are
> safe and effective and the consumers receive complete and accurate
> information about the risks and benefits associated with their use.
>
> Finally, we applaud the FDA for addressing this critical health care
> issue, and we support the agency in any of these endeavors.
>
> Thank you.
>
> MR. BARNETT: Thank you, Dr. Griffin.
>
> Diana Zuckerman?
>
> DR. ZUCKERMAN: Thank you.
>
> I am Dr. Diana Zuckerman. I am president of the National Center for
> Policy Research for Women and Families, and the theme of my remarks is
> going to be we need to know more. I, first of all, want to thank you
> all for the opportunity to speak today and for holding this very
> important meeting.
>
> I think everybody in this room knows that during the last few years,
> there have been several very widely used drugs that were removed from
> the market after they had been approved, and it is abundantly clear
> that the approval of a drug or a device that is based on relatively
> short-term information may not tell the entire story about the safety
> of that medical product.
>
> As Dr. Woodcock said\--and I agree completely\--it is not necessarily
> that there is anything wrong with the approval process. It is that the
> way the approval process is, you are only going to get pretty much
> short-term information.
>
> Under the current PDUFA, the user fees are not allocated for
> monitoring the safety of medical products that have been approved, as
> we all know, and so, as a result, as everyone has already said, there
> are very limited resources for post-market surveillance. This is a
> dangerous situation that really must change.
>
> The current situation is a recipe for disaster as more and more drugs
> are sold to more and more people soon after approval. Here is the
> recipe.
>
> I must say, my family would be surprised I even know what a recipe is.
>
> \[Laughter.\]
>
> DR. ZUCKERMAN: Here is the recipe. Number one, approve drugs more
> quickly.
>
> Number two, approve medical products that have known serious
> complications and adverse reactions saying that it is up to the
> physician and the patients to weigh the risks and benefits, but then
> not have the authority or the resources to ensure that physicians and
> patients have the information they need to objectively review that
> information.
>
> Number three, spend billions of dollars on direct-to-consumer
> advertising and promotions to physicians, thus, ensuring that very
> large numbers of consumers will be taking these drugs as they are made
> available and when they are still very newly available.
>
> Number four, rely on the manufacturers to do the post-market studies
> and spend very little Federal resources to ensure that products are
> studied carefully after they have been approved.
>
> Number five, spend very little money or resources to study the adverse
> reaction reports that are made or even to make sure that the reporting
> system is working appropriately.
>
> As you can see for these five ingredients, we can share the blame of
> who is doing what. I am certainly not blaming the FDA and I am not
> blaming any particular entity. If Congress is not giving enough money,
> is not providing the ability for the FDA to have the resources, then
> certain efforts are going to be inadequate. Of course, if the law also
> ties the FDA\'s hands in terms of what they can and cannot do, then
> the law needs to be changed.
>
> As somebody who worked in Congress for 10 years, when I talk about
> PDUFA and how it needs to be changed, I don\'t necessarily think of
> what it looks like right now and how to tinker with it, but how to
> make some rather more dramatic changes.
>
> But we have got the five ingredients. Quick approval, approving of
> medical products that are known to have adverse reactions, but relying
> on the physicians and the patients to figure out whether the benefits
> outweigh the risks, direct-to-consumer advertising and billions of
> dollars for advertising to physicians as well, relying on the
> manufacturers for a lot of these post-market studies, and having few
> resources to review the reports that come in as we saw in the slides.
>
> So we stir this altogether, and the results are clear. The results are
> going to be that some products are going to be on the market for an
> extended period of time after people are starting to have rather
> serious adverse reactions, and, of course, we all know that there will
> always be some adverse reactions to any product. We are not naive
> about that, but when you have millions of people or hundreds of
> thousands of people or even tens of thousands of people taking drugs,
> you are going to see some adverse reactions that obviously weren\'t
> apparent when the drug was approved, but we still need to know about
> that as soon as possible. Under the current system, we are not finding
> out about it as soon as possible.
>
> Because of PDUFA, there are fewer resources available to the FDA to
> conduct or monitor post-market surveillance, and I won\'t get into
> that distinction without a difference of how much is Congress\' fault
> for not providing more direct appropriations for the FDA and how much
> is a law that requires user fees to be used for specific activities
> and not to be used for others.
>
> As bad as the situation is for drugs and biologics, consumers with
> implanted medical devices are even more vulnerable, and this is part
> of an even larger problem because PDUFA does not refer to and does not
> include medical devices. Yet, post-market surveillance, particularly
> for implanted medical devices, seems obviously, extremely important.
> If you have an implant in your body, wouldn\'t you like to know what
> the long-term impact is going to be?
>
> I am going to provide four brief examples of the need for better
> post-market surveillance. Number one is the well-known example of
> Fen-phen, a widely used diet pill, used by thousands of people, mostly
> women, some of whom died or experienced permanent health problems as a
> result. Fen-phen were two drugs that were separately approved, but
> were not approved as a combination use.
>
> The risks were discovered by health professionals who happened to see
> several women who had these very unusual health problems, rare health
> problems, who they knew they had also seen in their diet program
> taking diet pills. If those women had gotten Fen-phen from the
> Internet or from some other medical facility\--I mean, this was just
> luck that the women who were seen in one part of this medical facility
> for their diet pills were also seen for their other problems. So the
> health professionals there happen to notice it. If it hadn\'t been for
> that, it would have been even more years before this link had been
> discovered.
>
> Number-two example, I would like to use a medical-device example of
> jaw implants. Jaw implants are a permanent device used to treat TMJ
> disorders, and they were fairly recently approved by the FDA, despite
> very high patient attrition rate in the studies. So studies were done
> that were supposed to be long-term studies, but most of the people in
> the studies did not have any data collected after the first month or
> so.
>
> In that particular situation, the FDA\'s advisory committee made it
> clear that careful post-market surveillance was absolutely essential,
> but there is no evidence that that has been done.
>
> In the meantime, and even before the approval of these devices which
> were grandfathered devices, some patients have reported debilitating
> pain, permanent damage to the jaw and the skull, including holes in
> their skull, and other serious health problems caused by the implants.
>
> It is widely agreed among health professionals that terrible adverse
> reactions can occur with these jaw implants, but because of the lack
> of research, nobody knows how often that happens and whether, in fact,
> the benefits of these implants do outweigh the risks.
>
> My third example, briefly, will be saline breast implants which were
> approved by the FDA last year, despite a 3-year complication rate of
> more than 70 percent\--more than 70 percent among mastectomy patients
> who had saline implants for reconstruction. In fact, the complication
> rate was so high that there were members of the FDA advisory committee
> who questioned whether it could actually be true, and they started
> thinking, well, what did they mean by pain, did they mean unrelenting
> pain or did they mean just the kind of normal pain that you would have
> after surgery.
>
> They also wondered whether the multiple surgeries that so many of the
> patients were reporting were due to problems with the implants or,
> again, part of the regular reconstruction process where a nipple
> reconstruction is done after implants are inserted, some months later.
>
> Again, the advisory committee made it clear that careful post-market
> surveillance was absolutely essential, but, again, that hasn\'t been
> done. In fact, the FDA has received more than 65,000 adverse reaction
> reports for saline breast implants and more than 127,000 adverse
> reaction reports for silicone gel implants, but all of these reports
> have not been comprehensively evaluated yet.
>
> Meanwhile, a study by the National Cancer Institute suggested that
> there are potentially long-term risks of implants related to various
> cancers.
>
> So, again, we don\'t yet know because the NCI reports aren\'t studies
> of the implants that are currently on the market. They are previously
> made implants. So we need studies to find out what is going on with
> the implants that were just approved.
>
> Then I will just very briefly mention cholesterol-lowering drugs, this
> is something that is close to my particular heart because my husband
> is on them. Now, my husband started feeling not quite right after he
> had been taking these drugs for a while, and he is a physician. Those
> of you who are a physician know that that means that he either will do
> nothing at all about it or thinks he knows all about it even when he
> doesn\'t, but in this particular case, he knew that something wasn\'t
> quite right.
>
> So he went to his doctor who was not really able to tell him anything
> other than what he already knew, which was that there are some studies
> suggesting some potential problems.
>
> Then there was the question of what are the risks of
> cholesterol-lowering drugs, obviously clear benefits, but what are the
> risks and do the risks outweigh the benefits, and he was left in a
> situation of not really knowing and just assuming that, of course, the
> FDA would be doing post-market surveillance of these drugs. But I
> think it is a really good example of a physician who even did manage
> to go see another physician for advice, and between the two of them,
> they still didn\'t really have the information they needed to make a
> reasonable decision of what is best.
>
> So here is just four examples of how drugs and devices can be approved
> when the long-term safety is not clear and how our current system
> doesn\'t enable the FDA to have the resources it needs to do the
> post-market surveillance that is so essential.
>
> We are currently mostly relying on manufacturers to do this work, and
> we know from experience that a manufacturer might be reluctant to
> admit that they are selling a product that could potentially cause
> serious health problems, and that is why we have regulatory agencies.
>
> This is a dangerous situation for consumers across the country, and a
> recent GAO report tells us that the health products that have been
> taken off the market most recently were disproportionately used by
> women and disproportionately caused harm to women.
>
> The FDA clearly needs more money and staff to do post-market
> surveillance and related activities, and whether that money comes from
> PDUFA or whether that money comes from Congress, it has to come from
> somewhere and it has to be stable over time, but, in addition, I think
> it is very clear that the FDA needs more regulatory muscle in addition
> to more resources to enable them to regulate these medical products
> that are already approved. And I would say especially implanted
> devices and drugs that are taken for chronic health conditions.
>
> Potential strategies. Changing the system of post-market surveillance
> with a stronger regulatory role for the FDA, increasing user fees and
> including the cost of comprehensive post-market surveillance in those
> user fees, requiring user fees for medical devices pre- and
> post-market. I didn\'t have on my list, but I very much agree with the
> idea of direct-to-consumer advertising and better regulation of those
> ads as part of what is necessary for this process. Changing the
> formula used in the allocation of Federal funds for various FDA
> regulatory and scientific activities in PDUFA, if it is going to have
> a formula, that needs to be changed, dramatically increasing the
> amount of Federal funds and staff available for post-market
> surveillance of drugs and devices and, of course, just some
> combination of all of these things.
>
> So, again, I really want to thank you for the opportunity to speak
> today, and I was really pleased how much I agreed with so many other
> people who have spoken, but, again, on behalf of our center, I really
> want to express our support for the FDA and our hope that you will
> have the resources that you need and that we can help to make that
> happen.
>
> MR. BARNETT: Thank you, Dr. Zuckerman.
>
> Jeff Bloom?
>
> MR. BLOOM: Thank you.
>
> Just to be clear, I am not testifying on behalf of the Patient and
> Consumer Coalition today. I am a member of it, but I am here on behalf
> of Title 2, the T-2 Community AIDS National Network. I am an AIDS
> advocate and also a person living with AIDS for the last 14 years. So
> I fully understand the benefits of pharmaceuticals. I wouldn\'t be
> here today without them, but I also fully understand the dangers. For
> people that think that we have to wait to see what is going to happen,
> for disasters to happen, we are seeing them already now.
>
> Particularly with the AIDS drugs right now, we have a situation where
> you can take a number, you can pick a number. Some people say 50
> percent. Some people say 70 percent. It depends on the clinic you talk
> to. But it is safe to say that about half the people that currently
> are in AIDS care are going to see the doctor from the side effects of
> the medicines that they are taking. These are the medicines that are
> supposed to be making them well.
>
> No one could have foreseen this at the time of approval because we
> just don\'t have that information. It is impossible to extrapolate
> from 24 weeks of information on 1,000 people what is going to happen
> when tens of thousands of people take medicines for 5 or 10 or 15
> years, and it could very well be a Faustian bargain that we have. I
> take these medicines. I know what they are doing to my cholesterol. I
> know what they are doing to my triglycerides. It may very well be
> giving me heart disease, liver problems, kidney problems in the
> future. It is a great bargain in the short run, but we really need to
> find out what is happening in the long run.
>
> There are two things about PDUFA that are extremely troubling. This
> should be said over and over again. The person from Scripts had asked
> the question before about what was the Patient and Consumer Coalition
> position on PDUFA. I don\'t believe we have ever opposed PDUFA.
>
> I think what we have said, and what I will reiterate today and I will
> say as Yogi Berra said deja vu all over again, PDUFA represents
> fundamentally the Federal Government\'s failure to fund the FDA
> adequately to protect the public health and safety of the American
> public.
>
> We have three pillars of public health in the United States. We have
> NIH which, to the Government\'s credit and very much in the correct
> way, has continued to increase their funding, with the goal of
> doubling NIH\'s funding in the next decade, to provide all of this
> innovate research, to get better medicines, to get better products, to
> get breakthrough therapies out to people. We have the CDC which gets
> funded at a tremendous amount of money to do their role, and then we
> have the FDA. It gets about \$24 billion. I am not sure what the CDC
> number is, but it is up about that.
>
> The FDA\'s budget is \$1.4 billion. That is \$1.4 billion to regulate
> a \$270-billion pharmaceutical industry. One of the problems with
> PDUFA is it sort of makes the FDA look like it only regulates drugs.
> That is such a small part of what they do. They have such a broader
> mandate, and now the focus is it looks like it is a drug approval
> agency with disregard for the rest of the things, and there has to be
> greater congressional funding for the FDA.
>
> I do not know if additional user fees are the answer, but these things
> need to be done. They are not getting done. Even if the post-marketing
> trials and the confirmatory trials that the companies are doing or
> agree to do or sometimes do under the current things, the patients are
> still not getting the information. The third-party payers, the
> care-takers are not getting the information about how to use these
> drugs properly with patients, and that is still a problem.
>
> The interesting thing is that the PDUFA has created drugs and gotten
> them out to the market at a faster rate. There is no question about
> it, but the question is at what cost, and we are starting to see that
> cost now.
>
> We don\'t have a good handle on that cost because we don\'t have a
> good adverse event reporting system. We don\'t have good
> post-marketing studies, and we don\'t have any of these things. It is
> good to hear the FDA being very candid about these problems, and I
> appreciate them being very forthcoming about the situation that this
> has created.
>
> A perfect common-sensical thing here that should be apparent to anyone
> in this room right now of why having a strict stricture on PDUFA
> funding only going for drug approvals is the current situation we find
> ourselves in now. We are at war. We have a bioterrorism problem. The
> FDA is involved in this situation.
>
> Right now, they can\'t take any of that money in this emergency
> situation and take those funds and use it for the public health
> because it has to be allocated to only drug reviewers. That makes no
> sense whatsoever.
>
> Something has to be done to give the science back to the scientists.
> The FDA needs to not be a political institution, but a
> scientific-based institution, based on science, and let the scientists
> at the FDA make the decisions, not artificial time deadlines, not
> artificial performance goals that are not realistic, and,
> unfortunately, at the time they were negotiated, did not quite seem to
> be the way they were. The meetings and time deadlines have turned out
> to be an extraordinary burden that are not paid for right now, and
> that is something that needs to be addressed.
>
> One of the interesting things is that the tools for all of this are
> already there, and I am going to read a small section because I don\'t
> think you can divorce the two things. As much as industry would love
> to have a conversation about PDUFA without talking about FDAMA\--they
> didn\'t have that problem in \'97 when the two were linked together.
>
> I am going to read a section of FDAMA to you. It is just food for
> thought because this is really what we need. This is a section of
> FDAMA that talks about the activities that should be done, and this is
> the conduct of state-of-the-art clinical and laboratory research for
> the following purposes: (a) to increase the awareness of the new uses
> of drugs, biological products, and devices; two, ways to improve the
> effective use of drugs, biological products and devices; and, three,
> risks of the new use and risks and combinations of drugs and
> biological products; (b) to provide objective clinical information to
> the following individuals and entities \-- and this gets to what the
> Blue Cross person was talking about, which I think is incredibly
> important \-- health care practitioners and other providers of health
> care goods or services, pharmacy benefit managers, health maintenance
> organizations or other managed care organizations, health care
> insurers or governmental agencies, and then consumers, and also to
> improve the quality of health care while reducing the cost of health
> care through the appropriate use of drugs, biological products or
> devices and, two, the prevention of adverse effects of drugs,
> biological products, and unnecessary hospitalizations, the conduct of
> research on the comparative effectiveness and safety of drugs,
> biological products, and devices.
>
> Now, you might think since this is in FDAMA that that would be FDA\'s
> mandate, but that is not FDA\'s. This is the CERTS. This is the
> Centers for Evaluation and Research in Therapeutics that are supposed
> to be doing this, but this is what patients need. This is what the
> third-party payers need. This is what the insurers need. This is the
> information that we need that with this faster approval that we need
> to have this information on the back end, and perhaps the FDA, if we
> can\'t convince Congress to fund the FDA more fully to do these
> things, perhaps they will fund an independent organization like the
> Centers for Evaluation and Research in Therapeutics, which,
> thankfully, is in here, but this does give us the tools that we need.
>
> Some people are talking about a disaster waiting to happen, and I want
> to go back to what Dr. Woodcock said on that one slide, and I think
> that was a very telling slide. There isn\'t a disaster waiting to
> happen. There are disasters happen.
>
> When you look at a slide and you see that there is 50- to 100,000
> deaths, some of them obviously from drugs, in hospital, that is not
> even counting nursing homes. That is disasters already happening, and
> that number doesn\'t seem so ominous because it doesn\'t all happen in
> one day, but you can guarantee if all 50,000 of those people died in
> one day, there would be hearings on the hill in half-a-second. 400,000
> tires blew up. They had hearings for 3 weeks. 50,000 levers explode.
> No hearings at all. Part of that is industry probably needs to take
> greater responsibility for the safety of their products. I don\'t know
> if user fees is the answer. There might be some other roles, such as
> after a drug is approved that there is a fee attached where there is
> some post-marketing and safety things that the company has to pay for.
>
> There is no question that the FDA provides the pharmaceutical industry
> a tremendous opportunity for profit and growth, and they are the last
> hurdle before they get through this. Yet, they are the least-funded
> part and the most important part. This has to change.
>
> One of the things that has always disturbed me is that it is really
> wonderful and I think it is great that the United States is first now
> in the world in approving all of these things. That also means,
> though, that there have been thousands and thousands of patients,
> including myself and many other people probably sitting out here, that
> have volunteered to participate in clinical trials. We are willing to
> be guinea pigs. We are willing to take the chance. We are willing to
> take the risks because we have no choice.
>
> If you have a serious or life-threatening illness, you don\'t have a
> choice but to take this gamble, but it should be an educated gamble.
>
> One of the things that has always been troubling is after you are in
> this 24 weeks of a trial, that is it. You are gone. You are a piece of
> data, and you are gone, but nothing is done to track people. There is
> this valuable database of patients out there that could be tracked
> more, that could be a subset from the trials, that are followed over a
> period of time, where we can find out what the events are. There is no
> possible way of having a crystal ball to see what is going to happen
> with the drugs 5 years down the road.
>
> No one could have predicted that protease inhibitors, which in 1996
> revolutionalized AIDS, now, 5 years down the road, would be causing
> lipodystrophy, fat redistribution, diabetes, osteoporosis,
> cholesterol, triglycerides. All of these other side effects were
> unforeseen at the time, but we don\'t have good information on it
> because we don\'t have a good system, and it has to be funded. Whether
> it is going to be user fees or congressional appropriations or funding
> to the Centers for Evaluation and Research in Therapeutics, if it is
> not done, the only people that are going to lose are the patients, and
> the patients are paying the price now and the third-party payers,
> insurers, and the Government is paying the price.
>
> It is interesting to have these conversations in abstract, and there
> is no question\--I talked to PhRMA last week, and I met with them. I
> must say, some of their things are very interesting. They would like
> to have a clean PDUFA. Their position is that if they could have the
> 1997 PDUFA rolled over, 2002-stamped, passed, they are happy with
> that. Obviously, they are. They have got the best situation. They have
> cherry-picked the plum of the thing. They pay for only when a new drug
> application goes in. They don\'t pay for any other stuff that the FDA
> does, for all the pre-meetings, all the consultations, all the
> up-front meetings that they do, including when they stop developing a
> drug, wasting millions of dollars, saving the industry potentially
> millions, if not billions, of investments.
>
> If it cost \$802 million to develop a drug, which no one believes that
> number, but that is the latest number, the FDA, when they help
> industry in consultation with them prior to filing an NDA to stop
> going down that path, is saving millions and millions of dollars. That
> is never recognized.
>
> CBER and CDER right now review over 5,500 protocols a year for
> clinical trials. No one is paying for that, and that number is only
> going to increase. We have more and more foreign clinical trials being
> done, more and more foreign productions. They don\'t have inspectors
> for this.
>
> Out of 30,000 clinical trial sites, they only inspect 1,100 a year.
> That means at the current rate, it would take 30 years to inspect
> every clinical trial site. So, yes, there has to be more money.
>
> Whether it is user fees or not, I don\'t have an answer for that now.
> I have some qualms about having more industry money in the FDA, but
> the need to have more information after drugs are approved is vital in
> order for patients, doctors, third-party payers, and everyone else to
> know what is going on in their bodies, what is happening to their
> health, and what are the long-term effects of the consequences of this
> accelerated approval.
>
> MR. BARNETT: Thank you.
>
> Judy Cahill.
>
> MS. CAHILL: Good morning. Thank you very much for the opportunity to
> be here. I do appreciate the agency taking the initiative on this to
> pull together stakeholders.
>
> I am here as the executive director of the Academy of Managed Care
> Pharmacy. The academy of a professional society representing the
> interests of pharmacists who practice using the principles of managed
> care. They are directly involved with the oversight of building of
> networks that provide prescription drugs access to over 170 million
> Americans in the country.
>
> AMCP believes extending the PDUFA user fee program is a necessity. The
> program has made a significant contribution in securing the financial
> resources to expedite the Food and Drug Administration\'s drug and
> biologics review and approval process.
>
> My comments today will focus on whether PDUFA should also allow the
> use of user fees for the purpose of monitoring safety after a drug has
> gone through the approval process.
>
> My observations are drawn from the academy\'s 4,800 members who have
> the responsibility of pharmacy benefit management for the American
> population as a whole.
>
> Those pharmacists are employed by health plans, pharmacy benefit
> management companies, integrated health care delivery systems,
> third-party administrators, and retail pharmacies. Their views are
> reflective of what the profession of pharmacy encounters in the
> ambulatory setting.
>
> The fundamental goal of the agency is to promote and protect the
> public health by determining in a timely manner a drug or biologic
> safety and effectiveness based on clinical research and taking
> appropriate action on the marketing of these products. It is that
> latter charge to the agency that we want to focus on this morning.
>
> The academy believes the objective of FDA\'s post-market surveillance
> program must be on the ongoing collection and review of data related
> to problems associated with a drug\'s use in order to determine if
> that drug should continue to be allowed to be marketed to the public
> under its original approval or whether it should be modified based on
> experience in the post-market environment. Those might include
> restrictions on distribution of the drug or it might go to the point
> of actually withdrawal, which we have heard a lot about this morning.
>
> Consequently, we consider post-market surveillance to be an essential
> programmatic function for the agency if it is to fulfill its mission
> of promoting and protecting the public health.
>
> Pharmacists in the ambulatory setting depend on the FDA to perform its
> post-market surveillance responsibility for four principal reasons.
> First of all, the agency is in a unique op to be able to collect that
> data. Secondly, the expanded experience which we have heard referenced
> several times this morning that is available in the post-market
> environment is crucially important for understanding how a drug
> affects people. Thirdly, what we learn from post-market surveillance
> data is essential in enhancing patient care. Fourthly, it is also
> essential in reducing the cost of that care.
>
> Let\'s take a little closer look at each of those four items. First,
> the agency\'s ability to aggregate data, in the inpatient setting,
> there is the institutional structure that provides a mechanism to
> collect data on drug use in a systematic way. The highly fragmented
> nature of health care delivery in this country defies a systematic
> aggregation of adverse drug events in the ambulatory setting. Only in
> the most highly integrated health care organizations are there
> structures and processes in place to allow reporting, collecting,
> storing, and analyzing of adverse event data that arise from a single
> organization\'s covered population.
>
> Notwithstanding what integrated health care organizations may be able
> to do, the reality is that most health care organizations look to the
> FDA to provide vital post-market surveillance data. Even integrated
> delivery systems must rely on FDA data to validate the observations
> that arise out of their own patient population.
>
> Second, the data collected after approval is arguably more important
> than that collected during the drug approval process. The information
> gained from clinical trials and pre-approval is limited. Studies are
> conducted in small populations under strictly controlled parameters.
> It is only when the drug is in the marketplace being used by a
> sizeable population over a prolonged period of time that the effects,
> attributes, weaknesses, and problems that are associated with the drug
> can truly be evaluated.
>
> Third, post-market surveillance data are a vital source of information
> that health care professionals use to enhance patient care.
>
> I will turn to the managed care setting for an example of that because
> there is no more efficient way of approaching total patient care than
> in the integrated health care delivery system.
>
> Integrated delivery systems share post-market surveillance with the
> prescribers who are under contract with them. They are able to
> reinforce what the FDA has issued in its Dear Doctor letters, and they
> are also able to take that information and to adapt to their practice
> protocols that are used by their providers to enhance patient care.
>
> Additionally, pharmacy and therapeutics committees employ post-market
> surveillance data as one factor in determining whether a drug should
> be recommended for use by its patient population. FDA reports allow
> the committees to validate patient reaction within their own
> populations, weigh the potential harm of a drug, for instance, its
> potential benefit, make informed decisions about inclusion on the
> formulary, and identify high-risk patients who need to be targeted for
> specific case management review because of what has been learned about
> a drug\'s reaction.
>
> Fourth, problems associated with a drug\'s use directly impact the
> overall cost of care in this country. Numerous studies in recent years
> have demonstrated that many physician visits, hospital admissions,
> emergency room visits, laboratory tests, expenses across the spectrum
> of health care expenditures in this country result from improper use
> of drugs or inappropriate reaction to the use of those products.
> Clearly, a post-market surveillance program helps avoid adverse drug
> events and can, thus, save our health care system significant dollars.
>
> But where does that responsibility lie for post-marketing
> surveillance? I would submit to you that the Federal Government, drug
> manufacturers, and prescribers all have responsibility and obligations
> regarding post-market surveillance.
>
> Until relatively recently, the programs of the FDA were almost
> entirely focused on the drug approval process, and from what we have
> been hearing this morning, that still is certainly the primary
> emphasis. To some extent, that has changed, and we greatly support the
> move to greater and more comprehensive post-market surveillance.
> Legitimate questions can be raised as to whether the agency has been
> able to implement effective post-market surveillance.
>
> I was quite taken aback to find out that the MedWatch program is
> staffed by three people. Something needs to be done, definitely.
>
> Similarly, drug manufacturers must recognize their obligations to
> assure throughout the life cycle of their products the safety of all
> of their products and that they must be accountable to both the public
> and to the regulators in providing those assurances.
>
> Prescribers. Prescribers are in the most critical position for
> assessing the problems associated with drug use because of their
> direct interaction with patients and because of their overall
> responsibility for monitoring and directing patient care, the need to
> better understand their responsibility for reporting drug safety
> problems. Unless the prescriber becomes far more engaged in the
> post-market surveillance process, its potential for success will be
> limited.
>
> The FDA must use its resources to encourage far greater reporting by
> the prescriber. FDA, manufacturers, and prescribers must be far more
> proactive in the gathering, evaluating, and disseminating of
> information about drug safety after market approval of a product.
>
> I would like to conclude by issuing four recommendations from the
> Academy of Managed Care Pharmacy. First, FDA\'s current post-market
> surveillance system for identifying previously unknown adverse effects
> of drugs suffers from a lack of resources. A new user fee imposed on
> manufacturers should be added under PDUFA and should be designated for
> an approved and coordinated post-market surveillance program. Such an
> earmarked fee is appropriate, given the manufacturer\'s responsibility
> to provide a drug that is both safe and effective throughout its
> entire life cycle. The funds collected from user fees should be of an
> amount sufficient to recognize that post-market surveillance is as
> important as the drug approval process is.
>
> Secondly, prescribers, pharmacists, manufacturers, and health plans
> are remiss in reporting adverse drug events and other problems
> associated with a drug\'s use. The FDA should initiate an aggressive
> educational campaign targeted at patients and health professionals,
> stressing the importance of and encouraging the reporting of adverse
> drug events and related problems to the agency.
>
> Thirdly, the FDA should undertake an audit of the notification
> mechanisms it uses to ascertain if all parties with a need to know are
> being informed; that this is happening on a timely basis and with
> sufficient and detailed information and appropriate opportunity for
> feedback and input.
>
> We do hear from the members of the Academy of Managed Care Pharmacy
> that frequently pharmacy directors and health plans do not receive
> from the agency notification about what has been discovered in the
> post-market surveillance. They generally hear it from one of the
> doctors who has received the Dear Doctor letter, and this overlooks an
> opportunity to get out to a vast network of health care professionals.
>
> Fourthly, we suggest policy-makers consider the alternative of
> creating an independent organization responsible for post-market
> surveillance, separate from the FDA. The public agency would collect,
> analyze, and disseminate information about the safety and efficacy of
> drugs in use in the marketplace. The arrangement would be similar to
> the one that exists between the Federal Aviation Administration and
> the National Transportation Safety Board. Both the FDA and the
> post-market surveillance agency would serve the public in assuring
> that safe and effective drugs were available. A separate agency would
> provide significantly higher visibility to post-market safety issues
> and be independent of the decision-making process that originally
> approved the drug for marketing to the public.
>
> The separation of pre- and post-approval functions would enable
> distinct, independent assessment of the critical issue of product
> safety.
>
> The Academy of Managed Care Pharmacy supports changes that would
> result in a significantly improved and comprehensive program for
> identifying problems associated with the use of drugs by patients.
>
> We look forward to working with the agency and any other public
> authority in achieving that end. Thank you very much.
>
> MR. BARNETT: Thank you.
>
> It is time now to once again open the floor for comments, and if you
> have any, come on up to the microphone. Remember, these are comments
> on the post-market aspects of PDUFA.
>
> Just identify yourself.
>
> FLOOR QUESTION: I am Susan Cohen, and I am a consumer member of an
> advisory panel. So I bring my dimension to this. I usually have a loud
> voice.
>
> I have two concerns about the approval process. One is I am concerned
> about the conflict of interest when a researcher receives money from a
> pharmaceutical companies and then speaks on behalf of the product, and
> I am also concerned that the medical officers get all the respect they
> possibly can because they provide us a lot of information.
>
> I also feel very strongly that any insert that you get with medication
> or from the pharmacy, that they give you a number to call if you have
> an adverse effect, and it should include some questions so people have
> some parameters in which to do that.
>
> I think that there should be a separation out of drugs that are
> already on the market, and this is just one more drug that does the
> same thing. First, it is something that is entirely new and very
> special. I think there should be a separation out of that.
>
> I am also concerned that in the process there is not enough testing of
> children because so much of these drugs go on to children, however it
> is done. I think we need more of that.
>
> I also am concerned that the consumer really understands what the
> advertising means. That is why I want to see on a bottle a label that
> gives them the phone number to call and really points out the
> specifics because the end product of this from my point of view is not
> money. It is about the consumer and how they can be protected.
>
> I know we have talked about recalls. Do we know how many recalls there
> were under PDUFA, the process of PDUFA, how many?
>
> Dr. Woodcock, do we know?
>
> DR. WOODCOCK: Well, we know the rate. The exact number changes over
> time, but the rate of recalls before PDUFA of new molecular entities,
> new products introduced into the United States is 2.7 percent of all
> products introduced were recalled.
>
> Under the user fee program, it is 2.8 percent of products that have
> been approved under the user fee program have been withdrawn..
>
> FLOOR QUESTION: I am just curious since the PDUFA process is different
> than the other process I have seen. Are the questions unique to the
> process of doing PDUFA that you wouldn\'t normally ask on the usual
> process?
>
> Well, I think that is something that should be considered. Thank you.
>
> MR. BARNETT: Thank you.
>
> MR. BLOOM: Could I make a comment about what she has just said?
>
> MR. BARNETT: Yes.
>
> MR. BLOOM: Excuse me, ma\'am. Ms. Cohen, just to reemphasize something
> that you brought up, which I think is an excellent point, about a
> number on the bottle in terms of adverse events, one of the things
> that we have talked about at the Patient and Consumer Coalition
> meetings\--and it is not a formal position that we have yet, but I
> think that your point is excellent.
>
> One of the things, we are stuck with this world of DTC advertising and
> television advertising and this plethora of marketing now. Your point
> is extraordinarily well made in that how can we use this DTC
> advertising for the betterment of patients as well. One of the things
> that we think that would be very useful is to do exactly what you are
> recommending. It is to have a number on there, to have an information
> thing to say if you have a serious adverse event or if you have any
> questions or problems with this medication, call this number, report
> what happened, so that there is more information coming in and more
> reports because we do capture such a small thing. So it is an
> excellent, excellent recommendation.
>
> FLOOR QUESTION: And the print should be larger.
>
> MR. BLOOM: Absolutely.
>
> FLOOR QUESTION: For people who are older\--and I am an old lady, I can
> tell you\--on the television there is something that flicks by your
> eye. You don\'t know what it is, and also in the print in the paper,
> since you got me going.
>
> MR. BLOOM: It should be in everything. I agree with you. That is a
> great idea.
>
> MR. BARNETT: Yes, sir.
>
> FLOOR QUESTION: Hi. Ben Peck with Public Citizen.
>
> One of the comments that Diana Zuckerman made about how the adverse
> reactions as a result of Fen-phen were discovered prompted me to think
> about a recommendation that is referred to in a GAO testimony about
> the creation of sentinel sites where drugs would be released to
> specified sentinel sites where their adverse reactions could be
> monitored more carefully.
>
> I was wondering if I could get reactions from Dr. Woodcock or others
> on the FDA panel about their views on that sort of process being
> created.
>
> Then, also, I would love to hear reaction to the idea of an NTSB-like
> setup for the post-marketing surveillance process that the last person
> on the panel talked about.
>
> Thank you.
>
> DR. WOODCOCK: With regard to the issue of sentinel sites, that whole
> idea is part of a broader issue of should we have some active
> surveillance, which is something we don\'t have. We have to all be
> aware of that. We do not have active surveillance of adverse drug
> reactions in the United States, and we have passive surveillance. We
> hope somebody will send a report in, and if they do, we will find it.
>
> It works pretty well for the extremely rare, startling, unexpected
> adverse events, and we do find those pretty quickly, but as was point
> out, there is a whole range of adverse events that occur and we also
> don\'t know the rate. That is the biggest problem with passive
> reporting. We just know that a few occurred. We don\'t know how many
> actually occurred, and we don\'t know how many people were taking the
> drug, and at risk. So we don\'t have that rate information or
> comparative information. Well, it is bad for this drug, but if you
> read about it in the paper, you start reporting. But what about all
> the other drugs? Are they worse, actually? We just don\'t know about
> it?
>
> So we have looked at this, and, actually, in the recent appropriation,
> there is some money for the device center. We thought we should start
> there, as it is the greatest need, and they have already had some
> pilots of something called MedSun. That would be hospital-based, but
> it would be promoting a more active surveillance through education of
> the clinicians there and giving them a computer system to report
> through and so forth.
>
> We would hope that we could more generalize that effect if that pilot
> would be successful and add drugs in biologics, and, of course, for
> those we would have to add other settings because, although the
> reports are from hospitals because they are all collected together, we
> think most of the action is out in the outpatient world.
>
> MR. BARNETT: Okay.
>
> FLOOR QUESTION: Hi. Jay Lee from the National Center for Policy
> Research for Women and Families.
>
> Like Dr. Griffin, I was very pleased to see that the President
> recently signed a measure increasing the budget for monitoring patient
> safety and adverse event reports from 48- to \$58 million, but I was
> also dismayed to see that the estimated revenue from PDUFA in this
> coming fiscal year was reduced from \$162 million to \$135 million. So
> funding from PDUFA may be less reliable than from congressional
> appropriations. Also, others have noted that PDUFA funding may raise
> more concerns about conflicts of interest.
>
> My question to both the FDA panel as well as to the panel of guest
> speakers is: Should certain elements of post-market surveillance in
> PDUFA III, assuming that PDUFA III does fund such things, be funded
> exclusively or primarily by congressional appropriations while other
> functions are funded primarily or exclusively by PDUFA III?
>
> DR. SUYDAM: I think that is the critical question we are here to
> discover your and other points of view on. I think it clearly is an
> issue for us.
>
> The reason the PDUFA number went down was because of the formula that
> is used to determine how the funds are allocated, and the fewer number
> of applications we have coming in means that we have fewer dollars
> coming in. The rate of applications coming in from the pharmaceutical
> and biologics industry has been going down over the last couple of
> years, and as a result, there is less money to support the program.
>
> I think it is clear that we need to have a more active post-market
> surveillance program. It is something that we have put in our budget,
> proposed in our budget for the last 4 years, and, hopefully, this year
> was the first year that we really had a breakthrough that we got \$10
> million for it and we hope that will continue.
>
> FLOOR QUESTION: Great. If I may ask one follow-up question quickly. I
> know money is fungible, but are there currently programs that are
> funded by PDUFA where certain elements are specifically funded by
> congressional appropriations and others in that same program funded by
> PDUFA?
>
> DR. SUYDAM: No.
>
> FLOOR QUESTION: So there is no separate issue at this time.
>
> DR. SUYDAM: The way the program was set up, we\--am I right on this?
>
> DR. WOODCOCK: Yes.
>
> DR. SUYDAM: I am. The way the program is set up is that there would be
> no specific program that would be PDUFA only. So you have the flow of
> money comes into the drug center, and you have it paying for a
> percentage, for example, of the library services or a percentage of
> the IT activities, but you can\'t tell which percentage or what
> activities. It is not specifically designated for that.
>
> FLOOR QUESTION: In PDUFA III, I would suggest that there be more
> careful accounting of that.
>
> Thank you very much.
>
> MR. BARNETT: Thank you.
>
> FLOOR QUESTION: My name is Niki Colton \[ph\], a health care attorney
> in the area.
>
> My question is with all of these suggestions, we are looking at a
> go-forward issue, and if we are depending on PDUFA, it would be
> prospective for new drugs, new applications, and the revenue of that
> is uncertain.
>
> What is the suggested strategy for the drugs that are currently on the
> market, protease inhibitors, for example, as to how do we catch up?
>
> MR. BLOOM: I will take it. How will we catch up? How we will catch up
> is Congress and the Federal Government has to live up to their
> responsibility to fund the FDA properly, and if they inadequately fund
> it\--I am floored. I would like to see a show of hands, just out of
> curiosity. Let me take a little random survey here.
>
> MR. BARNETT: Hey, who is the moderator?
>
> \[Laughter.\]
>
> MR. BLOOM: I am now.
>
> MR. BARNETT: Go ahead.
>
> MR. BLOOM: In this room, how many people here\--raise your hand if you
> think that three people in the MedWatch program are an appropriate
> number of people to have to be overseeing adverse event reporting for
> the FDA?
>
> DR. WOODCOCK: Well, Jeff, let me clarify what the three people do.
> They take the direct reports.
>
> MR. BLOOM: Right.
>
> DR. WOODCOCK: We have a group of people, and then those are put in the
> database by our contractors. Then our safety evaluator looks at them,
> but my point is to have a robust program to teach clinicians,
> pharmacists, everyone, the importance of reporting, to run that
> outreach, to make it easy.
>
> We had some Members of Congress who tried to file reports on our
> computer screens a while ago, and they weren\'t able to do it because
> it isn\'t that modern. That is the kind of thing I am talking about.
> We need an outreach program. We know.
>
> We ran one about a decade ago in Rhode Island, and we increased the
> volume of reports, I think, 17 times. We got 17 times more reports by
> publicity, teaching, training people to report. Now, I don\'t know
> what we\'d do with 17 times more reports. We are swamped now, but the
> point is in that outreach and handling the direct reports program,
> there are three people.
>
> MR. BLOOM: Right. That same situation happens at the FDA with DDMAC,
> the division that oversees all of the advertising. They are incredibly
> inadequately staffed in relation to the volumes of new DTC,
> television, print, media. There are 70,000 drug detailers that visit
> doctors\' offices. Thanks to PDUFA, there are 1,000 less non-PDUFA
> employees at the FDA, down to 7,000 people that work on other things.
> The disproportionality of this is staggering when people think about
> it.
>
> So the bottom line is that it is very good that we are having this
> meeting here today, and it is a good discussion to have, but this is
> the message that has to be carried to Capitol Hill, to Congress, and
> the administration that they absolutely, positively must start funding
> the FDA or the CERTS or some other function, like an NTSB thing.
>
> We are not opposed to the independent safety board. We think it is a
> good idea in some ways. To have this happen\--because we are losing
> this information. We are getting further and further behind every day,
> and we are putting more and more new drugs on the market without the
> systems in place to still get the information, and that is the real
> issue here. People are putting these things in their bodies every
> single day, and we really need to know what happens, not just this
> year or next year, but 5 years and 10 years and 15 years, and we
> don\'t have that information in a good way now. It is a matter of
> appropriations, and the dollars have to be put up for it.
>
> MR. BARNETT: Thank you.
>
> Yes.
>
> DR. ZUCKERMAN: I just wanted to add to that. We are in the ironic
> situation of having a Vice President whose life depends on an
> implanted device that may or may not be having any kind of rigorous
> post-market surveillance, but, also, of course, I would assume a lot
> of Members of Congress now taking cholesterol-lowering drugs and other
> drugs for chronic health conditions. One of the things that would be
> helpful would be to have the information available for those of us
> who\--of course, we do not lobby, but educate Congress to let them
> know that the drugs that they themselves are taking, to let them know
> what the resources are currently available to check on the long-term
> safety of those drugs once they have been approved. I think that would
> be a very valuable lesson that would hit close to home.
>
> MR. BARNETT: Anyone else? Yes.
>
> FLOOR QUESTION: I am Ann Rose. I am president of a company that
> specializes in helping the biotech industry and small pharmaceuticals
> who are mainly research-based, help them in their development so they
> have credible proof of concept, Phase I trials, so that, as Jeff said,
> we don\'t have more patients exposed to potential harmful devices or
> drugs.
>
> But I am not here on that behalf today. I am very much interested in
> the discussion that went on, and Judy made a comment that I think
> elicited in my mind the following, and that is that responsibility can
> be shared across all fractions. Whereas, FDA needs more assistance,
> and I had been in the Department in prior years for a good number of
> years, understand the FDA issues, I think, at least to an informed
> consumer point of view.
>
> There is responsibility for all the organizations, managed health
> care, insurers, et cetera, who have direct contact with their members
> to inform them to report the adverse experiences they are seeing.
>
> I was appalled when Janet put up the small number that comes from this
> type of reporting, and there is a responsibility for each of us in our
> roles and those particularly in the organizations that are dealing
> with that to spend a concerted educational effort at doing just that.
>
> Secondly, I think Jeff hit on a point that is also close to my heart,
> and change comes from advocacy groups. I happen to have been in the
> administration when AIDS hit the public health. A large measure of why
> there is change and why there was change in the FDA and in Congress
> had to do with the vocalization. So it is not, in my mind, good enough
> for us to sit here and bitch and complaint about Congress not going
> it. We have a personal responsibility to make that cause known, and I
> think the AIDS issue, as Jeff knows, did miraculously different things
> in the entire approval process.
>
> MR. BARNETT: Thank you.
>
> MR. BLOOM: I thank you for that comment, and I want to support what
> you said. I think you are right. Everyone does have a responsibility,
> and patients even have a responsibility.
>
> I can give you a very small example that sort of gives you a broader
> perspective of this, and this is a very small example, but it shows
> you exactly, to highlight her point.
>
> I went to the doctor about 2 years ago and I had ingrown toenails. It
> was sort of a strange thing to sort of suddenly have. I was sitting
> there with the doctor, and they asked me if I was on a particular
> medication. I will leave the name of the protease inhibitor unstated
> for the purposes of this meeting, but suffice it to say, he said,
> \"Oh, you are the fiftieth person that has come in with ingrown
> toenails that has been on this medication.\" I said, \"Well, have you
> turned in any of these reports to the FDA?\" He said, \"No. I didn\'t
> think about that.\"
>
> There may not be a cause-and-effect there that there is 60 patients at
> one podiatrist office that all have ingrown toenails that are on the
> same drug, but there is a good bet that there is some relationship
> there, and he turned in those reports.
>
> But you are right, it is everyone\'s responsibility, and it is
> everyone\'s responsibility because you do have to press your doctors
> to turn in the reports, but, also, I think Janet can tell you that is
> another thing about getting MedWatch and all of these things put up
> more is patients can report these adverse events themselves, friends
> of patients, their family members. So the ability is there. The effort
> has to be made. The public effort has to be made to broaden it and to
> make it more important, and perhaps the FDA is not the best place to
> do this. The CERTS might be. The CERTS are going a fairly good job of
> this right now. Maybe Congress will be more willing to fund them.
> There is some reluctance, obviously, on Congress\' part to feel that
> the FDA should be funded. They don\'t like regulatory agencies.
> Unfortunately, regulatory agencies exist for a reason.
>
> We have them because they are regulators. They are here for a purpose.
> They are here to make sure that drugs are safe and effective and do
> what they are supposed to do, and Congress tends not to like
> regulators until things go wrong and then they come up and say, \"All
> these tires blew up.\" Well, you didn\'t give any money to the NTSB to
> do anything about this.
>
> So we would like to try to prevent the disasters, but you are right,
> it is everybody\'s responsibility, and I totally agree with that.
>
> MS. CAHILL: I would just like to underscore the point that the
> questioner raised and that Jeff underscored and, Janet, that your
> figures speak to direct reports. I identify what I hear from a number
> of my members who are pharmacy directors in large health care networks
> that have thousands of physicians under contract, and when they go out
> and have face-to-face meetings with their physicians about what they
> have experienced with given drug products, by and large, they hear
> what Jeff heard from his podiatrist, \"Oh, no, I just never even
> thought about reporting that. Oh, yeah, I see that all the time.\" And
> it is that type of lack of consciousness that I think would underscore
> the need for an educational campaign.
>
> I was impressed by what you had to say, Janet, about what happened in
> the Rhode Island pilot experience. When you start talking to people
> about these things, all of a sudden, it begins to interrupt the cycle
> of normal operations, if you will, and people start attaching the
> importance to it that needs to be.
>
> MR. BARNETT: Please go ahead.
>
> DR. GRIFFIN: The only other comment I was going to make to follow on,
> a lot of it goes back to the money train, and it goes back to active
> versus passive surveillance. Passive surveillance is obviously a lot
> less expensive. You sit and you receive whatever reports you can get.
> Given past levels of funding, passive surveillance is essentially what
> can be done.
>
> Moving to active surveillance, where you go and you look for certain
> things, if someone is placed on a drug that you would expect to be a
> permanent medication and they don\'t renew it after 90 days, there is
> a hint in there that, well, either they didn\'t like it, they had an
> adverse reaction, or they were changed to something else, but then the
> question becomes why. To be able to go after that, though, takes
> funding, and the funding needs to be stable funding, not tied to the
> portico winds that happen to blow from year to year in the way our
> budgetary process sometimes works.
>
> MR. BARNETT: Thank you.
>
> FLOOR QUESTION: I am Jill Waxler. I am the Washington editor of
> Pharmaceutical Executive magazine and some other magazines in this
> industry.
>
> Just to clarify, everyone agrees that FDA should have more reliable
> funding to do a lot of post-market surveillance and other
> safety-related issues, and there have been various proposals. One can
> assume that Congress would probably never supply all the funding for
> all the various proposals that everyone has.
>
> Does this panel and other people who have talked see that the
> preferable option is for the manufacturers to pay more user fees for
> FDA to have more flexibility and control over how they use a specific
> finite amount of user fees or for some of these activities to be
> handled by a totally separate agency as some people have referred to?
>
> MR. BARNETT: Before anyone answers, let me just remind you that we
> have about 5 more minutes before lunch.
>
> Do we have a response to this?
>
> DR. GRIFFIN: The first one is, obviously, we get to certain places by
> drifting different lines, but we have to acknowledge where we are. To
> create a new agency or a new safety board or other things would add
> even more to the cost, and I think it is a little purgative to the
> Food and Drug Administration which I think has done a very good and a
> very impartial form of dealing with the resources that they already
> have allocated.
>
> The funding goes back to where is the money going to come from and how
> do we make sure that it is a stable source. User fees might not have
> been my initial choice when building it, but certainly going forward,
> we look at where we are and I think it is the best vehicle to tie
> future funding to.
>
> MS. CAHILL: I think that there ought to be serious consideration of an
> independent safety board, and that is not to cast any aspersions on
> the job of pre-approval that the agency is doing.
>
> I, for one, as I look at the track record that the agency has, am very
> impressed by the independence from the manufacturers that the agency
> maintains. The suggestion for an independent safety board is rooted
> really in the observation that medicine is not a science, it is art to
> a large extent. So, if you do have two parallel bodies that are
> looking at drug products, you are probably better assured of getting a
> reasonable assessment of the safety of a given product. I think that
> that underscores some careful looking at whether or not there should
> be an independent safety board set up.
>
> DR. ZUCKERMAN: I just wanted to add something. I just think the whole
> issue of conflicts of interest is a very complicated issue. We can say
> that ad nauseam, I suppose.
>
> In the ideal world, certainly, I think user fees raise an appearance
> of conflict of interest and perhaps a sense that companies are paying
> for approval as opposed to paying for review, and I think that is an
> appearance problem. Of course, it is also true that medical devices
> are not paid for by user fees, and I don\'t think anybody would say
> that that seems to be a system that is working better or has fewer
> conflicts.
>
> I think there are a lot of conflicts of interest in medicine and in
> regulatory review. We all know that people work at the FDA and then go
> to work for the companies that they previously reviewed. So this is a
> big issue, and I think that user fees are just a small part of a much
> bigger issue. So, before we solve the problem by getting rid of user
> fees, I think we probably need to look at more direct conflicts of
> interest of individuals who do reviews or participate in reviews and
> the whole advisory committee process that includes people who have
> potential of financial links to the products and so on.
>
> I also just want to say that having worked in Congress for a dozen
> years or so, I think that Congress could be persuaded to be much more
> generous and appropriate in their funding of the FDA. I think it will
> take work to make that happen, but I absolutely believe it is
> possible, and I also know that Members of Congress and their staff
> don\'t understand the FDA. They don\'t understand what you do. They
> don\'t understand why you are important, and that is a job that you
> all have to do better and we all have to do better, too.
>
> Thank you.
>
> MR. BARNETT: On that hopeful note, yes, another one.
>
> DR. WOODCOCK: Sorry. I just had two comments I wanted to make, but I
> forgot one of them.
>
> Oh, yes, I do remember. First of all, the Center for Drugs has
> established a separate office of drug safety that recently happened
> that is independent. It has an independent reporting chain very high
> up in the organization, independent from the pre-market side.
>
> Second, I would just like to say vis-a-vis all this, the panel really
> struck at a number of issues. I think the source of the greatest
> professional frustration I have had in working at the Center for Drugs
> for the last seven years is our inability to get this information that
> is needed in the hands of the people who need it in a way that is
> timely and that is useful and is preventive of problems happening. We
> need to work everywhere. Managed care, managed care pharmacy, the
> patients and the consumers, and the physicians need this information
> in a way they can use, and it is very complex why you don\'t have that
> information. It is a very complex series, but we are working on it.
>
> I don\'t think it is lack of will. It is just our lack of ability to
> mobilize the resources to get that information, but that is definitely
> one of our goals.
>
> MR. BLOOM: Getting back to your question, ideally Congress should be
> the source of the funding, but if they can\'t be the source of the
> funding, you will have to find another source of funding.
>
> Perhaps what we should be calling it instead of Prescription Drug User
> Fee Act for approval is after a drug is approved, perhaps we should
> have the Prescription Drug Approval Act, that after the drug is
> approved that they pay fees for post-marketing and safety because they
> are certainly making the profits after the drug is approved, and that
> is a source of funding.
>
> The question is do they have a responsibility once the drug is out on
> the market for the safety of their product, and I think most people
> would argue, yes, they do, except for the companies because they seem
> to think they don\'t.
>
> MR. BARNETT: Okay. Thank you very much.
>
> We are going to go to lunch now. I have 12:10. There is a restaurant
> here. Let\'s make it one hour. Let\'s make it 1:10 back here.
>
> \[Whereupon, at 12:12 p.m., a luncheon recess was taken, to reconvene
> at 1:19 p.m., this same day, Friday, December 7, 2001.\]
>
> **A F T E R N O O N S E S S I O N**
>
> \[1:19 p.m.\]
>
> **Panel III - Finance**
>
> MR. BARNETT: We are ready now for our third and final panel PDUFA,
> this one having to do with the financial aspects of program.
>
> Our FDA representative this time is Theresa Mullin who is associate
> commissioner of the Office of Planning in FDA, and our non-FDA
> panelists\--and, again, I am going to go in the order that they are on
> the agenda. Just raise your hand when I call your name. Mary Rouleau,
> deputy legislative director at the United Auto Workers; Sharon Levin,
> associate medical director for the Permanente Medical Group, Diane
> Dorman, senior director of public policy with the National
> Organization for Rare Disorders, and Mike Warner, vice president for
> Bioethics at the Biotechnology Industry Organization, or BIO.
>
> We will start out with Theresa.
>
> MS. MULLIN: Good afternoon. My name is Theresa Mullin, as Mark said. I
> am the associate commissioner for Planning at the Food and Drug
> Administration, and this third panel is going to focus on questions of
> funding versus performance for FDA\'s human drug activities and what
> we might call the fundamentals, which we have been talking about I
> think throughout the day, of PDUFA.
>
> Based on our experience with PDUFA I and II, we know that these
> fundamentals need to be in alignment for the program to work as
> intended. In PDUFA II, FDA has learned that there can be a fair amount
> of uncertainty on the funding side of the equation, and we need to
> find a way to balance that against the predictability that
> stakeholders want from FDA in meeting previously set performance
> goals.
>
> Although we have, by and large, delivered on the promises for those
> performance goals, we think that we are now seeing some side effects
> of the uncertainty on the resource side, and going forward, we would
> like to find ways to ensure more stability and/or flexibility on both
> sides of these fundamentals to keep them in balance.
>
> Before the enactment of the Prescription Drug User Fee Act in 1992, we
> had a backlog of new drug applications, and timely review was a
> problem. PDUFA added resources to supplement. The fees supplemented
> FDA\'s appropriation for the human drug review process, and in
> exchange for the funding for user fees, FDA agreed to meet specific
> performance goals that would help expedite the review of the new drug
> applications. The extra money made it possible to hire review staff
> and have the information systems to be able to do that.
>
> Under PDUFA I, 1992 to 1997, that exchange worked pretty well. The
> applications with fee revenues came in, and we were able to hire the
> staff to meet those deadlines. The time for approval got shorter.
> Patients got access earlier, and it basically worked.
>
> Under PDUFA II, 1998 to the current day, things have not gone as
> expected, and the balance between the revenues and FDA\'s performance
> obligations, which we had in PDUFA I, had changed unexpectedly in
> PDUFA II.
>
> This graphic, I think, illustrates pretty well why that is. The user
> fee revenues are all driven by essentially the volume of fee-paying
> applications, and as you can see, the first 5 years of the program, to
> the left of that vertical line, there was a pretty consistent upward
> trajectory in the number of applications paying fees, but subsequent
> to that, on the right of that line, PDUFA II, we have had a lot of
> volatility and a downward trend in those numbers.
>
> In PDUFA I, we anticipated\--and we in the industry, biologics and
> pharmaceutical industry, the reps we discussed this with and others
> involved in the process looking at the PDUFA I experience assumed that
> there would be a continuing increase in the amount of fee revenues
> ample to fund any increase in performance obligations, and FDA agreed
> to an expansion of those performance goals in PDUFA II based on those
> assumptions, but I should say the match hasn\'t really happened.
>
> What we did see was an increase in the overall work, though, that now
> was obligated under PDUFA. The top row of these graphics, this is a
> snapshot of the workload for PDUFA, and then the upper left graph
> shows the fee-paying application workload. As you can see, that has
> gone down a bit in recent years. The others have steadily increased
> across the top, and the four on the bottom of this slide show
> additional things that FDA agreed to meet in goal deadline from 1998
> onward.
>
> These are graphics for meetings with companies to get feedback and
> guidance through the development of the product, FDA\'s evaluation of
> special protocol questions submitted by companies, responding to
> clinical holds, and dispute resolutions. We think these are all really
> valuable activities. We think that these activities have helped to
> make development more efficient, have helped to reduce clinical
> development time, and is in the spirit of what PDUFA is supposed to be
> doing and FDA\'s public health mission. They do help get drugs, safe
> and effective drugs, to patients more quickly, but they also do
> involve a lot of additional work.
>
> The agency has been trying to meet the workload involved here by
> out-spending, in fact, current collections. If you think about how the
> fee-paying applications are going down and the effort involved is
> going up, this graphic is showing what is going on there.
>
> The green bars here are what is being spent, and the beige bars are
> what is being collected. In 1998, as you see, the collections exceeded
> what we spent, and in a few other years, we have a little bit of that,
> fee carryovers that we were able to use in subsequent years to help
> make the difference up between current collections and what we needed
> to cover the program costs.
>
> In fiscal year 2001, the difference between what we needed to cover
> and what we had available from current collections was \$22 million,
> and in fiscal year 2002, based on the formula for fee collections, we
> think that we are going to exhaust the carryovers because we know that
> our spending is likely to exceed what we will be able to collect.
>
> That is a particularly bad situation to be in, looking ahead to the
> sunsetting of the program, because we won\'t have any money to help
> keep it going beyond the date when the program ends in September.
>
> Some people have asked us why don\'t you just make up for the
> shortfall in fee collections by using appropriations, and this, I
> think, just illustrates the problem with that and I think it also
> speaks to the earlier discussion about the relationship between PDUFA
> and the appropriations and the dynamic there.
>
> The sort of pale purple color along the bottom shows the history of
> spending on human drug review from appropriations. The dark purple
> area is the appropriations spent on other activities outside of that
> human drug review, and this is data just for the Center for Drug
> Evaluation and Research.
>
> So all the blue is appropriations, and you can see there is a steady,
> but modest, increase in the amount of appropriations that has been
> spent on the process of human drug review. The amount of fees has gone
> up much more and remains additive, but it is really the amount of
> appropriations in total that have gone down. That is why it is
> difficult to take any more from appropriations and put it towards the
> human drug review process. There are many other critical activities
> that we need to cover.
>
> FDA\'s financial goal for PDUFA III would be to get things back in
> balance. We think that there are probably many alternative ways to
> bring the agency\'s performance obligations in better alignment with
> the available resources, and we would like to hear your views on that
> and what you think should be considered.
>
> The other thing I might point out on that last slide, those last years
> were the years of peace and prosperity budgets for us. So we don\'t
> know how it is going to be in a period of war and deficits.
>
> So here are three questions that we have framed to hear from you and
> to hear from our panel. How can FDA ensure that PDUFA goals are met if
> there continues to be a funding shortfall? If the funding shortfall
> persists, should FDA, in order to best protect public health, set
> review priorities, and if so, how? Should there be flexibility in
> setting user fees to cover the increased cost of the program?
>
> Thank you.
>
> MR. BARNETT: Thank you.
>
> Let\'s go to our panelists again in the order that they are on the
> agenda. So, Mary Rouleau, you are first.
>
> MS. ROULEAU: Thank you. Thanks for giving us the opportunity to speak
> here today, and I also would like to thank you all for keeping the
> meeting on time. You run a very good meeting here. I like meetings
> that are run on time. It is very helpful for people who have got tough
> schedules. So thank you for that.
>
> You got my comments in your packet. I am not going to read all of them
> because a lot of them have been covered.
>
> I want to point out a few things up front, and that is that the UAW is
> a member of both the Patient and Consumer Coalition and RxHealthValue.
>
> I spoke at the September 16th meeting you all had on PDUFA. We were at
> that point emphasizing some drug safety issues that we were concerned
> about.
>
> Along with other members of the Patient and Consumer Coalition\--and
> you are hearing from most of us today\--we have identified many
> concerns we have about the user fee system, and I have laid them out
> there.
>
> I want to reiterate a point that my colleague, Jeff Bloom, made this
> morning, and I couldn\'t agree more, which is this is a really
> interesting and good exercise, but this is the kind of exercise that
> we really need to have in front of Congress for two reasons. Congress
> is the appropriators, number one, and, number two, they are going to
> rewrite or write PDUFA III. They are going to write the terms and
> conditions for the use of user fees and any other funding schemes they
> throw in.
>
> So, while I thank you for this meeting and this is important, it is
> incumbent on us in the audience to understand. The real audience, I
> believe, for this meeting is the Congress.
>
> I want to also point out that for the last couple of years, the UAW
> has joined with other patient and consumer coalitions on lobbying the
> Congress on the appropriations issue. WE have asked for more money for
> the FDA, especially for post-market surveillance, protection of human
> subjects in clinical trials, product and facility inspections, and
> DTC, and also for fair cost-of-living increases for your very
> important employees. So we are trying to put our money where our mouth
> is, so to speak, not that we have been all that successful, but we
> hope others will join us.
>
> Of course, we are happy to see that the 2002 budget does include an
> increase, but it is not enough.
>
> Theresa, you just said the goal might be to get things kind of back in
> balance, and that is important. Yes, we agree with that, but the
> reality is, folks, we have a problem right now, and we are looking
> forward and we are designing PDUFA III or lobbying for appropriations.
> We need to factor in a couple of things that have been mentioned this
> morning, which is that we expect a big increase in the number of drugs
> in the pipeline. So the workload we have now, I believe, is only going
> to get that much bigger at the FDA.
>
> The second thing is these drugs are being disseminated to the public
> faster and faster. We are getting older, and we are taking drugs for
> more things. So this is not arithmetic, if you will. We are looking at
> a different type of formula here. So it is absolutely incumbent that
> we understand that as we move forward and design a system that will
> probably take us at least 5 years out, maybe more.
>
> I need to say as a matter of public policy where the UAW is on this,
> as a matter of public policy. We think all funding should come to the
> appropriations process, and that we should get adequate revenues for
> appropriations through a progressive tax system. So I don\'t want us
> to be locked into the idea that we have no choices here but a user fee
> system.
>
> There are some political ramifications and realities, and we will play
> to that, the UAW will, but the reality is we could get enough general
> revenues for the agency and for other important health and safety
> needs if we had the political will.
>
> Part of it is, yes, there is a revenue problem and it is going to get
> worse for a combination of reasons, which I could rant and rave about
> for hours, but I won\'t.
>
> One important thing is that there is this Tax Code out there that has
> a lot of loopholes and deductions, and we have to ask whether people
> who are benefitting from our system are really paying their fair
> share. I have said that, so I will move on.
>
> Obviously, if the user fee system is to continue\--and let\'s say it
> is a 99.999-percent chance that it will\--we believe there must be a
> wholesale revamping of this system.
>
> We would suggest one thing to consider, and I say consider because no
> one has all the answers right now, but we need to have the dialogue
> that teases the right answer out. It might be utility model approach.
>
> Now, in the world of public utilities in many States, what they do is
> they assess the public utilities based on their relative size. The
> money goes into a pool, and that funds the activities of the public
> service commissions, but the point here is that the utilities don\'t
> get to blind-item and parcel-out where the money goes. That discretion
> is left up to a public service commission. We think this is important.
> We want the FDA to have the sole discretion about how to use this
> money and where because, if they are not going to do their job, we
> will be up there lobbying them and lobbying Congress. We have faith in
> the integrity of that process.
>
> There should not be, for example, some kind of trigger formula like
> exists currently that requires the FDA to make artificial decisions
> about spending, merely so it can get its hands on the user fees.
>
> Maybe, perhaps, if the FDA does not receive a budget increase, then
> the PDUFA drug approval goal should decline accordingly.
>
> Maybe, perhaps, fees should be imposed from the time that the FDA
> activities with drug companies begin.
>
> So we are calling for a reevaluation of the user fee system. We also
> believe that the performance goals must be renegotiated with all
> concerned stakeholders. That means patient and consumer groups should
> be at the table when we are designing these performance goals.
>
> I have listed some things that you have already heard\--I am not going
> to repeat them\--what should be considered as a part of a redesign of
> the performance goals, but I will add that I very much agree with my
> colleague, Amy, from the National Women\'s Health Network who said
> maybe it is time to consider performance goals on the public safety
> aspects, also.
>
> So, in principle, we are opposed to the further expansion of user
> fees, in principle. However, if this is our fate\--and I am betting it
> probably is\--we want to make sure that these fees are used for safety
> initiatives, subject to the sole discretion of the FDA, without the
> requirement of collaboration or consultation with the industry or with
> others.
>
> At the meeting last September, representatives from PhRMA, BIO, and
> the American Medical Association mentioned the need for adequate FDA
> funding. Great. We want to work with them on that. This is part of our
> job. Those of us who are passionate, either for or against user fees,
> we have another responsibility, and that is to lobby Congress on the
> appropriations.
>
> One thing that maybe we could discuss in the question-and-answer part,
> I have come to the conclusion that a big part of the problem\--and I
> don\'t know the historical reason, and maybe you guys can explain it
> to us, but the FDA funding, it seems to me, should be in HHS, and that
> being in the Agricultural Committee is a big problem because you run
> into staffers over there who have no idea what you are talking about.
> Let\'s face it. The farm team in Congress is very strong, and there is
> good reason for that, but I just think the FDA appropriation does not
> get proper attention, and I think part of the problem is where the
> appropriation is housed. Maybe there is a good reason for that, and
> you can tell me why I am wrong.
>
> Let\'s go to the questions because I think at this point in the say,
> these questions are largely rhetorical. How does the FDA ensure that
> PDUFA goals are met if there is a funding shortfall? Well, it
> doesn\'t. You can\'t.
>
> The FDA has already said that it expects the performance goals to slip
> because of a resource problem. That is a problem, but, also, and
> further, it is totally unacceptable\--totally unacceptable that safety
> issues suffer because of resource constraints.
>
> If the funding shortfall persists, should the FDA set review
> priorities, this question is purely rhetorical. Of course, it should.
> It should be looking at the drugs that are for serious and
> life-threatening conditions or rare disease and for which there is no
> reasonable substitute. That should get the first priority here.
>
> Lifestyle drugs, \"me,too\" drugs in our view of the world, UAW, we
> see the low priority, or should. Should there be flexibility? Of
> course. If there is going to be a user fee program, it shouldn\'t be
> tied to appropriations triggers. Fees should kick in earlier. Protocol
> for fee-waiving might need to be reviewed to make sure that it is not
> too generous, and maybe we should look for some new sources, like some
> of the money that comes from the pediatric exclusivity provision. We
> know that drug companies are doing quite well in that regard.
>
> Some of the fast-track issues, which you all have publicly said, have
> drained some of your resources. We should look for additional sources
> of revenue from the companies.
>
> Thank you.
>
> MR. BARNETT: Our next speaker, again, in the order on the agenda, is
> Sharon Levine.
>
> MS. LEVINE: Thank you. It is a real pleasure to be here, and I want to
> thank the agency for convening this meeting of stakeholders. I suspect
> that my comments are certainly congruent with everything that Mary has
> said and I know with almost everything that has been said today.
>
> I am here today actually in two roles, one on behalf of RxHealthValue,
> a coalition of consumers, health care practitioners, purchasers, and
> health plans, who have come together to sponsor research, educate the
> public, and recommend public and private sector solutions to assure
> that consumers realize the economic and health value of prescription
> drugs.
>
> I am also here as a prescriber. I have practiced pediatrics for 25
> years with the Permanente Medical Group in California and represent
> the more than 4,000 Permanente physicians in our Medical Group who
> participate in the Kaiser Permanente Pharmacy Program in Northern
> California and care for 3.2 million Northern Californians.
>
> Collectively, the members of RXHealthValue represent about 135 million
> Americans whose vital interests rest in securing value for the
> resources they spend on prescription drugs, whether that spend be
> through deferred wages, public and private health insurance, or direct
> purchase.
>
> Our concern in RxHealthValue and my concern as an individual physician
> is that without adequate funding in the future, the food and drug
> agency, the FDA will not be able to fulfill its most critical public
> health duties, and its public health duties extend from the very
> beginning of the process; that is, the integrity of research, the
> quality and safety of the manufacturing facilities, the robustness of
> post-marketing surveillance, looking for adverse drug events after the
> launch of a drug, and the rigor of oversight of promotion to
> physicians in advertising to consumers.
>
> It is critical for the FDA to have the resources to do that in order
> for prescription drugs to do what they are designed to do, with the
> least possible risk to those of us, to all of us who will ultimately
> use prescription drugs.
>
> As a coalition, we are terribly concerned that the rapidly evolving
> and growing need to assure patient safety and drug availability is
> clearly, as Theresa has said, outstripping available funding.
>
> The vital public health functions performed by the FDA are of value to
> every American and are going to increase significantly as prescription
> drugs continue to play an increasing role in health care.
> Increasingly, prescription drugs are the mainstay of the therapeutic
> interventions available to the physicians who care for all of us.
>
> Last week, we were pleased to see that the Congress passed and the
> President signed legislation that actually provides the agency with a
> budget that includes more money than the agency asked for, and this is
> a great first step, but I think it is critical to remember that this
> is only a first step. And we urge the administration in its budget
> proposal for fiscal year 2003 to propose an increase that would put
> the agency on a path similar to what happened with NIH in the \'90s
> that would lead it to doubling the appropriations for the FDA by the
> end of the decade.
>
> We believe that this is absolutely critical for the FDA to fulfill its
> much-needed and often under-appreciated public health
> responsibilities. If this were actually to occur, the FDA might be
> able to have sufficient resources on a predictable basis to do without
> user fees, which certainly would be the preference of RxHealthValue\'s
> members, but as Mary said, I think we have to be realistic about the
> environment in which we are living at the moment and it is really
> unlikely that that increase will be proposed, or if it is proposed,
> that Congress will enact the taxes necessary to meet this.
>
> PDUFA appears to be a fact of life for us, at least for the immediate
> future. Given that, it is absolutely essential that the distribution
> of efforts within the agency not be distorted by the funding. We are
> concerned that the goals established under PDUFA have forced the FDA
> to redirect resources for many of its vital functions for review of
> new drug applications.
>
> I think what we need here is a change in frame. New drug review, as is
> in the statute, which is defined as processes for the review of human
> drug applications, begins with the release into the market of a new
> drug. It doesn\'t end there. Things like post-marketing surveillance
> and compliance activities such as regulation and oversight of
> promotional materials to physicians and direct-to-consumer advertising
> are an essential part of new drug review, and the work begins with
> release into the market. It doesn\'t end there.
>
> PDUFA only allows user fees to support the narrow piece of the review
> of new drug applications. The agency, responding to manufacturers over
> the last number of years, as Theresa\'s slide showed, has devoted
> increasingly significant resources to consulting with manufacturers
> during the discovery and development phase, so that new drug
> applications meet all requirements. I think your performance has been
> outstanding, almost a 30-percent increase in successful applications
> coming through the FDA.
>
> Manufacturers, in effect, are depending on the FDA as if it were a
> consulting firm. One can imagine the cost to the manufacturers of
> paying private consultants for the same technical support and advice
> that is increasingly being provided as a service by the FDA, and we
> would recommend that you look at the process of formalizing your
> capacity to provide this assistance to manufacturers, beyond your
> regulatory obligations, and then those manufacturers that choose to
> take advantage of it would actually pay for it on an as-needed basis.
>
> Similarly, it is critical for the FDA to continue the excellent work
> it does, to have adequate technical expertise to review rapidly
> developing new technologies that are used in drug development in the
> private sector.
>
> The FDA has maintained a scientific program to ensure that physicians,
> pharmacists, and other staff have the technical expertise and support
> that they need to respond to new developments. If appropriated funds
> are not sufficient, what we could consider, certainly, is financing
> this kind of activity our of user fees because it is part of the new
> drug review process.
>
> Driven by the demands of PDUFA, the FDA now acts on new drug
> applications with great speed and under considerable pressure. This
> can result in inadequate clinical experience, and I say this as a
> clinician, with new drugs before they are introduced into the market,
> driven by massive promotional efforts to physicians and the ubiquitous
> direct-to-consumer advertising that has appeared since the loosening
> of restrictions in 1997.
>
> The speed with which many of these drugs are adopted in the prescriber
> community has been greatly accelerated compared to the past, and we
> have got some startling examples of that since 1997.
>
> This one-two punch, faster approvals with less clinical information
> and more rapid market uptake, means that to maintain the same level of
> public safety that we have come to expect, more resources, not fewer,
> must go towards these increasingly important FDA responsibilities of
> post-marketing surveillance and oversight of promotional activities.
> Under current law, as you all know, user fees may not be used for
> these purposes. Congressional appropriations have clearly been
> inadequate to finance the scope and depth of these activities.
>
> RxHealthValue\'s core mission is to ensure that Americans have
> affordable access to health-improving medications. Our members have
> adopted a consensus recommendation to the FDA regarding the necessity
> for improvement of post-marketing surveillance and the importance of
> oversight of information provided both to physicians and consumers.
> The prescriber community and the consumer community today is
> dramatically handicapped by the absence of credible independent
> third-party information, a base on which they can base prescribing and
> utilization decisions.
>
> Clearly, we strongly believe that user fees, if we are going to live
> with them, could be expanded if we look at what the definition of new
> drug review is to cover these kinds of activities.
>
> The questions posed to this panel specifically were about flexibility,
> priority-setting, and the question that I think I have addressed which
> is how can PDUFA goals be met if there continues to be a funding
> shortfall, I think the short answer to that is PDUFA goals need to be
> redefined to be much broader.
>
> The FDA must have the ability, the flexibility to balance the
> competing demands as they see them to ensure the public safety around
> prescription drugs. That being said, responding to a funding shortfall
> is something we all live with, and it is never easy. The notion of
> review priorities where some group or individual determines that
> certain new drugs have potentially greater health value than others is
> appealing and would clearly require the wisdom of Solomon.
>
> I would urge the FDA if it pursues this approach to involve at every
> level of consideration groups representing patients, providers,
> purchasers of health benefits and health plans.
>
> We would suggest that the agency attempt to make any prioritization
> decisions with the question of health value in mind. Applications for
> drugs to treat now ineffectively treated life-threatening or seriously
> debilitating conditions should be viewed as the highest priority, and
> I think we would all agree with that.
>
> In contrast, so-called line extensions intended to preserve
> manufacturers\' market share in the face of patent expiration or loss
> of market exclusivity should be much lower priority. Active metabolite
> products like esomeprazole, combinations of generics like
> metformin/glyburide, extended release products like the slow release
> metformin are just not as important to the consuming public as drugs
> for conditions that are currently untreated.
>
> Continuing input from stakeholder groups is going to be essential if
> priorities need to be established, and the FDA has a long and
> distinguished history with advisory groups. I would argue that this is
> a fruitful path to pursue.
>
> One final comment. Probably more germane to the FDA\'s overall mission
> than to PDUFA, I think it is critical that policy-makers realize that
> outside the Beltway and outside the policy community, there is an
> enormous gap between what the FDA\'s mission is and what my
> colleagues, physicians and consumers, actually believe it is.
>
> Patients and providers think the FDA is working not just to determine
> that a drug is safe and effective compared to placebo, but that the
> drugs that you approve are safe and more effective than others you
> have previously approved. As the administration develops a proposal to
> submit to Congress next year, I would urge you to consider seeking a
> broader mandate from Congress, a mandate that would actually fit with
> what the public believes you are currently doing. It will take more
> resources, and it will take more information from manufacturers and a
> different kind of information that will enable prescribers and
> consumers to actually make judgments about the relative effectiveness
> of drugs available to treat therapeutic indications.
>
> I want to thank you for the opportunity on behalf of those whom I
> represent to present at this hearing.
>
> MR. BARNETT: Thank you.
>
> Diane Dorman.
>
> MS. DORMAN: I first want to thank the FDA for giving NORD the
> opportunity to, once again, talk about PDUFA.
>
> By way of background, NORD participated in FDA\'s meeting last
> September and also testified before the House Energy and Commerce
> Health Subcommittee last May to express our views on the effectiveness
> of FDAMA. NORD is also an active member of the Patient and Consumer
> Coalition and also RxHealthValue.
>
> One of NORD\'s primary goals is to promote the development of new
> treatments and the cures for rare diseases and to make these therapies
> accessible to patients. Under the Orphan Drug Act, a rare disease is
> defined as a health condition that affects fewer than 200,000 people
> in the United States.
>
> Keep in mind that there are more than 6,000 rare disorders,
> cumulatively affecting an estimated 25 million Americans. NORD\'s
> mission, therefore, is enormous and very much reliant on the successes
> achieved by academic scientists, pharmaceutical and biotechnology
> companies, medical device manufacturers, and most of all the FDA,
> which regulates these entities.
>
> In the 10 years prior to 1983 when the Orphan Drug Act was passed,
> only 10 products were developed for rare diseases, and that is why
> Congress established the Office of Orphan Product Development and
> provided money for the Orphan Product Research Grant program to
> provide funding for critically important clinical trials on new orphan
> drugs, devices, and foods for rare conditions. These treatments have
> small potential markets and would not otherwise be attractive to the
> commercial sector.
>
> Today, FDA has approved 220 designated orphan products, proof positive
> that cooperation between academic researchers, the private sector, the
> patient community, and the Federal Government can create breakthrough
> treatments for life-threatening and crippling diseases.
>
> I bring this to your attention only to demonstrate that the FDA with
> support of all stakeholders, not just industry support, can, and must,
> continue to, first and foremost, do no harm.
>
> There is a perception by some that the agency is beholding primarily
> to the drug industry and continues to play roulette with the lives of
> patients nationwide. All one has to do is read the headlines to
> understand how much of the public, including patients and doctors,
> have lost a certain degree of faith in the FDA\'s ability to protect
> and enhance the public\'s health.
>
> This is not to say that we want to revert back to the good old days
> when desperately needed therapies took years to reach patients. To the
> contrary, we all want to see the agency thrive. We all want to see the
> agency properly and sufficiently funded so it can speed the approval
> of safe and effective treatments to the American public, but it is
> this perception of sleeping with the enemy that continues to cloud the
> agency\'s representation. A feasible balance must somehow be reached
> and achieved between speed of approval and safety.
>
> A colleague of mine likes to say sunshine is the best disinfectant,
> and I couldn\'t agree with him more. Decisions affecting the health
> and well-being of patients must no longer be made behind closed doors.
> Transparency in the approval process must be achieved if the FDA is to
> regain the complete trust of the patient community.
>
> Before outlining NORD\'s position on PDUFA reauthorization, I do have
> a couple of points that I would like to make regarding PDUFA as it
> relates to the rare disease community.
>
> Written into the user fee regulations is an exception for designated
> orphan drugs. The language reads that a human drug application for a
> prescription drug product that has been designated as a drug for a
> rare disease or condition pursuant to Section 526 shall not be subject
> to a fee under subparagraph (a) unless the human drug application
> includes an indication for other than a rare disease or condition.
>
> Regulations go on to say that in order to qualify for this exemption,
> a company or entity must qualify under the fee waiver or reduction for
> small business. At the moment, FDA\--and I quote\--generally considers
> an entity with less than \$10 million in annual gross revenues and no
> corporate parent or funding source with annual gross revenues of \$100
> million or more is less likely to be able to continue to provide
> products that benefit the public health and develop innovative
> technologies because of user fees.
>
> First and foremost, NORD and the rare disease community would like
> assurances from the FDA that during PDUFA negotiations, this exemption
> is not going to disappear. That is very, very important.
>
> Secondly, because both CBER and CDER have a financial stake in the
> decision to allow an exemption or not, we believe these decisions
> would be best made by a more independent entity and consult in
> consultation with FDA\'s Office of Orphan Product Development. Without
> this exemption, many small and startup companies would be unable to
> bring vitally needed orphan products to market.
>
> Thirdly, because no allowance was made for inflation and because the
> \$10 million and the \$100 million are based on \'93 figures, the rare
> disease community will advocate for an increase in the small business
> exemption as it relates to orphan products, with an inflation index
> included.
>
> In my written remarks, I have included several examples of some of the
> problems that have been realized by some of the very small companies
> developing products for orphan diseases. So I won\'t go into them now,
> but I will make one point in my comments. I made mention of Elliott\'s
> Solution B as having revenues of \$500 million. It is only \$500,000,
> and I apologize. So, if someone would make note of that, it is quite a
> huge difference.
>
> DR. WOODCOCK: Too many zeroes.
>
> MS. DORMAN: Yes, too many zeroes.
>
> Although revenues in excess of \$10 million may sound substantial,
> development costs are very, very prohibitive for as yet unprofitable
> or startup companies, and most entities must consider the contribution
> of each product individually in order to determine if it will be a
> contributor or a drain on their bottom line.
>
> While the PDUFA legislation attempts to make exceptions in order that
> development and commercialization of medications for rare disorders is
> attractive, the issues and possible solutions should be given serious
> consideration as future legislative approaches are explored.
>
> Now I would like to go into the first part of question three, which is
> how can the FDA ensure that PDUFA goals are met if there continues to
> be a funding shortfall.
>
> It is evidence that PDUFA goals will continue to be met now and into
> the future, much to the detriment of other critically important
> programs established to protect the public health. According to a
> statement made by an FDA official earlier this year, PDUFA-related
> program funding has risen 27 percent. It is only the non-PDUFA
> programs that suffer. Funds are being siphoned from essential programs
> such as post-marketing surveillance, health fraud investigations,
> inspections of IRBs, enforcement, training, management, staff
> retention, advertising enforcement, and adverse event reporting, to
> the tune of 20 percent in order to meet the letter of the law. This
> erosion from what I understand has created a \$200-million shortfall
> for these programs over the past 10 years.
>
> As a matter of principle, NORD continues to oppose the concept of user
> fees with its inflexible performance goals and triggers. However,
> given the current political and economic climate, it is safe to assume
> that Congress will not fully fund the FDA sans user fees.
>
> I would like to congratulate Congress, however, for their recently
> taking that first big step to increase funding for the agency. We feel
> that is very, very important.
>
> DR. WOODCOCK: Baby step.
>
> MS. DORMAN: Baby step, yes.
>
> Just as the NIH has enjoyed record funding, the agency should also see
> a doubling of its budget in order to fulfill its increasingly
> important public health responsibilities, but whatever the solution,
> whether it is increased user fees, requiring user fees at the earliest
> phase of development or expanding the use of user fees outside of the
> new drug approval process, a creative solution to this dilemma must be
> found.
>
> With the mapping of the Human Genome and the increasingly complex
> biologic and chemical compounds being developed by industry, the
> United States will remain in the forefront of medical discovery if,
> and only if, the FDA is given necessary resources to fulfill its
> mandate.
>
> Part two of that question, drugs for serious and life-threatening
> disease require different risk benefit calculations. They should be
> reviewed more quickly and considered for marketing as early as
> possible because those suffering with life-threatening diseases or
> those with no satisfactory alternative treatment options, especially
> those with untreatable rare orphan diseases, will more often than not
> accept the risk a new drug might pose in exchange for the benefits it
> might well provide.
>
> The FDA should take all steps necessary to ensure that effective new
> drugs are made available to patients with these serious and
> life-threatening conditions as soon in the development process as
> possible.
>
> However, in recent years, it appears that the agency has rushed too
> many \"me, too\" drugs through the priority process when they should
> have been given standard review. We urge the agency to change the way
> it categorizes standard and priority reviews.
>
> We believe the overriding success of the agency must not be measured
> by the speed of its work, but by the completeness and scientific
> soundness of its work in order to protect the health and welfare of
> the American public. A one-size-fits-all approach must not be taken.
>
> FDA reviewers should be given the latitude to review new drug
> applications at a slower rate if it is deemed scientifically or
> ethically necessary, especially when a drug is not a life-saving
> therapy.
>
> It is obvious to me that some of the drugs removed from the market in
> recent years might have been approved with more adequate labeling if
> FDA had taken the time to recognize adverse events and had required
> appropriate labeling when the drugs were first approved.
>
> As far as part three of the question, we agree most definitely that
> the FDA must be able to adapt to the changing market place. Stringent
> appropriation triggers should not obstruct the agency\'s ability to
> efficiently and effectively pursue the goals of ensuring that safe and
> efficacious products are brought to the marketplace. As currently
> written, performance goals and mandatory deadlines do not allow for
> this flexibility.
>
> I thank you very much for giving me the opportunity to speak.
>
> MR. BARNETT: Thank you.
>
> Mike Warner.
>
> MR. WARNER: Thank you, and I will echo my changes to the agency folks
> for giving us the opportunity to testify this afternoon.
>
> I am Michael Warner. I am vice president for Bioethics at the
> Biotechnology Industry Organization, or BIO. We represent more than
> 1,000 biotechnology companies and academic institutions in all 50
> States.
>
> Just so you appreciate who we are, more than 90 percent of our members
> are involved in finding new therapies for currently unmet medical
> needs, like Alzheimer\'s, Parkinson\'s, various cancers, heart
> disease, and diabetes, and the vast majority of our members have no
> revenue and have no products currently on the market.
>
> Let me address one thing which one of my colleagues brought up and
> say, first off, our relationship with the FDA is strictly
> professional. The biotech industry and FDA are not partners. We are
> not colleagues. Sometimes we are not friends. Our relationship is
> arm\'s length, and we view it as one between scientific peers.
>
> I appreciate the opportunity today to speak about the Prescription
> Drug User Fee Act, or PDUFA. PDUFA III is of enormous importance to
> our companies, particularly our small emerging companies. Since the
> statute expires in October of next year, as you all know, it is
> appropriate to take the time now to assess its successes as well as
> its shortcomings.
>
> A lot has changed since the statute was first passed in 1991. Remember
> that the biotech industry barely existed back in 1991, and now we have
> an unprecedented number of potential new drugs in late-stage clinical
> development.
>
> We have set up internal committees of our members to develop
> suggestions about reauthorization, and we are taking the advice of
> those who work with FDA on a day-to-day basis. We hope to have
> detailed recommendations developed shortly, but in the spirit of this
> public meeting, I can share with you some general comments.
>
> First of all, since its inception, PDUFA has worked. The law has led
> to reduced review and approval times, which has meant that patients
> have had access to new therapies and diagnostics and treatments
> faster. Put simply, the law has both changed and, in fact, saved
> lives.
>
> PDUFA has also demonstrated that if given the proper resources, the
> FDA can effectively administer, review approval programs regarding new
> drugs and biologics. Despite these successes, bio companies have at
> least preliminarily identified some concerns with the current process,
> and I will just highlight and speak in general terms of three.
>
> First, despite a trend of reduced review and approval times over the
> years, reports indicates that for FY2000, these times, in fact,
> increased. This is a big concern for our members, again, particularly
> the smaller companies, and we just need to understand why that
> happened.
>
> Second, although one of the purposes of PDUFA is to provide the
> industry with a more predictable review process, there are some who
> believe that this is not happening. Specifically, there have been
> complaints of inconsistency throughout the agency, and consistency,
> predictability, communication from the agency is critical, again,
> particularly to our small companies. Some of our companies\' very
> existence is threatened by unclear or confused actions at FDA.
>
> Finally, the lack of an FDA commissioner remains a problem. Now,
> obviously, the commissioner does not review applications. However, the
> agency needs a strong leader who can provide direction to the various
> departments and, importantly, who can fight for additional resources
> for the agency. We hope to discuss these and other issues with
> policy-makers over the coming months.
>
> Let me talk about resources for just a second. The PDUFA
> reauthorization debate from our perspective provides an opportunity
> for a broad discussion about FDA resources, not just user fees, but
> the big issue, the larger issue of FDA resources. It is a given that
> our industry needs a talented science-based FDA. Indeed, commercial
> acceptance of our products depends upon a rigorous and thorough review
> process. The FDA must maintain and remain the gold standard for the
> rest of the world. We are very fortunate in this country, I think, and
> all of us recognize it, to have an agency such as the FDA, and we need
> to make sure that it has the resources it needs so that it can remain
> the gold standard.
>
> This is going to become even more essential in the coming years as our
> companies develop scientifically complex products designed to treat
> formerly intractable diseases, and simply put, we need to ensure that
> FDA has the resources it needs to do its job.
>
> User fees provide one source of revenue, and BIO has worked hard in
> the last few years to help increase the appropriation from Congress to
> FDA. And we intend to do that again next year. Reduced appropriations
> clearly will seriously impair this critical agency\'s abilities.
>
> The biotech industry\'s strict arm\'s-length relationship has resulted
> in more than 100 biotech drugs and vaccines reaching patients. These
> medicines have now helped more than 270 million people worldwide. In
> the coming years, we can and must do much more because patients are
> depending on us.
>
> At BIO, we look forward to fruitful discussions with policy-makers,
> patients, and the public to create a PDUFA program that ensures that
> we can all get the drugs, biologics, and treatments that we need.
>
> Thank you.
>
> MR. BARNETT: Thank you.
>
> We are going to do three things now. First of all, I am going to open
> the floor to comments about this particular issue, which was the
> financial aspects of PDUFA. Then, after that, I am going to call upon
> a couple of organizations that registered in advance to speak, and
> then, finally, I am going to open the floor again for anybody who has
> any questions or comments about PDUFA that were not covered by the
> panels.
>
> So, first of all, anybody with any questions or comments on the
> subject of this panel which is the financial?
>
> \[No response.\]
>
> MR. BARNETT: False alarm.
>
> FLOOR QUESTION: I guess this is not totally on the subject.
>
> MR. BARNETT: Would you identify yourself.
>
> FLOOR QUESTION: I am Sandy Marts \[ph\] from the American Medical
> Association.
>
> MR. BARNETT: Thank you.
>
> FLOOR QUESTION: This is not totally on the subject, but I noticed a
> number of the people who have come up to ask questions are reporters
> and people like that. I would just want to make sure we don\'t go too
> far in the direction of trying to say all the other things the FDA
> does besides new drug approvals are not effective.
>
> I know that I approve a lot of letters that go out from AMA that talk
> about the things FDA has done on keeping the blood supply safe and
> also keeping it adequate, antimicrobial resistance, trying to work on
> problems of drug and vaccine shortages. So, although FDA funding does
> need to be increased, a lot of what they are doing that are separate
> from PDUFA that are separately funded, are really very effective, and
> they are going a very good job. So I just want to point that out.
>
> MR. BARNETT: Thank you.
>
> Anyone else?
>
> \[No response.\]
>
> MR. BARNETT: Okay. We have one group that has signed up to speak in
> advance. It is the Colorectal Cancer network. We have Priscilla
> Savory. Is she here? Priscilla Savory?
>
> \[No response.\]
>
> MR. BARNETT: Not here. Okay.
>
> Another one was the Tufts Center for the Study of Drug Development,
> Chris Milne.
>
> Chris?
>
> DR. MILNE: I want to thank FDA for this opportunity to speak, and I
> apologize to the panel. I have been told I can turn the mike around
> and kind of work the audience Sally Jessie Raphael style. So I am
> going to do that.
>
> MR. BARNETT: You can even take it out and wander around.
>
> DR. MILNE: Well, I don\'t know. I don\'t want to make it too sort of
> theatrical, but I do have some slides today that will hopefully
> address some of the issues that have come up in the discussions with
> all three panels.
>
> I will talk a little bit about the Tufts Center. We are responsible
> for that figure recently released about the \$800-million cost of drug
> development. Hold your jeers and heckling to the ned. Head-nodding and
> head-shaking is okay, but I don\'t want to spend the time I have
> talking about that particular figure. It is an important figure that
> does impact on this area, but we have other things to talk about.
>
> The Tufts Center has been studying this area for 25 years. We are, in
> part, funded by industry, unrestricted grants, but that is all parts
> of industry, big pharma, biotech, and the software companies that
> provide services to the industry, CROs, everybody. We also sell
> products, publications, and we put on courses. So we kind of have an
> eclectic funding base, if you will.
>
> I think we should remember there are a lot of stakeholders involved in
> PDUFA companies, also patients certainly. Congress and FDA, we are all
> stakeholders in this, and you can read the intentions of PDUFA I,
> which I think have largely been met.
>
> PDUFA II wanted to continue PDUFA I\'s success, and then it had some
> additional emphasis on clinical development. There is not only the
> approval phase that we have to worry about, but certainly the clinical
> development phase when we are looking at getting drugs to patients
> faster. I think that is where there has been a little bit of a\--I
> don\'t want to say a problem, but some impacts that we might want to
> point out during this little discussion.
>
> I am going to run through a couple of these slides because there is a
> limited amount of time, and I know we all want to get to the general
> discussion. I am going to focus on a couple of the data slides.
>
> This slide is similar to the next few slides you are going to see. So
> I am going to spend a little time on it. This gets to, again, one of
> the issues companies are a stakeholder in this. PDUFA I and PDUFA II
> were supposed to shorten approval times as well as clinical
> development time. What you see there is the IND phase. It is the
> clinical development time, and the NDA phase is the approval time. The
> total phase is, of course, a combination of those two.
>
> You can see by comparing the three columns in each section there sort
> of a pre-PDUFA period, that white column. The blue column is then that
> first performance goal period, 1994 to 1997, with performance goals
> not starting until \'94, and then the most recent PDUFA II period. So
> you can see sort of a nice staircase of improvement, if you will, as
> far as decreasing times for approval and even clinical development
> time decreasing.
>
> There is a little bit of a problem in the NDA phase where you start to
> see a flattening-out between the PDUFA I and PDUFA II period.
>
> That was for priority drugs. As we get to standard drugs, you see less
> of that staircase of improvement, if you will, in the shortening of
> the times of getting those drugs to patients, and a little more
> flattening out again in that approval phase in that middle set of
> columns there, but, still, overall there is a shortening of the time
> from PDUFA I to PDUFA II of the total development time.
>
> For CBER\--again, these are drugs going to CBER. These are biological
> products, rather, going to CBER. Again, it is a little bit harder to
> see what is going on here, but, certainly, it looks like in the most
> recent period, \'98 to 2000, you have some increased clinical
> development time going on, even an increase in the approval phase for
> priority drugs, leading to a total development time that is increased
> from PDUFA I to PDUFA II. That is for priority drugs. Again, the
> criteria in CBER-land is a little more stringent for priority drugs.
> They have to in addition being an advance over currently marketed
> drugs, they have to be for serious and life-threatening diseases, more
> challenging obviously.
>
> Again, for standards, you don\'t see the staircase, and I have the
> direction as sort of a bumpy platform. It is hard to tell what is
> going on here exactly. There is a little bit of a decrease in the
> overall total development time from PDUFA I to PDUFA II. So talking
> about that balance that Theresa Mullin discussed, getting back to that
> balance of making sure that we are going to fulfill the goals of PDUFA
> I and PDUFA II and PDUFA III, getting back to, again, the important
> goal of getting markets out to market more quickly.
>
> But, overall, there has been a positive impact over the 10-year
> period. The PDUFA formula, if you will, has worked. Looking at that
> first column, increasing FDA staff has resulted in a 22-percent
> decrease in clinical development time, a halving, if you will, of
> approval times, and at the same time an increase by 33 percent of
> applications overall being approved.
>
> Now, part of the problem, perhaps, with the PDUFA II period has been
> these additional resources that had to be devoted to some of these
> FDAMA activities, drawing on some of the same personnel. In addition,
> there is also the emphasis to try to reduce that clinical development
> time by focusing on helping the industry to address certain issues
> with clinical holds and other clinical development issues, having
> meetings at critical junctures during clinical development.
>
> In addition, it talked about some new programs that had demanded a lot
> of resources from FDA, the pediatric exclusivity program, as well as
> the fast-track development program for serious and life-threatening
> illnesses. We have heard mentions of that already. This is just a
> quick summary of how beneficial and critical these programs are, but
> they do demand resources.
>
> So far, just in the 3 years that the pediatric program has really been
> in full swing, they have labeled 20 active noieties, 4 pediatric
> indications, and a third of those, they found significant differences,
> significant new information with regard to dosing and adverse effects.
> They were probably being used incorrectly, if you will, or not as
> appropriately as they should have been in the off-label world.
>
> Again, over 70 diseases are being addressed, 500 studies are in
> progress. Thirty-two percent of those are in, according to a survey
> that we did, in neonates and infants, very difficult subpopulation to
> address, again, dozens of formulations and biological sampling
> technique and clinical endpoint improvements. They are advancing the
> science of pediatric clinical trials.
>
> It is not coming cheaply. Our survey indicates that it is costing
> industry about a billion dollars to handle these 250 requests. So,
> again, there is some expense on that side as well, certainly, along
> with FDA, and we are going to see that in the next slide.
>
> FDA. They have had 65 staffs spread over 13 pediatric activities. They
> have also had other things that they have to do during this period in
> addition to now. We have the bioterrorism and some other activities
> going on. They have been spread very thin in that regard. They have
> the new office of Pediatric Development. That is good, but, again,
> stretched resources, and they have had to do this while there has been
> a doubling of pediatric supplements to review by that same review
> division personnel that we talked about that do your typical drug
> development review processes.
>
> Fast track, also, a tremendously beneficial program. We followed 65 of
> the first fast-track designations that we could get public information
> on. Of those, we found that 40, just from the information we could
> gather out in public sources, were breaking new ground. Frontiers of
> science handling refractory disease, diseases that have no other
> treatment, diseases for resistant organisms, novel approaches to
> diseases, again, very challenging, a very challenging program not only
> for developers, but certainly for FDA to have to assist, give
> consultation on development, and also to review those drugs.
>
> You see that there has been some benefits already, just in the
> half-dozen or so products that we have been able to identify as having
> been all the way through the process that we could get, developments
> times are looking at those gray bars. You can see that the clinical
> times and the approval times have been tremendously decreased or those
> fast-track drugs. That is why they call them \"fast track,\"
> hopefully.
>
> Given that total development time for this small cohort, it is less
> than 4 years from the time they submit their IND to the time they get
> approval. It is out on the market, less than 4 years. That is really
> terrific news to patients that are waiting for desperately needed
> drugs.
>
> Again, it doesn\'t come without its costs in terms of resources,
> again, not only for industry, but certainly for FDA. This is not a
> small program, 170 designations in about, again, 3, 4 years, five- to
> six-fold increase in the number of meetings that typically a
> fast-track sponsor will have compared to other sponsors. That is a lot
> of agency time. That is a lot of industry time. The agency might have
> to have 10 to 20 personnel involved in these formal meetings, again,
> tremendous resource drain.
>
> Reviewing clinical time would also be challenging because we are
> dealing, again, at the frontiers of science, serious and
> life-threatening illnesses, 30 or 40 of them, in populations that I
> call vulnerable because there is very little clinical trial data
> offered on some of these children. Even women, typically, were not
> involved in clinical trials, a lot previously, the elderly, and 50
> percent are for patients with rare disorders. You heard about them as
> far as the Orphan Disease Act is concerned and the implications for
> that program.
>
> Overall, conclusions, the intent of PDUFA I largely has been
> fulfilled, I believe. Again, they have to get back to that balance
> that was intended to occur in PDUFA II and PDUFA III hopefully will
> get that balance back.
>
> There is a perspective on safety that has to be considered. We don\'t
> want to sacrifice public health, certainly, in this process. I don\'t
> see that the evidence indicates that there has been a sacrifice of
> that yet. Certainly, that doesn\'t mean that should be any
> complacency.
>
> We looked at the data and we saw that from 1980 to 1993, the
> pre-performance goals cohort of drugs that were approved during those
> years, we found a 3.2 percent withdrawal rate for safeties, with about
> 4.6 years on average occurring before from the time that drug was
> marketed until the time that drug is withdrawn, looking at the
> post-PDUFA era out to the performance goals\--were implemented. You
> can see that the withdrawal rate is fairly similar, 3.4 percent, and
> there was actually a shorter recognition time, if you will, time from
> when the drug was approved until it was actually recognized as being
> problematic and withdrawn.
>
> Again, no recent for complacency. Lots of work has to be done. It is a
> much more challenging environment. More drugs are out there on the
> market, in the U.S. market first. We identified that as a problem.
> Also, these are more challenging drugs. You have many more people
> involved in the development process now, many new players, different
> types of approaches being taken. Certainly, it is a very important
> time to increase post-marketing surveillance. There are just limits to
> pre-market testing.
>
> You can, to some degree, take those into account by increasing your
> risk management and your post-marketing, but, in general, the overall
> program has to be brought back into balance by pouring more resources
> not only into bringing back the advancements that were made in
> approval and review times, but also in addressing some of these new
> concerns and challenges that are out there.
>
> Thank you.
>
> MR. BARNETT: Thank you, Dr. Milne.
>
> Anyone on the panel want to comment on this?
>
> Yes.
>
> MS. LEVINE: Yes, just a couple of things. I think we are using the
> word \"balance\" in two different ways. I think the panelists have
> been talking about balance between new drug review and the other
> public health activities that the FDA engages in on behalf of the
> consuming public, and I just want to talk about the issue of decrease
> and development time for just a second.
>
> I think with drugs, with prescription drugs, speed is not necessarily
> life. While it is true that 3.2 percent and 3.4 percent look like they
> are almost the same, the actual numbers are significantly different
> because they are a percentage of a different multiplier.
>
> The reason, I believe, of the shorter recognition time is because the
> clinical trials are continuing with a shorter development time and a
> rapid uptake after introduction in the market. What we are seeing is
> essentially a clinical trial that is continuing under less than ideal
> circumstances, and we are getting information, fortunately, but not
> perhaps in the best way possible.
>
> The other issue for me that is raised\--and this is not the subject of
> this panel\--by the dramatic decrease in development time is that
> patent life, effective patent life is related to historical notions
> about how long it takes to get a drug through development. So, if we
> are seeing based on the FDA\'s good efforts dramatic decreases in
> development time, somebody perhaps ought to look at whether we have
> excessive patent life based on a much shorter development cycle.
>
> MR. BARNETT: Thank you.
>
> Any other panelist want to comment?
>
> DR. MILNE: I would like to say one thing about the safety issue. Just
> looking at something I read in the paper yesterday where they were
> talking about a report about surgical errors, according to this
> report, there had been 108 surgical errors in the last 2 years. That
> would be about 4.5 per month, but they said that in the last month,
> there had been 11. So sometimes events occur as blips rather than over
> a nice scheduled period.
>
> Again, thinking about those 12 drugs that have been withdrawn since
> 1997, again, only I think 8 of them were actually approved in the
> PDUFA era, you can\'t draw too much from that, and, again, you can
> carve the data a number of different ways. Even if you don\'t find
> that that indicates a particular problem, safety withdrawals are only
> one aspect of the safety issue. Certainly, the warnings and the black
> boxes and the other things that occur are another issue, and no matter
> what you find, there is never any reason for complacency. Something
> that can always be improved is safety.
>
> As far as the balance, yeah, I think we can say that. Perhaps there is
> a couple of ways to think about balance, and I was using it in a
> different way.
>
> MR. BARNETT: Thank you.
>
> I think what I want to do now is ask if there is anyone in the
> audience who has questions or comments on something about PDUFA that
> was not covered by the panels. If so, now is the time to come on up.
>
> MR. BLOOM: Actually, I have two questions. I will take a follow-up,
> just like in the White House.
>
> This question is actually for Dr. Woodcock and Dr. Zoon. One of the
> things that strikes me is that I would like to hear a little bit about
> the appropriateness of having the same performance guidelines and the
> same time parameters for applications that go to CDER versus CBER
> because it seems to me that the difference in the quality of
> applications and particularly the fact that in one instance you have a
> thousand companies, small companies, usually not very profitable
> companies turning in applications versus large pharmaceutical
> companies with much better resources, longer relationship with the
> agency, I would imagine the applications, there is probably a great
> difference in how those applications come into the FDA.
>
> So is it appropriate to have the same goals for both divisions, or
> does it make sense to have different parameters? How does that affect
> you.
>
> I know that Dr. Zoon has been quite candid at previous meetings
> stating quite frankly that PDUFA has created a sweat-shop mentality at
> CBER, and I am wondering if the two of you would comment on that,
> please.
>
> DR. ZOON: I think you raise a very important point. I think the
> diversity of the different sponsors that the Center for Biologics
> works with is quite great, and I do think there is a lot more help
> that smaller companies or sponsors need because they are less
> experienced in drug development and product development. And it does
> require extra support and help to get them through the process.
>
> It also many times can affect the quality of the applications that are
> submitted to the agency. So I do think that communication is extremely
> important for the small companies, and especially if they don\'t have
> a lot of experience in drug development. My sense is we can talk about
> whether the goals should be the same or not.
>
> The other thing that I think is important to recognize, that many of
> our sponsors are at the cutting edge of technology, and having to have
> the proper science base for the agency to deal with novel technologies
> is also very challenging for the Center for Biologics and has been
> something that we have struggled and tried very hard to support the
> science base because, if you can\'t understand the technology, you
> can\'t very well regulate it well. I think part of our efforts,
> really, to try to make sure that our scientists are best prepared to
> work with the industry scientists to very best understand the products
> and often were having the right policy and guidance during the actual
> review of products because these are new and have never seen the light
> of day. So I think all of those things do make a complex situation.
>
> I think it is a legitimate question. I think some analyses would need
> to be done in regard to that, to look at what the issues are
> surrounding it and how that should be approached, and I also think
> many of the things that we do will continue to challenge the agency
> with respect to keeping up with the science. So I think that is
> something that we continue to look forward to working with all
> segments, both the industry and the public and our academic colleagues
> and Government colleagues to ensure that we can do a good job.
>
> Thank you.
>
> FLOOR QUESTION: I think that voluntary compliance is an oxymoron.
> Having spent a lot of time in consumer protection, nothing should be
> approved until all the information is in. It should be mandatory
> compliance. There is this tremendous rush now to get approval of
> drugs, and maybe if there is a penalty or a cost for drugs that are
> recalled, there might be a slowing down of trying to rush to get your
> drug approved.
>
> I also think I have been hearing for a long time about MedWatch and
> they don\'t have enough people. Well, in all the years I worked in
> consumer protection, I had a whole cadre of volunteers working for me,
> and Washington is filled with professionals who are retired. There is
> no reason why the FDA cannot use these wonderful retired people,
> professional people, to help them with MedWatch.
>
> I volunteer now in the State\'s Attorney\'s office. So we have a lot
> of people here who can contribute to society and would love to work in
> MedWatch, and I have a feeling it won\'t happen, anyway, but we have
> to keep reinventing the wheel and we have to use the resources we have
> and your money doesn\'t go that far, but I really feel that all
> information should be available before the drug is approved. It will
> save you money in the long run. They have to come back with more
> information and more information. So I don\'t know, and I guess I am a
> little cynical, and I am ashamed to admit it. Is this rush for
> consumers, or is it rush for profit?
>
> MR. BARNETT: Thank you.
>
> Anyone else?
>
> Yes, come on up. Identify yourself.
>
> FLOOR QUESTION: My name is Mickey Hunt and I am the president of
> Mickey I. Hunt and Associates, which is a health policy consulting
> firm based here in Washington.
>
> I would appreciate it if Dr. Woodcock and Dr. Zoon would clarify the
> criteria that are used to determine whether an application receives a
> priority review.
>
> I understand there is some difference in criteria between the Center
> for Biologics and Drugs and also that there are four routes that can
> be used within the Center for Drugs to qualify for a priority review.
>
> DR. WOODCOCK: A priority review is fairly straightforward. We have had
> this criterion in place before the user fee program, as you probably
> know. It relates to something that would provide a benefit above and
> beyond existing therapies. There have been some issues around that. It
> is usually taken up by the expert clinicians in the review division,
> which is the subspecialty area, who would determine that that therapy
> would propose an advance. It can be as straight forward as a
> once-a-day pill. That might seem trivial unless you realize that
> adherence to medications or lack of adherence is probably the
> number-one reason that they don\'t work for people. It is that people
> don\'t take the pills. So anything that promotes adherence to your
> medication is something that really can be an advance for patients,
> but some folks might dispute that and there is some controversy. It
> has to be an advance over and above existing therapy.
>
> Often, it is much more of an advance. It would be something that had
> been shown to have a survival benefit in clinical trials or something
> that is shown to have some major symptomatic benefit or addressing a
> disease that doesn\'t have therapy.
>
> Kathy?
>
> DR. ZOON: I would just most biologics that we deal with, looking at
> these, many of the drugs and products that we regulate represent new
> treatments or advance treatments for severe and life-threatening
> illnesses for which there have been no other potential therapies. So
> this has been both the medical advance and safety issues that are also
> considered in our triaging as well.
>
> Most of them are quite comparable to the Center for Drugs, and I think
> there are a few minor differences, but they are actually quite
> overlapping.
>
> MR. BARNETT: Anyone else?
>
> \[No response.\]
>
> MR. BARNETT: If that is the came, I am going to ask Dr. Suydam if she
> has any final comments to make before we break.
>
> DR. SUYDAM: I just want to thank everyone for their participation,
> particularly our panelists. I think we heard lots of interesting
> ideas, things that will benefit, I think, the process as it moves
> along. We appreciate your interest. We look forward to working with
> all of you in the future, and I think that together we can make this
> program work. And thank you again for supporting FDA to the degree you
> have. We appreciate it very much.
>
> MR. BARNETT: Okay. Thanks for coming, and speaking of safety, drive
> carefully.
>
> \[Whereupon, at 2:36 p.m., the public meeting was adjourned.\]
>
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