1
2 MEETING
3 OF
4 MANUFACTURER COMMUNICATIONS REGARDING UNAPPROVED USES
5 OF APPROVED OR CLEARED MEDICAL PRODUCTS
6 PART 15 PUBLIC HEARING
7 Conducted by Leslie Kux,
8 Associate Commissioner for Policy
9 Thursday, November 10, 2016
10 9:02 a.m.
11
12
13 Food and Drug Administration (FDA) White Oak Campus
14 10903 New Hampshire Avenue
15 Building 31, Room 1503
16 Silver Spring, MD 20993
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20
21 Reported by: Nate Riveness, RPR/CSR,
22 Capital Reporting Company
1 A P P E A R A N C E S
2
3 Leslie Kux, Associate Commissioner for Policy
4 Kristin Davis, Senior Policy Advisor, Office of Policy
5
6 Rachel Sherman, MD, MPH
7 Deputy Commissioner, Medical Products and Tobacco
8
9 Diane Maloney, Associate Director for Policy
10 Center for Biologics Evaluation and Research
11
12 Lauren Silvis, Deputy Center Director for Policy
13 Center for Devices and Radiological Health
14
15 Dorothy McAdams, Center for Veterinary Medicine
16 Supervisory Veterinary Medical Officer
17 Office of Surveillance and Compliance
18
19 Thomas Abrams, Director
20 Office of Prescription Drug Promotion
21 Center for Drug Evaluation and Research
22
1 Karen Schifter, Senior Counsel
2 Office of the Chief Counsel
3
4 Robert Califf, MD, Commissioner
5
6 Sarah Peddicord, Press Officer
7
8 Dr. Joshua M. Sharfstein
9 Johns Hopkins Bloomberg School of Public Health
10
11 Steven Francesco, Do No Harm Network
12
13 Kim Witczak, WoodyMatters
14
15 Veverly Edwards, Consumers Union Safe Patient Project
16
17 Robyn Edwards, Consumers Union Safe Patient Project
18
19 Lisa Gill, Consumer Reports
20
21 Dr. Yanling Yu
22 Washington Advocates for Patient Safety
1 Jack Mitchell, Director of Government Relations
2 National Center for Health Research
3 Patient, Consumer, and Public Health Coalition
4
5 Dr. Diana Zuckerman
6 National Center for Health Research
7
8 Melayna Lokosky, Federal Whistleblower
9
10 Dr. Margaret McCarthy, Executive Director
11 Collaboration for Research Integrity and Transparency
12 Yale Law School
13
14 Jeanie Kim, Fellow
15 Collaboration for Research Integrity and Transparency
16 Yale Law School
17
18 Amy Kapczynski, Professor, Yale Law School
19 Faculty Director, Collaboration for Research Integrity
20 and Transparency
21
22
1 Joy Eckert, Project Manager, Access Rx Project
2 D.C. Center for Rational Prescribing
3 George Washington University
4 Milken Institute School of Public Health
5
6 Cara Jones, Janet, Jenner & Suggs LLC
7
8 Alycia Hogenmiller, Project Manager, PharmedOut
9 Georgetown University Medical Center
10
11 Dr. Adriane Fugh-Berman, Associate Professor
12 Department of Pharmacology and Physiology
13 Department of Family Medicine
14 Georgetown University Medical Center
15 Director, PharmedOut
16
17 Dr. Doyle Stulting, American Society of Cataract and
18 Refractive Surgery (ASCRS) and the Alliance of
19 Specialty Medicine
20
21 Katherine McGahey, 1 Million 4 Anna Foundation
22
1 Sarah Christopherson, Policy and Advocacy Director
2 National Women's Health Network
3
4 Amy Leitman, Director of Policy and Advocacy
5 NTM Info & Research
6
7 Andrew Sperling, National Alliance on Mental Illness
8
9 Jon Furman, USA Patient Network
10
11 Dr. Megan Coder, Senior Director, Industry Programs
12 Pharmaceutical Care Management Association (PCMA)
13
14 Madris Tomes, Device Events
15
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1 C O N T E N T S
2
3 SPEAKER PAGE
4 Leslie Kux 8
5 Dr. Joshua M. Sharfstein 11
6 Steven Francesco 24
7 Kim Witczak 36
8 Veverly Edwards 49
9 Robyn Edwards 58
10 Lisa Gill 59
11 Dr. Yanling Yu 77
12 Jack Mitchell 89
13 Dr. Diana Zuckerman 104
14 Melayna Lokosky 125
15 Dr. Margaret McCarthy 132
16 Jeanie Kim 140
17 Amy Kapczynski 153
18 Joy Eckert 164
19 Cara Jones 171
20 Alycia Hogenmiller 182
21 Dr. Adriane Fugh-Berman 189
22 Dr. Doyle Stulting 205
1 SPEAKER PAGE
2 Katherine McGahey 217
3 Sarah Christopherson 233
4 Amy Leitman 240
5 Andrew Sperling 255
6 Jon Furman 262
7 Dr. Megan Coder 272
8 Madris Tomes 282
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1 P R O C E E D I N G S
2 MS. KUX: Everyone please take their seats,
3 and we'll get started.
4 I'd like to welcome everybody back to the
5 second day of our Part 15 hearing on Manufacturer
6 Communications Regarding Unapproved Uses of Approved
7 or Cleared Medical Products.
8 Let me start with introductions of the FDA
9 panel members for those in the audience who may not
10 have been here yesterday or who may not have been
11 viewing the webcast yesterday.
12 So I'm Leslie Kux, the associate
13 commissioner for Policy, and I'm the presiding
14 official at today's hearing
15 And now if the rest of the panelists could
16 introduce themselves?
17 MS. DAVIS: Hi. I'm Kristin Davis, a senior
18 policy advisor in the Office of Policy at FDA.
19 DR. SHERMAN: Good morning. I'm Rachel
20 Sherman, Deputy Commissioner for Office of Medical
21 Products and Tobacco.
22 MS. MALONEY: Good morning. I'm Diane
1 Maloney, Associate Director for Policy in the Center
2 for Biologics Evaluation and Research.
3 MS. SILVIS: I'm Lauren Silvis, the deputy
4 center director for Policy at the Center for Devices
5 and Radiological Health.
6 MS. MCADAMS: I'm Dottie McAdams in the
7 Center for Veterinary Medicine, and I'm a supervisory
8 medical officer in the Office of Surveillance and
9 Compliance.
10 MR. ABRAMS: Good morning. I'm Tom Abrams,
11 the director of Office of Prescription Drug Promotion
12 in the Center for Drug Evaluation and Research.
13 MS. SCHIFTER: I'm Karen Schifter. I'm
14 Senior Counsel in the Office of the Chief Counsel.
15 DR. CALIFF: And I'm Rob Califf,
16 Commissioner.
17 MS. KUX: Thank you all.
18 And if our press officer, Sarah Peddicord,
19 is in the room, if she could raise her -- she's way in
20 the back. Thank you, Sarah.
21 So we are aware that members of the media
22 who are here today may be interested in speaking with
1 the FDA about this public meeting. However, in
2 keeping with the purpose of the meeting, which is for
3 FDA to listen to comments from presenters, the panel
4 members and -- the panel members and other FDA
5 employees will not be available to make statements to
6 the media. If you have any questions, please contact
7 Sarah Peddicord.
8 Before we begin, I have the housekeeping
9 announcements. The meeting is scheduled from 9:00
10 a.m. to 5:00 p.m. today. Please silence your cell
11 phones or any other mobile devices, as they may
12 interfere with the audio in the room today. We also
13 ask that all attendees sign in at the registration
14 tables outside the meeting room.
15 The restrooms are located in the lobby past
16 the coffee area to the right and down the hallway.
17 We'll be taking one approximately 20-minute
18 break during the morning and one approximately 20-
19 minute break during the afternoon.
20 Today's lunch is scheduled from 12:26 to
21 1:30. And there are sandwiches, salads, and beverage
22 available in the lobby for purchase. And you can also
1 preorder lunch during the morning break.
2 Also, we've had some schedule shifts this
3 morning. And so there are a few speakers whose plans
4 have changed and have not been able to make it. So if
5 somebody -- if we skip a person, they've let us know
6 already that they're not going to be here.
7 So let me now turn to the speakers in the
8 agenda. We have -- I think we have about 30 speakers
9 today, and we're really looking forward to hearing
10 from everybody. Yesterday's presentations were really
11 helpful. We -- I think we got a lot out of what we
12 heard yesterday, and we're expecting the same today.
13 So thank you all very much for coming and speaking.
14 And we'll get started.
15 Dr. Sharfstein is our first presenter, Johns
16 Hopkins Medical School of Public Health -- sorry --
17 the School of Public Health.
18 DR. SHARFSTEIN: Excellent. Thank you.
19 Thank you all for the chance to talk about this
20 important topic. And I really want to thank FDA for
21 having this hearing.
22 I can -- I used to work here. And while you
1 can sort of take the person out of FDA, you can't
2 totally take the FDA out of the person. So it's great
3 to be back and to be able to be helpful in any way.
4 So why don't I jump in to my comments. This
5 is who I am.
6 So the first question was FDA is interested
7 in input on how increased communications from firms
8 about unapproved uses could impact the public health.
9 And this is a great question to ask. In fact, I would
10 just start by saying this is the right question to
11 ask. And I'm so glad FDA asked this question first
12 because FDA is a public health agency and is really
13 the last line of defense on public health. And the
14 moment you start to drift off into an ideological
15 First Amendment kind of discussion, in theory, you
16 lose your moorings from what's important for public
17 health. So it's terrific that FDA is very focused on
18 that.
19 And I think if you think about public
20 health, you think about benefits and risks. So if
21 you're going to do increased communications, what are
22 the benefits? What are the risks? And for health --
1 that's what it means.
2 Sometimes in this discussion people start
3 out by going, well, you know, if we just throw more
4 information out there, then it's got to be good for
5 health. From a public health perspective, that's not
6 necessarily true. You have to actually show that or
7 have a reason for that.
8 And when I think about the risk, I think
9 about the history of the FDA, just to start, that FDA
10 really emerged because of claims made by
11 manufacturers. It could have been soothing syrups at
12 the turn of the 20th century, the patent medicines,
13 the nostrums that were sold for every possible cure.
14 There are the products like heroin that was sold for
15 cough. The cancerine (ph) was a product in the early
16 20th century, considered a miracle cancer cure.
17 And then there was this product in the 1920s
18 -- Banbar for the diabetic, which was heavily marketed
19 for diabetes, did not work, and had the problem that
20 insulin had just been discovered. And so people who
21 took it weren't able to get the treatment that they
22 really needed.
1 People may be pretty familiar with this one,
2 Thalidomide, which really transformed drug regulation.
3 It was in this room that we honored Dr. Kelsey when I
4 was here at FDA, the reviewer who prevented
5 Thalidomide from being approved. And that was the --
6 a lot of the birth defects that happened were from,
7 essentially, a secondary use of that medication.
8 With me today is a public health student who
9 was born in 1961 in Great Britain. Her mom did not
10 use Thalidomide, despite it being recommended, but she
11 grew up with a whole number of kids in all her classes
12 who were severely affected.
13 And even if you look to today, you can see
14 all kinds of reasons to be concerned about the risks
15 of marketing of unapproved drugs. There are many
16 whistle blowers who have talked about pretty
17 unfortunate decisions made by companies to break the
18 rules. There are large exposes in journalism.
19 There's evidence from medical journals about harm for
20 patients from different types of off-label uses.
21 There's recently a study at the population level
22 showing how there's significant increase in adverse
1 drug events for unproven, off-label uses.
2 So I think that is where you start with,
3 with the risk. What about the benefit? What's the
4 benefit of extra communications? And I think that you
5 have to ask yourself what is the greater advantage of
6 off-label communication over and above what's allowed.
7 We're not talking about whether things can be
8 communicated at all. It's above and beyond the
9 medical literature, professional communications,
10 clinical practice guidelines, and the permitted
11 practices of answering questions and distributing
12 peer-reviewed research.
13 So when you pose a question that way, which
14 I think is really the right way to ask -- what is the
15 benefit of letting the companies make additional
16 marketing on top of everything that's allowed versus
17 the risks that really stem from history and current
18 evidence -- it is a very difficult to conclude off the
19 bat that you have benefit exceeding the risks. In
20 fact, I would probably say the evidence favors risk
21 exceeding the benefit for these reasons.
22 The other issue besides that is I think that
1 off-label promotion reduces the incentives for
2 research to know what really works. If companies can
3 get products sold without ever doing the definitive
4 studies, everybody loses. And having people argue or
5 having judges determine what in the gray area can be
6 said or not said is just so much worse than having the
7 evidence that really should be guiding patient care.
8 I do think that there may be some
9 circumstances where there are benefits of off-label
10 promotion, but it would exist in narrow, specific
11 circumstances that FDA should review that basic
12 setting and really be able to feel comfortable that
13 there's value.
14 So another question I would like to briefly
15 comment on is to what extent the changes in the
16 healthcare system provide incentives for firms to
17 generate high-quality data. I've had some experience
18 since leaving FDA with financial incentives in the
19 healthcare system as the secretary of health in
20 Maryland and really trying to move the entire system
21 towards better payment for value.
22 There is no question that off-label
1 prescribing that's without evidence and increases
2 adverse events should be dis-incentivized in that
3 environment. But the key question that everyone wants
4 to know in a value-based environment is what does the
5 evidence say.
6 FDA and the people who work in these
7 buildings conduct the best independent review of
8 safety and effectiveness in the world. And reducing
9 the ability of FDA to really look at the data
10 carefully and say what works and what doesn't and to
11 have the incentive structure for good studies to be
12 done is what a value-based healthcare system needs.
13 A value-based healthcare system does not
14 need all kinds of gray area, half claims, four out of
15 five doctors prefer this, or there's one little study
16 on that. That -- what the value-based health system
17 needs is to really understand the best possible data.
18 And finally, are there ways to mitigate the
19 potential public health harm of increased off-label
20 communications? Well, I'm sure you people have spoken
21 about the idea of disclaimers. The evidence on that
22 is, I would say, extremely weak that disclaimers are
1 helpful there.
2 Transparency on data I think is probably, in
3 general, a good thing, but that will not overcome
4 significant marketing that is based on uses that
5 aren't well proven. Transparency on sales incentives
6 I think would also be important. I think it matters
7 to know whether people are getting paid extra for
8 additional prescribing. But again, I would be
9 skeptical that that would really undo the potential
10 for public health harm. You could do all kinds of
11 surveillance.
12 And the big problem with all of these is
13 that they would require after-the-fact solutions by
14 FDA. So the enforcement of this would all be after
15 harm has been created.
16 So I would conclude by saying I think there
17 are major risks to public health in an ahistorical,
18 ideological view of the First Amendment. I think the
19 statement in the Amarin decision recently that this
20 wouldn't have come up a couple decades ago, but it's
21 just all the changes in First Amendment law,
22 hopefully, the judiciary will -- that are causing it
1 to come up -- the judiciary will take a step back from
2 the precipice and decide that it's better to leave
3 these regulatory decisions to the agency that knows
4 what it's doing.
5 If FDA is going to agree to more off-label
6 communications, each type of incident should be
7 justified in advance of the public health rationale.
8 And after-the-fact enforcement I think is a recipe for
9 a crisis.
10 Thanks so much for having me. I'm happy to
11 answer any questions.
12 MS. KUX: Thank you very much.
13 Panelists, any questions?
14 Dr. Califf?
15 DR. CALIFF: Thanks for a very clear
16 presentation, so clear that it's hard to ask a
17 question without getting into a very detailed
18 discussion.
19 But you really posited this thing that came
20 up a lot yesterday about the interpretation of the law
21 versus the interest of public health. Could you just
22 go one level deeper? I mean, you've held a lot of
1 jobs where that's been in the balance, and it would be
2 useful to get your perspective.
3 And I also think in writing a bit of
4 scholarly detail now that you're at Hopkins about that
5 would be extremely helpful in the docket.
6 (Laughter.)
7 DR. SHARFSTEIN: Excellent. Thank you.
8 Well, you know, one of the risks of being in
9 academics is there's an occupational hazard of self-
10 citation. So I did write a couple things about this,
11 including in the Journal of American Medical
12 Association. And I was -- I even gave a talk at Yale
13 Law School where I was invited to a very interesting
14 conference on the First Amendment in public health.
15 And embedded -- I am obviously not a lawyer.
16 But embedded in a lot of legal decision-making around
17 this is a framework which does have different kinds of
18 risks. And you know, there is no unfettered right.
19 You know, in -- even in the freedom of speech, you
20 can't yell fire in a crowded theater, you can't ring
21 the church bells at 2:00 in the morning. And the --
22 you have to think about what the different risks and
1 benefits are and the importance of the public
2 interest.
3 And there are legal frameworks around the
4 First Amendment which are very much based on what the
5 rationale is. And I think the FDA was founded onto
6 and the key laws were all passed by Congress in order
7 to protect the public.
8 And I think that FDA should be open to the
9 idea that off-label communication may have certain
10 public health advantages and should be really putting
11 the public health mission at the center of its
12 discussions and should be looking for a way to engage
13 the law on the turf of public health rather than what
14 I think is, unfortunately, happening where people sort
15 of have been starting from first principles and
16 winding up in, you know, places that could actually be
17 quite devastating.
18 And I don't think in the end when crises
19 happen that that's going to really be defensible to
20 anyone. It's better to think our approach to the law
21 is always about balance. And we need -- and FDA
22 should be very clear about what the public health
1 issues are at stake and how it intends to apply a
2 reasonable balance in a public health context.
3 And so, you know, setting up a process, for
4 example, well, there's some kind of use of data that
5 people want to have. Well, let's figure out a process
6 to look at the public health issues and decide there
7 might be a way around it rather than coming at it
8 from, like, a first -- you know, just a pure, you
9 know, first principles legal perspective.
10 And I think it's one that hopefully there
11 will be some sensible judges who will realize that
12 what's happened to the First Amendment is really
13 something that's, you know -- or is happening. It's
14 not all the way there and could be -- people could
15 step back from the precipice.
16 I don't think judges want to be making all
17 the calls that Tom Abrams's group makes or, you know,
18 so many different scientists make. And they can just
19 step back from that a little bit and give FDA some
20 room to apply public health principles. That would be
21 the best.
22 MS. KUX: Other questions?
1 DR. CALIFF: Feel free to submit your
2 articles, by the way.
3 DR. SHARFSTEIN: Okay. Excellent.
4 MS. KUX: Thank you, Dr. Sharfstein.
5 DR. SHARFSTEIN: Okay. Thank you very much
6 for the chance to be here.
7 MS. KUX: And I just -- I left a little bit
8 of information -- key information out of my opening
9 remarks.
10 As I think maybe you've noticed, up at the
11 podium to help the speakers keep to their allotted
12 time there's a timer. So it'll be green for the
13 speakers when you begin. And then at one minute to
14 go, it'll turn yellow. And then it turns red. And
15 when it turns red, we ask you to conclude your
16 remarks. And if you go over and we're running very
17 tight on time, I will be interrupting you and asking
18 you to finish up.
19 And so also, if there are folks in the room
20 who didn't register to make a presentation but still
21 would like to present some comments at the end of the
22 meeting, we are going to have an open public session.
1 And you can sign up out at the registration table.
2 We'll be giving folks three-minute blocks. So that'll
3 be available until the end of the lunch break.
4 Thank you very much.
5 And so our next speaker is Mr. Steve
6 Francesco from Do No Harm Network.
7 MR. FRANCESCO: Good morning. You're going
8 to be doing the slides for me? What am I using here?
9 So hit the red? Right arrow. Okay.
10 Thank you for letting me have the time to
11 speak today.
12 My approach may be a little bit different
13 from others because of my own experience. I'm taking
14 the point of view that off-label needs to be brought
15 into the 21st century. I think there is some parts of
16 off-label that may be working, but there are some
17 parts of off-label that need revision.
18 One of the key issues with off-label is, to
19 be quite honest, I find it to be a sloppy scientific
20 approach. I believe that population segments are not
21 equally protected. And I believe that therapy areas
22 have a uniqueness about them, particularly in terms of
1 safety and efficacy, which needs to be considered when
2 you're allowing consideration of relaxing off-label or
3 tightening up off-label. So for me, one-size-fits-all
4 simply doesn't work.
5 For example -- and I'll explain why I'm
6 going into this in some detail in a minute -- our
7 least protected population segment in the United
8 States is children. Seventy to ninety percent of
9 prescriptions to children are off-label. And this is
10 not known by the American public.
11 And in my anecdotal research -- and I
12 believe other people are doing more formal research --
13 it's a shock to hear that 70 to 90 percent of
14 medications prescribed to children are off-label.
15 That is simply not acceptable. And the reason it's
16 off-label is because there's no data.
17 My belief is that in the 21st century there
18 are opportunities for data which are different than 50
19 years ago so that, in fact, I am in support of
20 revision of off-label. I'm not in support necessarily
21 of expanding the availability of fish oil. But I do
22 believe that there are some important considerations
1 which need to be passed around.
2 And an example, with the absence of data is
3 the 12 billion that were fines for illegal promotion
4 in the children's area between 2003 and 2014. That's
5 12 billion with a B, and that continues.
6 In other words, where there is no data,
7 where you're not making decisions based on facts, you
8 have the Wild West. And understanding the fact that
9 this is a for-profit system and that there's going to
10 be a tendency to want to go to bonuses tells that, in
11 fact, I do believe there's a way to segment out
12 therapy areas and categories so that you can change
13 off-label in certain ways and make it more
14 conservative in other ways, make (ph) it official and
15 make it more relaxed.
16 Now, via off-label, for example, extending
17 the life of an oncology patient for six months seems
18 just. It definitely seems just. However, attempting
19 to change a child's behavior with untested powerful
20 drugs that can cause a permanent disability or death,
21 that's unjust. Off-label should not be treated the
22 same way in oncology as it is with children.
1 Above all, as you take serious consideration
2 for reform -- and I'm not going to get into the
3 legalistic parts of it -- one must not do what has
4 been allowed to happen in our healthcare system.
5 And I'm using a phrase from a sociologist
6 named Diane Vaughan. Above all, do not extend the
7 opportunity for normalization of deviance. And if you
8 wonder what normalization of deviance means, it means
9 a relaxing of standards bit by bit by bit until it
10 becomes part of the culture. Think of Volkswagen with
11 12 million cars having their pollution controls played
12 with. This happen, all right? So we must not extend
13 the opportunity for the normalization of deviance.
14 Now, who am I? Who am I to say this to you?
15 First of all, I've been in this room before presenting
16 on other situations. This is unique for me, this
17 therapy area. And that's because I've had 32 years in
18 healthcare, 23 with my own company, 9 with pharma.
19 But in 2009, I was crushed when my only son
20 died at 15 due to careless off-label prescribing. It
21 was malpractice. And I wrote a book called
22 Overmedicated & Undertreated. It took me four years
1 to write. It's a dramatic, powerful book. It's got
2 footnotes. It's scientific. And it's done very well.
3 But look at the subhead -- Overmedicated &
4 Undertreated: How I Lost My Only Son. Overmedicated
5 -- excuse me. My book is recommended by the New York
6 Times. It's recommended by Columbia Med School
7 Department of Psychiatry. It was the focus of an NBC
8 Dateline episode, which had tremendous feedback. It
9 is on the Columbia University Graduate School of
10 Journalism curriculum.
11 It has detailed recommendations. In the
12 center of the book is off-label, the inequities in
13 off-label, and the ways to improve it. And I would
14 like the FDA to take some of the reforms, what I put
15 into the book, on consideration. And as a promotional
16 piece, it's available on Amazon.
17 That, in turn, because of the response,
18 caused me to launch a new non-profit called Do No Harm
19 Network. And one of our objectives is to reform off-
20 label to children.
21 So my point here is we must look at the
22 population segments, meaning children or adult because
1 the protections are totally different and almost
2 totally missing in children. And we must look, in
3 particular, at certain therapy areas.
4 This is the new logo for Do No Harm Network.
5 This is the website, www.DoNoHarmNetwork.org. And I
6 don't know if you can see the third bullet point. It
7 says, "Reform off-label prescribing is at the center
8 of our purpose" -- at the center of our purpose. And
9 I am working on it, and there are ways to do it. And
10 I think the FDA needs to bring off-label into the 21st
11 century.
12 So that's my conclusions. My yellow light
13 is on. I suppose there might be some questions.
14 MS. KUX: Thank you very much.
15 Panelists, any questions?
16 Kristin?
17 MS. DAVIS: Thank you so much for your
18 presentation. And I'm really interested in the divide
19 you were drawing where off-label information, it could
20 be just to provide it, say, in the oncology setting.
21 And I wonder if you could talk a little more either
22 today or in your written remarks about what some of
1 the criteria would be, whether it's because it's life-
2 threatening or fatal without treatment and there might
3 not be approved treatments or what the kind of
4 characteristics would be of a situation where it might
5 be appropriate versus inappropriate.
6 MR. FRANCESCO: If I can go back to data,
7 this is a data issue, okay? You need to have
8 information to decide what to do. We don't have data
9 for children, and we should have data for children.
10 There's no reason in today's age we cannot have some
11 form of data for children. And maybe relaxing the
12 idea of clinical trials is not a bad idea, but it has
13 to be quality data.
14 In the oncology area, you -- I'm using that
15 as an example because often decisions, in effect, are
16 made at the last minute, and some oncologist is mixing
17 three drugs together hoping, hoping, hoping, okay? I
18 think that's -- in that case, you can't expect to have
19 data.
20 Now, that's what I can say right now. But I
21 will say that I will be submitting more information
22 prior to, I think, the January deadline.
1 MS. DAVIS: Thank you.
2 MR. FRANCESCO: Please.
3 MS. KUX: Any other questions?
4 Dr. Califf?
5 DR. CALIFF: First, thank you for turning,
6 you know, a tragic personal experience into something
7 with bigger impact. I know how difficult that is.
8 And my question -- I think since you've been
9 in the industry, you might have a particular
10 perspective. We -- in addition to needing data, we
11 often talk about risk-benefit. And some people will
12 get -- you know, your Do No Harm slogan, you know, in
13 perspective, some people will get harmed often in
14 situations where overall, on average, there's a
15 benefit.
16 I know you've dealt with this in developing
17 therapies yourself. I wonder if you could just give
18 us a little perspective on how you think about that in
19 this --
20 MR. FRANCESCO: Sure.
21 DR. CALIFF: -- context.
22 MR. FRANCESCO: The way I'm looking -- and
1 again, I'm focusing on children, okay? The way I'm
2 looking at it -- and I -- since we -- can I still
3 talk? It's red.
4 MS. KUX: Yes. Please go ahead.
5 (Laughter.)
6 MS. KUX: You're -- when Dr. Califf is --
7 MR. FRANCESCO: He's okay.
8 MS. KUX: -- or others are asking you
9 questions --
10 MR. FRANCESCO: Okay.
11 MS. KUX: -- you're certainly allowed to
12 talk.
13 MR. FRANCESCO: If it's you, it's all right.
14 (Laughter.)
15 MR. FRANCESCO: All right. Here's what's
16 going on. Here's what's going on. You need to
17 picture a child. And around the child, there are
18 other constituencies. There's the drug companies.
19 There's the insurance companies. There's the
20 prescribers. And in fact, there's the schools, okay?
21 So you do have the pressure on these kids,
22 in fact, to be medicated for a number of reasons. And
1 if you go back to prior to 1985, the pressures weren't
2 that intense.
3 Could you repeat your question? I'm -- I've
4 lost my thought. What I just --
5 DR. CALIFF: I was asking about risk-benefit
6 in --
7 MR. FRANCESCO: Okay.
8 DR. CALIFF: -- terms of sometimes it may
9 help a lot of people, hurt some, and how you put that
10 in perspective with regard --
11 MR. FRANCESCO: Right.
12 DR. CALIFF: -- to --
13 MR. FRANCESCO: All right. So what was
14 going on in 1985 is there were far more alternatives
15 than today. For example, today, alternative forms of
16 therapy are not reimbursed by the insurance companies.
17 They want 10 minutes in, a generic drug, and you're
18 out.
19 Doctors, per hour, make more money
20 prescribing per hour. And that's a historical fact.
21 Again, it's in my book, this book here. And then, of
22 course, you have the pressures from the schools.
1 So what's happened over time is alternative
2 therapies have been suppressed. And in my case with
3 my son, we could afford the best because I made a
4 decent income, but yet it was out of pocket. So in my
5 view, you need to have a more holistic view of therapy
6 and not just be so drug-oriented.
7 So yes, there will be situations where
8 there's a problem, but we can dramatically reduce it.
9 For example, I estimate that 2 million kids each week
10 are getting psychotropic medication in this country,
11 and there are many people who feel it should be more
12 like 500,000. And that's particularly true in the
13 foster care area and so on. So yes, you need
14 medication -- there's no question about that -- but
15 far less than what we have right now.
16 DR. CALIFF: One quick follow-up. I'm
17 sorry. I know I've gone a little overtime here.
18 But the other perspective, your request for
19 more data, I mean, we couldn't -- as you know, we
20 couldn't feel more strongly about that.
21 MR. FRANCESCO: No.
22 DR. CALIFF: But you're talking about
1 studies in children. Can you just offer a perspective
2 on that?
3 MR. FRANCESCO: Yeah. I attended a meeting
4 off campus. It was a follow-up for some neuroleptic
5 drugs. And everybody in the room said we wish we had
6 more data. So it's -- if you go to any FDA meeting
7 and you say raise your hand if you want more data,
8 everybody normally would raise their hand except the
9 pharma companies, for example, right?
10 So now, let's look at that. Is there a way
11 that we can get data, even three-months data? Now,
12 there's been a number of three-month studies that have
13 been done. And there are other -- what I think -- and
14 I'm still working on this. It will be part of my
15 submission for January. I think there are other ways
16 to get data other than the classical, you know,
17 clinical trial.
18 And the -- a three-month segment focused on
19 safety followed by a portion of that cohort continuing
20 to be monitored, we can get a lot done in about two
21 years. But we just have to have -- I think we have to
22 have the will to do it. I think the ethical arguments
1 have gotten in the way, but I also think the funding
2 has. And one of the things I'm working on with others
3 is getting the funding.
4 That's it. Thank you.
5 MS. KUX: Other questions?
6 Thank you very much.
7 Our next speaker is Ms. Kim Witczak from
8 WoodyMatters.
9 MS. WITCZAK: Good morning. I'd like to
10 first of all thank the FDA for this opportunity to
11 address this very important issue of off-label and its
12 impact on patients.
13 WoodyMatters was founded after the death of
14 my husband in 2003. We represent the voice of real
15 world patients who live every day with the
16 consequences of a flawed drug safety system.
17 Thirteen years ago, my life looked very
18 different than it does today. I was married to my
19 best friend, had a successful career in advertising,
20 traveled the world on productions, and was started to
21 -- we were planning to start a family.
22 However, all of that changed with one phone
1 call on August 6, 2003. My world as I knew it came
2 crashing down. Woody, my husband of almost 10 years,
3 was found hanging from the rafters of our garage, dead
4 at age 37.
5 Wood wasn't depressed, nor did he have a
6 history of depression or any other mental illness. He
7 had just started his dream job as Vice President of
8 Sales with a startup company and was having trouble
9 sleeping, which is not uncommon for entrepreneurs. So
10 he -- Woody went to his family doctor, whom he's gone
11 to for years and trusted, and his -- and he was given
12 Zoloft, an antidepressant off-label for an insomnia
13 diagnosis. The doctor said Zoloft would help take the
14 edge off and help him sleep. But five weeks later, he
15 was dead.
16 The three-week sample pack that Woody came
17 home with automatically doubled the dose from 25 to 50
18 milligrams, unbeknownst to him. There was no
19 conversation about cautionary warnings to be closely
20 monitored when first going on or dosages changing. In
21 fact, I was out of the country for the first three
22 weeks he was on the drug.
1 From the beginning, his death made no sense
2 to anybody who knew him. And everywhere we turned,
3 the so-called experts in mental health and support --
4 suicide support groups said he must have been
5 depressed, but I knew he wasn't in the deepest part of
6 me. So why would a guy who loved life take his own
7 life? So we started to dig into the only thing that
8 made Woody change during this short amount of time,
9 and that was Zoloft.
10 Unfortunately, Woody is not alone. There
11 are thousands of patients who, like Lewis (ph), was
12 given Seroquel in the hospital to calm him down; or
13 that there's two men who happened to be named Doug
14 (ph), but were both given Neurontin for pain
15 management; or Keith (ph), who was given Risperdal and
16 Haldol in the nursing home; and the babies that --
17 whose mothers were given Zofran to help manage morning
18 sickness. And then there's the beautiful Robyn, who I
19 know you're going to hear from along with some others
20 in a little bit, but I have to -- that are here to
21 talk about what happened to their loved ones.
22 But what do all these things have in common?
1 Off-label use. Here are a few drugs that have known
2 off-label use. Many of them are psychiatric drugs
3 given to people for conditions like insomnia, pain,
4 hot flashes, behavior issues, or target audiences, as
5 Steve had just mentioned, that were never approved,
6 like, for babies, kids, elderly. Many of these drugs
7 have also had serious adverse events, including deaths
8 associated with them.
9 The reality is, for most consumers, they
10 have no idea that -- when being given a drug off-
11 label. There is no informed consent given. They just
12 trust their doctor and assume that, of course, the
13 drug they're being given had -- is FDA-approved for
14 that condition. Or why would the doctor give it to
15 them? I don't think the average person has any idea
16 what off-label even means.
17 This actually hit home for me. A couple
18 weeks ago, I was -- I gave -- I spoke to a group of
19 well-informed active patient safety advocates. And
20 during the question-and-answer portion of the
21 presentation, a couple people raised their hand and
22 asked what off-label meant. And that was shocking to
1 me because these were the people who I thought should
2 know.
3 So if patients don't know what off-label
4 means, they don't know to ask the question. And there
5 certainly is no shared decision-making or informed
6 consent happening. Then let's throw the reality of 7
7 to 10 minutes with our doctors there to even have the
8 conversation or even the opportunity to discuss
9 warnings that are associated with the drugs.
10 And as we heard yesterday, a large
11 percentage of off-label prescribing lacks rigorous
12 scientific evidence and also has an increased adverse
13 reactions compared to FDA use. And then there's no
14 robust reporting mechanisms in place to track adverse
15 events.
16 As we know, companies have paid billions of
17 dollars in Department of Justice fines for off-label.
18 No wonder why they want to use the legal system and
19 claim First Amendment as their right to free speech.
20 It's a lot of money at stake.
21 However, I find it ironic because, at the
22 same time, these companies are arguing for their First
1 Amendment -- they're taking individuals' First
2 Amendment rights off -- away from them during their
3 legal settlements with gag clauses. This way, the
4 harmed or impacted individual can never tell their
5 story publically, such as what I'm doing today.
6 Look at what recent Pfizer shot up 2,700 law
7 -- Chantix victims who had lawsuits for psychiatric
8 side effects, which were -- they were silenced, and
9 then after which they approached the FDA with new
10 scientific data to remove the black box warnings that
11 led to the lawsuits in the first place.
12 Unfortunately, the FDA didn't get to hear their
13 stories because they couldn't talk. So now where's
14 their right to free speech?
15 Then this is assuming that the harmed
16 patient is even able to hold the company accountable
17 legally in the first place because they're -- the
18 companies are using federal law preemption. This is a
19 perfect storm.
20 I'm also concerned about how the drug
21 companies are going to be able to use the expedited
22 FDA approval pathways like breakthrough therapy
1 designation or the 21st Century Cures Act, which
2 they'll be able to get their drugs and devices to the
3 market more quickly and then only be able to then
4 promote the drugs off-label without having to do
5 rigorous studies.
6 Off-label is big business. As someone who
7 has spent her entire career in advertising, I think
8 it's a fine line between marketing and science,
9 especially when you have ghost-written articles in
10 medical journals, there's bias in the literature,
11 company-paid key opinion leaders who are speaking at
12 medical conferences, industry-influenced clinical
13 guidelines and/or screening forms, flawed study
14 designs, and its data being manipulated or selectively
15 reported.
16 Doctors and patients deserve more. This
17 shouldn't be in place of what the FDA gets to -- the
18 rigorous analysis that you do. To loosen the off-
19 label promotion guidelines, it diminishes the Agency's
20 role and mission to protect the public. And it's a
21 perfect -- as you can see, it opens the floodgates.
22 At the end of the day, we should never put
1 sales before science. It's a balancing act. And
2 doctors are free to prescribe off-label and -- which
3 is -- there is benefit, as Steve mentioned earlier,
4 like my best friend, who is -- all of the sudden was
5 told she had Stage 4 glioblastoma tumor and was able
6 to use Avastin off-label through a study down at Duke.
7 And four years later, she's still alive.
8 But that is very different than people like
9 Woody and Dave and Robin, who were given off-label
10 drugs for another cause. They had no idea and just
11 trusted their doctor and assume what they were getting
12 was FDA-approved.
13 Everyone talks about us being the patients -
14 - or being about us, the patients, and, as I like to
15 say, customers sometimes. It's more like buyer
16 beware. We shouldn't be guinea pigs. We are not
17 anecdotes. We matter.
18 Thank you.
19 MS. KUX: Thank you very much for coming and
20 sharing the stories with us.
21 MS. WITCZAK: Thanks.
22 MS. KUX: Panelists have any questions?
1 Dr. Califf?
2 DR. CALIFF: I don't mean to be dominating
3 the questions. So please, others, ask.
4 But I think you and the previous speaker
5 have both raised, you know, something that's very
6 important to us, which is we -- I think we all feel at
7 FDA that having data, you know, liberates a lot of
8 ability to do things with confidence.
9 Speaking sort of practically, you suggested
10 that maybe off-label use should be handled by some
11 sort of consent and data collection. Can you say more
12 about how practically you would see that working?
13 MS. WITCZAK: Yes. And I can also supply
14 more comments. But I would love to see informed
15 consent. Is there a way -- and I don't -- I know you
16 guys don't control the practice of medicine or the
17 doctors. But I think if there's some kind of -- and
18 maybe it's with the drug companies -- but informed
19 consent forms, like, just something that we sign,
20 there's a conversation now.
21 And you know, on Monday, I had the
22 opportunity to participate in the strategic framework
1 conversation about how to communicate risk here at the
2 FDA. So I know it's something that you guys are
3 looking at.
4 And one of things, it was all about shared
5 informed -- you know, and shared decision-making. And
6 I think without that informed consent, without us even
7 knowing, then we're -- we, the public, pay the price.
8 So I would love to see some kind of informed
9 consent in general.
10 MS. KUX: Can you also say more about, you
11 know, sort of what your thoughts are on data
12 collection and the participation of patients in that
13 happening, assuming that there would be, you know,
14 some sort of informed consent framework?
15 MS. WITCZAK: Well, I would love -- I mean,
16 as we heard yesterday, there was a lot of conversation
17 about real world collection. So I think there is
18 opportunity.
19 I would love to see -- you know, I don't
20 know if it's -- you know, with the Canada study, they
21 were able to, through the records, which I wish we had
22 something like that. But maybe you could do that with
1 some of our bigger systems like the Kaiser or the Vet
2 where you could actually have, you know, you put your
3 diagnosis down so you have it officially in record and
4 what drug and if there were any outcomes because I
5 think that would be an opportunity to collect some
6 adverse events.
7 And you know, I think being willing to, you
8 know, just -- obviously, I think you -- this is
9 something you guys have to balance. And you always
10 hear, well, it's anecdotal and it didn't happen within
11 a clinical study. And I think as we look -- start
12 looking at data, there's a lot of different sources of
13 data.
14 And I think it's not always about -- the
15 data that we tend to hear about is all the benefit --
16 all the people who benefitted from something. But I
17 think it's really important that consumers that have
18 been harmed, we really look at that data as well and
19 go deeper into how and why.
20 MS. KUX: Thank you.
21 Other questions from the panel?
22 Tom?
1 MR. ABRAMS: Assuming that we can get more
2 data or company information, what mechanism would you
3 see as far as getting out to the public? Do you think
4 it's a company's responsibility or another party's
5 responsibility?
6 MS. WITCZAK: Personally, I don't think it's
7 the company's. I -- you know, I would -- I think it -
8 - coming from is -- you know, somebody like the FDA
9 that we have to trust -- I mean, I'd like to see it
10 being vetted. I don't -- I think there's too many
11 financial incentives for a company to do something
12 different than the initial intention.
13 And I'll give it some more thought and put
14 into my comments as well.
15 MR. ABRAMS: Thank you.
16 MS. KUX: Dr. Sherman?
17 DR. SHERMAN: Again, thank you for your
18 remarks.
19 If you could also give some thought to and
20 put in your comments unless you're prepared to address
21 today if, for instance, your friend that's part of a
22 study so is being informed through that study and has
1 a life-threatening disease that appears to be anything
2 very -- and this is similar to Ms. Davis's question
3 earlier. Do you see a gradation or a cutoff for
4 certain types of illnesses where some type of
5 communication about that use is appropriate or not
6 and, if so, what safeguards you might envision?
7 MS. WITCZAK: I'll definitely give some more
8 thought and put it in record. But just initially,
9 when I look at somebody like my friend, Molly (ph),
10 who, literally, people in Minnesota wouldn't touch
11 her, but she was able to get into Duke. And I know
12 because as a drug safety advocate, we've been -- you
13 know, looked at Avastin, and it had a lot of issues,
14 right?
15 But somebody like her, she was willing to
16 take that risk, and she knew it. She signed it
17 because she had no other alternative to, like, you
18 know, be able to live. And four years later, she's
19 here.
20 But somebody with like -- you know, I just
21 got a call from somebody who was given an
22 antidepressant who had no idea it was an
1 antidepressant for managing hot flashes and took her
2 life.
3 And so I think there's -- and I think it's
4 really happening in that area of the psych drugs. And
5 I think an area when we do know that there is a lot of
6 off-label use we should be requesting or demanding
7 further studies. And maybe it's -- you know, if it's
8 NIH or somebody else where it's not coming necessarily
9 from the companies where, again, I think there's
10 financial incentive. So thanks.
11 MS. KUX: Thank you very much.
12 MS. WITCZAK: Yeah, thank you.
13 MS. KUX: So our next speakers are Ms. Robyn
14 Edwards and Ms. Veverly Edwards from the Consumers
15 Union Safe Patient Project.
16 Thank you.
17 MS. V. EDWARDS: Good morning and thank you
18 all for having us this morning.
19 So my stance is, as far as off-label
20 promotion, I think it should not be allowed. It
21 undermines the whole purpose of FDA. The people of
22 this nation trusted you, FDA, are overseeing and
1 regulating to ensure that drugs and devices are used
2 according to what they have been approved for. If you
3 allow this, you are unleashing something deadly on the
4 people of this nation.
5 So in October of 2007, Robyn was actually
6 inducted into the Honor Society in the spring. And
7 that summer when she came home from visiting her dad
8 in Memphis, Tennessee, she had had a few numbing
9 sensations.
10 We had just moved into a new home. We were
11 leveling off from the divorce. My kids were active.
12 Robyn was an honor student. She played basketball.
13 She ran track. She danced. She sang. Whatever she
14 put her mind to she did it. And we were just in a
15 great place.
16 So when she started having these numbing
17 sensations, just a few, I took her to her primary care
18 physician. He referred her on to a neurologist. And
19 the neurologist, we went to see him. He took a look
20 at her. He had only seen her once, and he told me
21 that Robyn had a rare form of migraine -- not a
22 migraine headache, but a rare form of migraine which
1 is -- causes numbing sensations. And this particular
2 migraine is a hemiplegic migraine.
3 Well, he then prescribed her Zomig and
4 Depakote, which I knew nothing about either drug. And
5 I even asked him. I said don't you think you need to
6 do an MRI to be sure. He said, oh, no, I would not
7 recommend the MRI. I've seen this before.
8 So -- and I just want to stop here for a
9 minute. One of the things I -- after all this
10 happened, I did my research because I wondered why
11 would he have done this to my child. And I found out
12 that for African Americans there's a disproportionate
13 -- it -- the healthcare is disproportionate for us.
14 I found out one key point is that there are
15 times that doctors will not send us on for further
16 testing. So what this doctor did, instead of sending
17 my daughter on for further testing -- and even
18 accounting for economical differences because we had
19 two insurances -- she had my insurance, and she had
20 her father's insurance. So there was no reason. You
21 know, we were not on state-funded anything. There was
22 no reason for him not to send her on. But he decided.
1 He looked at her. He put her in a box and said Zomig
2 and Depakote.
3 Now, I later found out that Zomig is used
4 for migraine headaches only after it's been
5 established that this is a patient with migraine
6 headaches. He had just seen her. She hadn't had a
7 headache.
8 Depakote is for psych reasons and I think
9 seizures and manic depression, not for numbing
10 sensations. He didn't tell me this. He gave her a
11 drug for everything but what she was having issues
12 with.
13 So my dear Robyn, the honor student, the
14 track and basketball player, was declared brain dead
15 October 9, 2007. And I was devastated. Like I said,
16 we had just moved into our new home. Everything was
17 going good. We go to this doctor October 1st. He
18 gave her a drug.
19 October 4th, she's having a massive stroke.
20 I take her to the emergency room. The hospital still
21 -- they're going on what he says. She lays there for
22 11 hours or 12 hours before they even diagnose a
1 stroke because they're still looking at a migraine
2 headaches, which she never had.
3 So we're airlifted out of there, and we're
4 taken to Salt Lake City. We get there, and they tell
5 me, okay, her skull has to come off and she can stroke
6 again and die, you know. Seventy-two hours, if her --
7 if the swelling doesn't start to recede, there's no
8 hope. Her swelling didn't recede. She's declared
9 brain dead.
10 I tell the doctors no. No, she's not brain
11 dead. I prayed. She's not brain dead.
12 So she comes out of it 30 days later. But
13 then we're told that she'll never walk, talk, eat.
14 She'll have no quality of life. So it took -- it
15 takes us five months in the hospital.
16 And I'm telling you all this because I want
17 you to know what a family actually goes through.
18 Five months later, we go home. But I go
19 home with a 13-year-old newborn because the only thing
20 she can do is pick up a fork. So I'm told Robyn
21 should be put in a long-term facility, but I tell them
22 no because she wasn't born that way. That would
1 destroy her.
2 So I take her home. So I take her home, and
3 I lose my house. I can't work. My boys have to cut
4 back on all their activities. And so we're totally --
5 our lives have been turned upside down.
6 So in 2009, my ex-husband, he comes to me
7 and tells me, well, you know, you really need to
8 consider whether or not to file a medical malpractice
9 lawsuit. But I've gotten past this, and I really
10 don't want to relive it. And I tell him no. But then
11 he tells me it's for Robyn. So I said okay, I'll do
12 it.
13 We get into the lawsuit, and I don't realize
14 the network of corruption I'm in in Idaho. The
15 attorney we were using was actually working with the
16 doctors, and I didn't find out until six months prior
17 before the date for the trial.
18 So in May of 2012, he tried -- he undermines
19 me. He paints me at -- my attorney paints me as a
20 misguided mother. And this is so no one will look at
21 the records because, of course, after an attorney
22 paints you as misguided, who's going to take your
1 case? No one, especially me, an African-American
2 mother in this predominantly White Idaho Falls town
3 and these White males that I'm standing against
4 because I realize now that they've all undermined my
5 child's case.
6 So I appeal to the judge on the case when I
7 realized they've changed her medical records now, and
8 now she has a history of migraines, which she never
9 had and which was easy to actually look at the
10 evidence because Robyn had -- she loved school. This
11 doctor put in her records that she had missed days out
12 of school for a migraine headache. None of this could
13 be substantiated.
14 So -- but they could not have anybody look
15 at those records. So I'm painted as misguided. They
16 lie on the expert witness. They retain him for the
17 case, and they tell me that there is -- that he
18 refused to testify, that there was no testimony. But
19 when I refuse to dismiss the case -- and I took it on
20 myself because I could not find anybody. I ordered a
21 book and started filing myself.
22 I then find out that the eight-page
1 testimony existed and that this expert concluded that
2 this doctor took away any chances of my child having a
3 normal life by giving her these drugs.
4 So I go to the judge on the case, and I tell
5 him, you know, my attorney's working with the defense
6 attorney. Please investigate this. He wouldn't.
7 I then research and find that they've
8 crossed a criminal code in Idaho. So I tried to go to
9 the county prosecutor because that's who I was told by
10 the Attorney General's Office to go to. And they tell
11 me I have to go to the police. Well, the police
12 refused to take a report.
13 Then I go to the mayor and asked the mayor
14 to help me get the police to take the report. The
15 mayor asked for the city attorney's advice. The city
16 attorney in a letter that I wasn't supposed to get
17 says that it's not proper to prosecute this doctor.
18 Well, I also later find out that this doctor
19 is on this initiative in Idaho Falls along with the
20 hospital that she laid in for 12 hours before they
21 diagnosed a stroke. And they're getting ready to get
22 a Gold Seal from Joint Commission. And guess what it
1 is on? Early intervention of stroke care. So they
2 could not have her case going forward. So they kill
3 her case.
4 I also go to -- I write the representative.
5 I write the governor. I write -- oh, gosh, everybody
6 that I can appeal to I appeal to. I write the
7 President of the United States. I write the U.S.
8 Justice Department.
9 And this is the letter that I received from
10 the Justice Department. Now, this is so disconcerting
11 because here I write them a letter. I send them all
12 the evidence, and they send me back a form letter
13 that's not completely filled out. The lady's name
14 that's stamped on there from the Department of Health
15 and Human Services, I found her on LinkedIn. She
16 hadn't worked there in five years. Really?
17 So this is what happens to me and my family.
18 And I know that it's not just us. I know there's
19 other families dealing with the same thing.
20 So if you relax the rules, it'll just make
21 it that much harder for people like me, for people who
22 end up with these doctors. And not all doctors are
1 like this, but there are a lot that are. There are a
2 lot that are out there killing people. And that's
3 what you need to protect us from -- not the ones who
4 do the right thing, but the ones who do the wrong
5 thing.
6 So that's why we're here today. And I'm
7 going to let Robyn come up and say …
8 MS. R. EDWARDS: My name is Robyn Edwards.
9 I am a survivor of an off-use of Zomig and Depakote.
10 On October 9th, 2007, I was declared brain dead by a
11 medical team of doctors due to a massive stroke.
12 The neurologist prescribed the drugs -- who
13 prescribed the drugs took away any chances of me
14 having a normal life. I have my dreams ripped away
15 from one day -- I had -- and dreams ripped -- and
16 dreams -- he ripped away any chance -- he ripped away
17 my dreams from one day attending Yale University. I
18 was an honor student who loved math. I was one of the
19 fastest runners on my track team who took -- and took
20 them to conference.
21 I stand before you pleading do not loosen
22 your standards regarding the off-use label of drugs
1 because I don't want another child to suffer the same
2 thing I did.
3 Thank you.
4 MS. KUX: Thank you very much.
5 Any questions?
6 Thank you both very, very much for coming.
7 Our next speaker is Ms. Lisa Gill from
8 Consumer Reports.
9 MS. GILL: Thank you, Committee, for letting
10 us speak today. I'm here on behalf of Consumer
11 Reports. These are some amazing stories, and I have
12 my own but in a different kind of way.
13 Consumer Reports is an 80-year-old non-
14 profit organization that tests the safety and efficacy
15 of hundreds of consumer products, including cars,
16 refrigerators, lawn mowers, and gas grills. Through
17 our 10-year-old Best Buy Drug program, of which I am
18 the editor of, we also evaluate the comparative
19 effectiveness, the safety, and even the price of
20 hundreds of common medications to treat dozens of
21 disorders and conditions.
22 Consumer Reports accepts no advertising or
1 sponsorship. Our work is supported entirely by
2 individual subscribers to our website and our
3 magazine, and we have about 8 million subscribers.
4 Our work is also supported by individual donors, and
5 we don't accept any corporate donations.
6 The Best Buy Drugs program, specifically,
7 though, is supported by a grant. And it's from the
8 state's Attorney Generals' Consumer and Prescriber
9 Education Grant Program, which is funded by a multi-
10 state settlement of consumer fraud claims regarding
11 the marketing of the prescription drug, Neurontin.
12 But Consumer Reports has covered medications
13 since its first printed issue in 1936, which included
14 a story looking at the health claims of Alka-Seltzer,
15 which at the time we determined simply did not live up
16 to its hype.
17 So here's my story. Before my time at
18 Consumer Reports, I was the editor for a retail
19 pharmacy trade publication. And part of my job called
20 for me to ghost write and edit continuing medical
21 education, also known as CME for doctors, and for
22 continuing education, known as CE for pharmacists. I
1 also developed education grant requests that were
2 submitted to pharmaceutical companies.
3 For regular listeners out there, it's good
4 to know that doctors, nurses, and pharmacists must
5 earn annual continuing education credits to keep up
6 their medical license in their state, and that's what
7 I worked on. And I can assure you that the mechanism
8 for off-label communications between drug companies
9 and prescribers already exist.
10 My biggest projects involved work that
11 discussed the use of drugs like Risperidone and people
12 with dementia in nursing homes or Quetiapine in
13 children who were disruptive in the classroom or at
14 home. Both were off-label uses that we know now,
15 along with other atypical antipsychotics, can
16 substantially put people at risk for a slew of adverse
17 events, including death. And the trade-off is limited
18 or no benefit.
19 I am embarrassed to say, but we used terms
20 like emerging therapies; or advancement in clinical
21 practice; and this one is the worst -- expanding your
22 treatment armamentarium. And that was -- those were
1 code for off-label -- to describe off-label drug uses.
2 We also relied on a treasure trove of
3 published studies about these off-label uses conducted
4 by key opinion leaders, or KOLs, as we called them,
5 who received funds from drug companies to study these
6 uses and then were paid consulting fees by the same
7 companies to work on our continuing medical education
8 projects that communicated these new and off-label
9 uses.
10 So my point here is just to assure you that
11 this mechanism definitely exists. It's a well-oiled
12 machine. And for a time, I was part of that machine.
13 So I come to Consumer Reports with an
14 unusual background and pretty deep insights into how
15 the flow of money moved through the legal drug system
16 between pharmaceutical manufacturers, insurance
17 companies, pharmacy benefit managers, wholesalers,
18 retailers, and the public and how companies work to
19 expand the market through off-label uses for their
20 products and their drugs.
21 So today with that knowledge, I am lucky.
22 And I get to focus on the consumer side of this
1 equation, and I'm committed as part of my work to
2 assuring people can make clear choices about
3 affordable, safe, and effective treatments and have
4 access to those treatments without going bankrupt in
5 the process of -- and also making sure that they don't
6 risk unnecessary harm.
7 We know that drugs prescribed off-label have
8 at least two problems. And based on a recent analysis
9 published in the Journal of the American Medical
10 Association -- it's been referenced several times
11 throughout these proceedings, but it's excellent to
12 bring it up again. The first problem is that more
13 than 80 percent of prescribing is not backed by good
14 science.
15 And the second -- maybe not even a surprise
16 so much. The second problem is that patients who are
17 -- who take medications that have been prescribed off-
18 label are far more likely to experience harm. Off-
19 label prescribing, as we have learned, can put sick
20 people in precarious and vulnerable spots.
21 So in preparation for this hearing -- and
22 this is -- I want to mention this for sure. Consumer
1 Reports conducted a nationally representative survey
2 of American adults just a few weeks ago. We called
3 more than 1,000 people and asked them about their
4 expectations in the medications that they take. And
5 let me assure you, Committee, that consumers heavily
6 rely upon the regulatory might and the oversight of
7 the U.S. Food and Drug Administration. They rely on
8 your Agency as the arbiter of safe and effective
9 medications. And honestly, it's an awesome
10 responsibility.
11 Here are five important points I wanted to
12 convey that people told us were of very high
13 importance to them. The first is 86 percent of people
14 told us that they -- it's extremely important to them
15 that they know of all the medications' possible side
16 effects and any other risks.
17 The second thing -- 83 percent told us that
18 they also want to know how well medication is expected
19 to work.
20 Third, 80 percent said that they would --
21 not only do they want to know how well it works and
22 how safe it is, they'd really like to know how well it
1 works compared to other treatments.
2 Fourth, three-quarters of people said that
3 it's very important to them that a medication that's
4 been advertised for -- to be used in a certain
5 condition, that that is approved -- that use is
6 approved by the FDA. That's really huge.
7 And the fifth and final thing people told us
8 -- 60 percent of people said that it was very
9 important that any advertising or promotion of an off-
10 label use is actually FDA-approved, the advertising or
11 marketing itself.
12 Now, I'm going to switch gears. For
13 listeners out here who may or may have not read the
14 preparation documents for this meeting, I'd like to
15 quote from the opening paragraph in the Background
16 Section of the Federal Register Notice that sets us up
17 for these discussions.
18 And I quote, so, "The FDA is responsible for
19 regulating medical products under the Federal Food and
20 Drug and Cosmetic Act, the FD&C Act, and the Public
21 Health Services Act, also known as the PHS Act, as
22 well as all relevant implementing regulations."
1 Collectively, the FDA authorities is what that is
2 called. Here's the important part. "To promote and
3 protect the public health by," helping us -- "helping
4 to ensure that these products are safe and effective
5 for their intended use."
6 This is -- my next part's a reflection on
7 the questions that you asked. There were some good
8 questions, but I just want to say many people out here
9 may not realize that speakers and people who were
10 asked to comment were asked to look at eight different
11 things. And here's my concern. Many of them were
12 designed to figure out a way to offload this off-label
13 responsibility to either drug companies, payers,
14 medical journals and that it's over the decision-
15 making power of doctors or, worse, the sick patient or
16 family members.
17 Given that the responsibility -- giving that
18 responsibility to drug companies in the hope that they
19 might be incentivized to do studies so that insurance
20 companies and pharmacy benefit managers will include
21 their drug in a formulary -- essentially, pay for the
22 drug -- or the hope that drugs, overwhelmed by high
1 volumes of patients and medical information, can wade
2 through drug company materials to make off-label
3 prescribing decisions is not only bad medicine but, I
4 would argue, is a violation of the public trust and
5 social contract that the FDA holds with the American
6 public.
7 My final thing that's important to mention -
8 - one out of every five prescriptions is written off-
9 label. Our national telephone survey told us --
10 people told us only 6 percent had ever been told that
11 their medication was for an unapproved use. And
12 what's even more concerning, two-thirds of people said
13 that if they had been told, they would not have taken
14 the drug.
15 Thank you very much.
16 MS. KUX: Thank you very much.
17 Questions, Panelists?
18 Dr. Califf?
19 DR. CALIFF: I'll defer. Someone else had a
20 question. I'll defer and follow up.
21 MS. DAVIS: Thank you.
22 So my question is as part of the comparative
1 effectiveness research you do in the Best Buy Drug
2 program, I wonder if -- is part of that in -- if you
3 look at any therapy areas where there might not be
4 approved treatments and, if so, what you're looking
5 for in terms of the evidence that you would evaluate
6 before you would provide recommendations to consumers.
7 MS. GILL: Certainly. And I think I would
8 agree with almost all speakers. More research does
9 need to be done, comparative effectiveness research,
10 for many people out here may not realize most drugs
11 are studied compared to a sugar pill or a placebo.
12 That's actually how they get approved.
13 We try to look at studies where an active
14 ingredient is compared with another active ingredient
15 and compared with the placebo. That kind of research
16 actually is under threat. There's not a lot of it out
17 there, and a lot of funding for it has disappeared.
18 We are always actively looking for it.
19 So actually, lack of comparative
20 effectiveness evidence is a problem. And it's an
21 essential tool, I think, to help regulators like the
22 FDA along with medical societies and consumers and
1 doctors make those good decisions.
2 MS. KUX: Dr. Califf and then Tom.
3 DR. CALIFF: I have four questions. So I'll
4 try to -- and I mean, I think in some ways we've
5 gotten a common message from this panel. So some of
6 these are pretty quick.
7 Would you say that everything you said also
8 pertains to devices, not just drugs?
9 MS. GILL: I'm sorry. Could you repeat that
10 question into the microphone?
11 DR. CALIFF: Would you say that what you've
12 discussed today pertains to devices and not just
13 drugs?
14 MS. GILL: Oh, absolutely, yes. My focus --
15 it -- we -- it definitely applies to devices as well
16 as drugs. My focus as the editor of Best Buy Drugs
17 program, I'm very drug-focused. But Consumers Union
18 and Consumer Reports is extremely concerned about the
19 impact of your decision-making on device and device
20 manufacturers and the --
21 DR. CALIFF: I think it's helpful. And any
22 written comments you send, please make that point.
1 MS. GILL: Absolutely. Thank you.
2 DR. CALIFF: It's helpful.
3 The second question is are the results of
4 your survey publically available.
5 MS. GILL: Yes, yes. We have an article
6 that was published yesterday. We also have the full
7 results that we will be submitting as part of our
8 written commentary.
9 DR. CALIFF: Great. Third, we heard a lot
10 yesterday in particular about First Amendment rights.
11 And this is a hard question to answer succinctly. But
12 what would your response be to the arguments made
13 yesterday about First Amendment that that's a
14 fundamental -- it's called First Amendment for a
15 reason. It's first.
16 MS. GILL: Sure. Sure. So I'm -- just to
17 qualify, I'm not an attorney. I'm a journalist, which
18 is sometimes even worse.
19 But the important thing is we have cited --
20 at least we've been in agreement with Public Citizen
21 that these cases deserve further in-depth review as to
22 how they're being interpreted. There is a lot of room
1 for interpretation. We would question and at least
2 ask you to look deeper at that and make sure that you
3 are not misinterpreting or that there is another
4 pathway outside.
5 DR. CALIFF: Just two more. You're being
6 very good about succinctness, so I don't think we're
7 going to take up too much time.
8 Did you assess in any way in the survey
9 whether people would be willing to participate in
10 clinical trials --
11 MS. GILL: No. You know, it's a good
12 question, and I actually think that we could
13 absolutely ask that for future surveys. What we were
14 really trying to understand is how do people see the
15 role of the FDA. Do people realize that drugs are
16 used off-label -- in other words, for unapproved uses?
17 Most people, obviously, had no idea. Their doctors
18 also did not communicate that.
19 So the issues with clinical trials I think -
20 - we treat it as a separate issue.
21 DR. CALIFF: And then the last one -- and
22 this -- I hope you understand I'm not trying to be
1 defensive here about some of the things you said. But
2 we do have this issue of practice of medicine versus
3 the role of the FDA and the assigned rights of
4 physicians by society. How do you put that in
5 perspective with some of the things that you said --
6 MS. GILL: Well, I mean --
7 DR. CALIFF: -- about the role of the FDA?
8 MS. GILL: Sure. So I'll -- I can try to
9 answer that by saying, you know, physicians have a
10 right, and they -- they're -- it's legal for them to
11 prescribe any drug that they see fit for a specific
12 patient or a patient's condition. I don't think --
13 that is -- we're actually going to leave that on the
14 table. We don't want to address -- we don't want to -
15 - we're not taking that issue on, and I don't think
16 we're trying to change that, necessarily. I think
17 that patient and prescriber relationship is important.
18 In terms of medical practice, I think what
19 we're really trying to talk about is the need for more
20 education, the need for greater transparency around
21 off-label, both off-label -- the safety, the efficacy,
22 and potential consequence, especially other
1 treatments. And it get -- it kind of gets back to the
2 comparative effectiveness information that we're
3 lacking.
4 DR. CALIFF: Just quickly based on what you
5 said, you're not -- then you're not advising that we
6 swoop in on practicing physicians for their off-label
7 prescription --
8 MS. GILL: No. I would say we would want to
9 arm them with better information and also make sure
10 the patients have clear communication, that there's
11 clear communication, there's clear understanding that
12 a medication is being either -- even promoted or
13 prescribed for an unapproved use. That's what we
14 heard very clearly, I think, in our national telephone
15 survey results.
16 MS. KUX: Tom had a question.
17 Tom?
18 MR. ABRAMS: You mentioned it would be
19 beneficial to have more research done. Any
20 suggestions how we as a society can encourage more
21 research and more clinical studies?
22 And then what's your thoughts about
1 communication of those results? At what point should
2 they be communicated, to who, and in what fashion?
3 MS. GILL: To your first question, you know,
4 getting things on the national agenda can go beyond
5 the FDA. And I think that was mentioned earlier by
6 Kim. You know, whether it goes to the NIH or it
7 becomes an institute of medicine, a sort of key
8 priority area, we've done a lot -- think about the CDC
9 has done a lot of work on antibiotic resistance and
10 overuse of opioids.
11 Off-label prescribing and off-label
12 communications, I think, could be one of those
13 potential areas. But it requires, I think, a
14 concerted effort possibly beyond just the Agency. And
15 I think that would be an important thing. Considering
16 that when you think about spiraling out of -- you
17 know, sort of out of control medical costs for
18 individuals and for health systems, inappropriate use
19 of medications is -- falls squarely on that.
20 And can you repeat your second question,
21 please?
22 MR. ABRAMS: Yeah. Once we have data on
1 off-label uses, how should that be communicated? And
2 what different phases to different groups does it
3 become publically available? What standards are put
4 in place for that?
5 MS. GILL: I -- we can address that in our
6 comments. Part of my goal today was just to really
7 impart upon you how the American public told us they
8 see your role as a regulator.
9 That kind of information, I will say we
10 absolutely believe it should be transparent. It
11 should be easily findable. It shouldn't be hidden
12 within drug companies, you know, in a vault somewhere.
13 A lot of information -- a lot of trial data,
14 most people may not realize, is actually not released
15 to the public. Usually, it's only positive studies
16 that wind up in medical journals. So we don't
17 actually see the full picture of a medication, and
18 that's a dangerous place to be as well. So I would
19 say full transparency.
20 And you know -- and I'll say one final
21 thing. You know, 40 percent of drug companies receive
22 or use or rely upon publically funded research through
1 the NIH. Those -- the drugs that they develop as a
2 result of that research to us, it's an investment that
3 the public has made into research, right?
4 And my logic here -- and the logic is that
5 that research, the results are ours, that we own that.
6 And by not being able to understand the full depth and
7 breadth of the risk or efficacy of a medication is a
8 scary place to be.
9 MR. ABRAMS: Thank you.
10 DR. SHERMAN: It was actually -- my
11 question's related to Tom's. And either you could try
12 now or in your comments.
13 I wasn't sure when you were talking about
14 the CME/CE example whether you were stating that there
15 is a mechanism in place already that's -- where
16 there's appropriate oversight for these types of
17 communications or whether you were suggesting that the
18 off-label promotion is going on through these
19 mechanisms or something else.
20 MS. GILL: Well, actually, it's both. My
21 main goal in describing that is that, you know, we
22 heard half a day's worth of industry testimony
1 yesterday. You know, and it sounded very dire. It
2 sounded as though doctors were unaware of potential
3 off-label uses and that they weren't getting the
4 important information that they needed.
5 And my argument is that that continuing
6 medical education mechanism is in place. It's been in
7 place for a really long time. And off-label -- what
8 is considered -- what we're talking about is off-label
9 prescribing or emerging treatments. That is a sort of
10 safe harbor of communication that exists, and it's
11 there.
12 And so to -- I find it sort of irresponsible
13 to come up and try to tell the public, well, the --
14 you know, doctors have no clue. Well, that's not
15 exactly the case. Especially in specialty areas, this
16 continuing medical education is -- like, it's
17 proliferate. I mean, it's just -- it's everywhere.
18 MS. KUX: Thank you.
19 MS. GILL: Thank you.
20 MS. KUX: Our next speaker is Dr. Yu from
21 Washington Advocates for Patient Safety.
22 DR. YU: Good morning. First of all, I
1 would like to thank the FDA for provide the public a
2 opportunity to share the perspective from all
3 stakeholders, in particularly for the patients, as you
4 have heard some stories.
5 My name is Yanling Yu. I'm a researcher at
6 University of Washington from Seattle. I'm also a
7 member of a consumer report patient safety network. I
8 also serve on the FDA Pulmonary and Allergy Drug
9 Advisory Committee (sic). But I'm here to speak as an
10 individual citizen. I have no conflicts of interest.
11 Of the many issues involved the
12 manufacturers’ communications off-labels, I would like
13 to focus my testimonies on patients' perspectives of
14 why regulating off-label communication is so critical
15 to patient safety.
16 First, I would like to share some patient
17 stories as briefly can have shared with you. Black --
18 Lewis Blackman (ph), a healthy, 15-years-old was
19 prescribed a course of Toradol to relieve his pain.
20 Lewis's family was never told the drug was off-label
21 and never approved by FDA for children his age. And
22 it wasn't approved for children. Lewis died of
1 internal bleeding caused by the drug.
2 Dr. Keith Blair (ph), a retired dentist, was
3 hospitalized for back pain. He was given Haloperidol
4 and Risperdal as a chemical restraint (ph) when in a
5 hospital, despite he was lucid. No one told Dr. Blair
6 and his family that this off-label use was not
7 approved by FDA and carries significant risk,
8 especially for elderly. He died after suffered the
9 typical side effect of those two antipsychotic drugs.
10 Reba Golden (ph) and Joan Bryant (ph) were
11 both injected with a bone cement into the spine to
12 relieve their back pain. Blood clots killed both of
13 them after the material contacted with their blood
14 stream. The patient was never told that such use is
15 off-label and FDA has prohibited its use in spinal
16 surgery.
17 Xingxun Yu (ph), an 81-years-old gentleman,
18 was give four dose of Diamox. The way the doctor used
19 the drug is not approved the FDA. The drug
20 information lists this particular indication as
21 unlabeled and investigational. And there were
22 warnings for contraindications for his medical
1 condition. In fact, there's not enough safety data
2 that shows this off-label is safe. According to the
3 (inaudible) review, Xingxun died of multi-organ
4 failure after reaction to the drug, and Xingxun is my
5 father.
6 This is just five example of patients, and
7 as you've heard other patients just testify. There
8 are many, many more patients have been harmed or even
9 killed by unsafe, off-label use.
10 Based on these patients' experience, I have
11 serious concerns relating to off-label uses and their
12 regulation. I recognize that off-label is legal in
13 the United States, and it can be beneficial when used
14 in a safe, sound -- with safe, sound evidence.
15 But a study has showed that a disturbing
16 statistic, as mentioned yesterday and today, that is
17 73 percent of off-labels has little or no scientific
18 support. For those unlucky patients, including my
19 dad, this is no better than playing Russian Roulette
20 on them because a recent showed that off-label use
21 increases the rate of adverse event -- drug events by
22 74 percent when off-label use lack of strong
1 scientific support, in particularly for patient with
2 vulnerability.
3 However, despite the lack of scientific
4 support for off-label uses and their increased risk
5 for ADEs, rarely patient were told when the doctor
6 decided to use off-labels. Most patient believe that
7 the drugs and device approved by FDA to be safe before
8 doctor can recommend them. That is not true. None of
9 the families in the story I mentioned were told the
10 treatment was off-label and there are particular risk
11 to them.
12 But patient need that information to
13 consider for themselves the additional risks versus
14 the benefit and the medical uncertainties associated
15 with off-label use. Unfortunately, many doctors don't
16 know or don't have the time to check FDA approval
17 status either for each drug indication. In a national
18 study, over 40 percent of physicians believe that
19 their off-label prescription have been approved by
20 FDA, despite uncertain drug efficacy and no supporting
21 evidence.
22 So what is left for the patient is a huge
1 regulatory gap to ensure them their safety and their
2 being informed. Now, I fear the gap may grow even
3 wider, which may have far-reaching impact on those
4 unsuspecting patients and subject them to more unsafe
5 off-labels, if we lose regulation on off-label
6 communications.
7 I understand the recent federal ruling such
8 as that off-label promotion is protected free speech
9 as long as the communication is truthful and not
10 misleading. But even truthful communications can
11 still be misleading to patient and even to providers
12 if only side of story is told or the research trial of
13 high quality.
14 I already told you story of those five
15 patient, including my dad, who died because inadequate
16 information that have been deemed truthful and is a
17 current court ruling. But all of them lack of
18 scientific evidence support.
19 So to narrow the regulatory policy gap, I
20 believe that FDA should not loosen, but tighten its
21 regulation on off-label communications. It is crucial
22 for FDA to maintain this regulatory authority and
1 fulfill its purpose to protect the public safety using
2 quality research and clinical trial to ensure the
3 safety and the efficacy of medical products is a gold
4 standard and should not be eroded.
5 The FDA should also update on its website
6 the guideline to healthcare providers about off-label
7 use of a market medical products that guidelines
8 should recommend informed consent and share decision-
9 making.
10 Lastly, I think the FDA should aggressively
11 foster a national off-label reporting and tracking
12 system such as a building on the existing FDA Sentinel
13 Initiative. The reporting should include the intended
14 use for each off-label use, diagnosis code, gender,
15 and age. This will enable FDA to monitor and assess
16 risk of certain off-label uses for public safety to
17 ensure timely warning or remove products off the
18 market.
19 Manufacturers -- lastly, I will say
20 manufacturers has great interest investing off-label
21 use for marketing. So it would be logic to require
22 them to submit data from off-label use for FDA-
1 approved products as part of a post-marketing
2 surveillance requirement.
3 I believe these regulatory policies are
4 essential for FDA to strike a balance between the need
5 to provide certain patients access to off-label
6 products and the need to protect the public safety, a
7 paramount duty for FDA.
8 I thank you for the opportunity to testify
9 here.
10 MS. KUX: Thank you very much.
11 Panelists, any questions?
12 Dr. Califf?
13 DR. CALIFF: I was very interested in your
14 description of collecting data about off-label use.
15 And you know, after many years of working in a big
16 health system, one of the hardest things to get is the
17 reason why the doctor prescribed the medication.
18 I'm wondering if you've had discussions with
19 medical groups about this because, in general, they've
20 been very opposed, citing increased workload and other
21 issues in requiring that information in prescribing.
22 Have you discussed this with physician or other
1 practitioner groups?
2 DR. YU: Yeah. I think there should be
3 right now -- you know, I'm a scientist, too. I look
4 at the data. And I just felt if you don't have data,
5 you don't know what's going on. So we first have to
6 look at the data.
7 As far as how to collect the data, I
8 shouldn't -- we -- I think FDA should encourage all
9 stakeholders like physicians, like health providers
10 and to require them. Actually, right now, they --
11 base -- it's based on voluntary reporting data. But I
12 think it should have a requirement to submit it -- the
13 outcome, the indication they prescribed the drug.
14 Is that what the questions of you asking?
15 DR. CALIFF: The question was have you found
16 any group of providers or physicians who are in favor
17 of this.
18 DR. YU: I actually -- before I came over, I
19 spoke to a physician, a good friend. And he really
20 supported about saying that should support that, you
21 know, to contribute the data. And I think that, you
22 know, if you look at FDA FAERS database data and also
1 Sentinel Initiative, there are reportings from
2 physicians. It is not many.
3 And so I think, you know, to build a
4 national database that I think is so critical,
5 especially given the talk about the children that are
6 facing in special disease -- with special disease and
7 disorders -- and they have a huge percentage of a drug
8 which prescribed as off-label. And if we don't know
9 how those drugs really react to how many adverse
10 events out there, we really don't have any sense about
11 how emergency -- emergence to the public health and
12 safety. And we should involve all the stakeholders to
13 get involved with this.
14 Did I answer your question?
15 DR. CALIFF: I think you did. And my --
16 again, just to articulate, my concern and hope is --
17 I'll just articulate. My hope is that you'll spend
18 time with physician groups to help get them on board
19 because they're almost uniformly opposed to this, in
20 my experience. I'm totally with you on the data, but
21 that was really -- I think you answered my question.
22 DR. YU: Yeah. I think maybe put an
1 incentive into it. You know, I don't know what is the
2 incentive for this.
3 And also, another point I just want to bring
4 up -- patients really know what's happened to their
5 body. They know something's wrong. They know there's
6 adverse events, as we've heard all the stories.
7 I think that this database should also build
8 in the patient reports. I think FDA has been on that,
9 has think about, oh, maybe already building database
10 with the public input. I think that should be a part
11 of the system.
12 MS. KUX: Other questions?
13 Rachel?
14 DR. SHERMAN: This -- we've talked a lot
15 about lack of data. But -- and we haven't talked as
16 much about, if there are data, whether it's getting
17 into the labeling and, if it isn't, why not. So this
18 is really for all the panelist may perhaps think about
19 it in your comments. I mean, FDA owns some of that,
20 but one could argue so do the manufacturers.
21 So when you're thinking about incentives --
22 and you briefly touched on this -- a post-marketing
1 commitment, a registry -- I mean, how do we not only
2 address the evidence gap but then address the label
3 and communications gap?
4 DR. YU: Let me rephrase your question.
5 Your question is how do we address the labeling
6 communications question. Is that right?
7 DR. SHERMAN: Well, it's both. It's the
8 evidence gap. And I thought you hinted at perhaps for
9 common off-label uses. Could there be either
10 incentives requirements such as registry?
11 And then the second part of that is if part
12 of the evidence gap has been addressed, do we still
13 have a problem if we're not communicating it through
14 the mechanisms we have in place. And why -- how might
15 we address that?
16 DR. YU: I can think about the questions and
17 then write any in. But I think that's a very good
18 question. Collect evidence and then address the gap,
19 as is the best approach.
20 DR. SHERMAN: Thank you.
21 MS. KUX: Thank you very much. Thank you.
22 DR. YU: Thank you.
1 MS. KUX: Our next speaker is Dr. (sic) Jack
2 Mitchell, Patient, Consumer, and Public Health
3 Coalition.
4 MR. MITCHELL: Good morning. I want to
5 thank FDA and its distinguished senior officials for
6 holding this meeting and for inviting all points of
7 view to be heard. We very much appreciate our
8 opportunity.
9 I'm Jack Mitchell, and I'm the director of
10 Government Relations for the non-profit National
11 Center for Health Research, which performs public
12 health research and conducts patient advocacy.
13 This morning, I'm speaking on behalf of the
14 many members of the Patient, Consumer, and Public
15 Health Coalition, to which NCHR belongs and helps to
16 coordinate. This coalition includes both large and
17 small non-profit organizations across the country that
18 are united to ensure that medical treatments are safe
19 and effective and to enhance the scientific and public
20 health focus of the FDA. We represent millions of
21 patients, consumers, researchers and medical
22 professionals.
1 Our coalition has opposed previous efforts
2 to allow the promotion of off-label use, and we still
3 strongly oppose it.
4 There are, of course, valid reasons to
5 prescribe treatments off-label. Many drugs are
6 prescribed off-label as a common accepted practice.
7 However, doctors and patients should discuss the use
8 of these treatments with a clear understanding of the
9 level of medical evidence, the doctor's reasoning, and
10 the potential risks.
11 Earlier, we spoke of informed consent and
12 what form should that take. Dr. Califf asked a
13 question about that. We believe that patients should
14 have informed consent of off-label use, which includes
15 a piece of paper that explains that the product is not
16 approved by the FDA for the indication that the
17 product is being prescribed for.
18 It should also include a discussion of what
19 that means concerning the lack of objective evidence
20 that the benefits outweigh the risks for most
21 patients. That is the critical calculus that FDA
22 always must balance and constantly struggles with,
1 usually very well.
2 We are concerned that the FDA does not have
3 the resources to monitor such off-label promotion and
4 patients will therefore be harmed. In our view, off-
5 label promotion has one primary goal besides the
6 possible patient care. The real goal is to increase
7 the use of medical products for conditions and
8 indications for which this product is not approved by
9 the FDA. It is not approved because the company is
10 not adequately or a sponsor has not adequately proved
11 to the FDA that the product is safe and effective for
12 that indication.
13 The result of that can be that the patients
14 may be more likely to have prescribed treatments that
15 are not effective or safe for their specific
16 condition. Patients may also be more likely to have
17 prescribed treatments that may be more likely to harm
18 rather than help them.
19 It is also impossible for FDA or any other
20 agency to ensure that off-label communications are
21 uniformly truthful and scientifically sound in all
22 cases. That would be an extremely resource-intensive
1 task for an agency which we all know has its resources
2 stretched to the limit on an almost daily basis.
3 Representatives from our coalition testified
4 at FDA advisory committees regarding medical products.
5 Some of these products initially looked promising in
6 the company's presentation trials. But then expert
7 FDA reviewers identified key problems that raised
8 major concerns about the study and its underlying
9 data.
10 In other words, the entire FDA process is
11 based on the sound assumption that a sponsor's
12 analysis is not always unbiased, nor of sufficient
13 scientific quality to merit FDA approval. This is why
14 we believe that the critical importance of FDA's role
15 and why we oppose the promotion of medical products
16 for off-label uses.
17 Now, as I mentioned, off-label uses are
18 already widespread and commonplace for some drugs,
19 and, in fact, a significant portion of prescriptions
20 are off-label. Unfortunately, research shows that
21 off-label use has increased the number of adverse
22 events. If promotion of off-label usage is allowed,
1 we believe more patients will be inevitably harmed.
2 Increasingly, FDA is sometimes approving
3 drugs and devices based on smaller somewhat
4 preliminary studies. In the case of medical devices,
5 the vast majority are not required to do any clinical
6 or human trials for approval. Frequently, the
7 apparently promising results of an exploratory study
8 or clinical experience fail to be confirmed when
9 further testing is done in a larger controlled trial.
10 Sponsors already have few, if any, incentives to
11 robustly test their product once it is on the market
12 either for its approved indication or for other
13 indications.
14 Some observers have suggested that the
15 increased transparency, or data sharing, about
16 clinical trials may allow practitioners and patients
17 to evaluate clinical trials and other data themselves.
18 Supposing that there is sufficient data for groups
19 like ours to evaluate the data that is not selectively
20 released, most medical professionals and non-profit
21 organizations have neither the time nor expertise to
22 take on that kind of burden.
1 Now, those advocating, as you've heard
2 yesterday and today, for off-label promotion of
3 devices contend that such claims are protected free
4 speech and that restricting off-label promotion is an
5 unfair abridgment of that free speech. Well, I'm a
6 recovering and lapsed journalist. And as such, I'm a
7 big fan of the First Amendment.
8 But if that is true, why do industry
9 companies would settle lawsuits with patients who have
10 been harmed, insist on non-disclosure agreements,
11 which make it impossible for those patients to
12 communicate their own free speech and to communicate
13 with FDA to find out what happened to them? Why are
14 patients who settle such lawsuits so frequently not
15 allowed to speak publically about what happened to
16 them? Such restrictions, we believe, are another
17 barrier to identifying potential patterns of adverse
18 events involving medical devices and drugs.
19 Now, companies don't always have an
20 incentive to disseminate clinical trials that show
21 that their product does not work. It's relatively
22 easy to find on the internet examples of where a
1 product supposedly works on one or several or a small
2 number of patients. Such information is not very easy
3 to find when the patients were harmed because it is
4 either not published or promoted.
5 The history, I'm sad to say, of promoting
6 off-label use in the pharmaceutical world has been
7 dismal, from my perspective as a former congressional
8 investigator. The list of major violations includes
9 almost all the major pharmaceutical manufacturers.
10 Each has been successfully sued for improper and off-
11 label -- illegal off-label marketing tactics.
12 Collectively, they've been fined hundreds of millions,
13 if not billions, of dollars.
14 As former Chief of Oversight for the Senate
15 Special Committee on Aging, I've seen the devastating
16 human impact of the overuse and abuse of massive off-
17 label prescribing of antipsychotic drugs in nursing
18 homes, for which multiple pharmaceutical companies
19 have been fined hundreds of millions of dollars.
20 Nevertheless, those hefty fines and legal
21 settlements have not discouraged or curtailed these
22 activities, and many violators are repeat offenders.
1 Neither FDA nor the Justice Department, despite their
2 best efforts, has been able to curb these abusive off-
3 label practices with lawsuits and fines. It is
4 difficult to believe that the legitimizing of off-
5 label promotion for medical devices will not make
6 these type of abuses even more widespread.
7 You've heard from a number of respected
8 academic, medical, and legal experts yesterday and
9 today that off-label promotion for drugs has increased
10 risk for patients. Credible surveys cited by Consumer
11 Reports both yesterday and today tell us that American
12 consumers and patients by a large margin do not want
13 such off-label promotion permitted by FDA. And it's
14 also pretty clear from what we were told that most
15 patient -- only a miniscule percentage of those
16 patients even understand what the off-label promotion
17 means or off-label means itself.
18 You've heard a lot about that short -- the
19 shortcoming also involving the use of medical journals
20 from a variety of experts. Fraud in scientific
21 research has increased 10-fold -- as much as 10-fold,
22 according to what we were told yesterday by research
1 experts. That is very disturbing.
2 So in summary, we oppose allowing the
3 promotion of device products for off-label uses. We
4 believe there are not adequate safeguards to allow
5 such promotion to be limited to only scientifically
6 sound, complete, and unbiased data.
7 While admittedly some off-label use is
8 accepted and has positive incomes, as you were hearing
9 from patients' testimony at this meeting today and
10 yesterday, many have been harmed by off-label use.
11 The patient, Jeremy Lew, related yesterday the painful
12 details of his coming very close to death or complete
13 paralysis because a device was surgically inserted in
14 his neck, which is not approved by FDA for that
15 purpose, but which was advertised as being okay to use
16 for that purpose.
17 And so as we all know and all understand,
18 this is not an academic or legal discourse. It is a
19 decision with profound human consequences, as I know
20 are -- the FDA officials before me understand.
21 Allowing off-label promotion would conflict with the
22 risk-benefit delicate balance and tends to remove an
1 important incentive for companies to complete high-
2 quality clinical trials for new indications, which in
3 turn would produce reliable data of efficacy and
4 safety.
5 I worked in the commissioner's office at FDA
6 for seven years, and I know and I trust the expertise
7 and dedication of FDA employees. And I know that when
8 they're given the resources and the information they
9 need, they will do their jobs. We fear that this off-
10 label promotion will upset that informational and
11 resource balance. And therefore, we oppose it.
12 And I thank you very much for your time and
13 attention.
14 MS. KUX: Thank you.
15 Questions, Panelists?
16 Dr. Califf?
17 DR. CALIFF: Three questions -- only three
18 this time.
19 First is really just a request that your
20 statement that individual docs are not equipped to
21 handle information from clinical trials, to the extent
22 that you can document it in the written record, that
1 would be very helpful for a variety of reasons.
2 MR. MITCHELL: Yes, Doctor. Thank you.
3 DR. CALIFF: The second is I've asked this
4 before, but I'm interested in your group's experience.
5 And I'll just say this. In 1978, I spent a lot of
6 time trying to figure out how to ask the question why
7 did you do what you did to doctors. And it's actually
8 pretty hard to get that information.
9 But I'm interested because knowing why
10 prescriptions are written or why a device was inserted
11 would give us extremely valuable information. And
12 linked with other information like Sentinel or the
13 NEST for devices, you could really begin to get a
14 handle on this like the Canadians did in the article
15 that they wrote.
16 Do you have experience trying to see if
17 doctors would get on board with prospectively
18 recording why they wrote a prescription or why they
19 inserted a device? Have you approached medical groups
20 about this?
21 MR. MITCHELL: I apologize, Doctor. I was
22 unable to hear part of your question.
1 DR. CALIFF: Understanding why a device was
2 inserted or why a drug was prescribed is really
3 valuable information. Have you approached medical
4 groups about whether they would be in favor of giving
5 that information?
6 MR. MITCHELL: We'll certainly take that
7 under consideration. I will certainly discuss it with
8 the many members of our coalition. It's a useful
9 suggestion. We will discuss and take that under
10 consideration, sir, and let FDA know of our final
11 decision.
12 DR. CALIFF: Others have suggested that we
13 should require -- we have limitations on the way and
14 control of medical practice. So it would be helpful
15 if doctors were on board to give us that information.
16 MR. MITCHELL: We agree.
17 DR. CALIFF: The last, because I asked
18 people who were advocating on the other side this
19 question in inverse, you've talked all about the
20 negative side of off-label prescribing. Do you see
21 any possibility there's a positive side to it as
22 evidence accrues and there are patients who may have
1 problems that are --
2 MR. MITCHELL: Well --
3 DR. CALIFF: -- that are not otherwise
4 treatable within labeled indications?
5 MR. MITCHELL: Yes, sir. I do believe,
6 Doctor, that there are useful and legitimate off-label
7 prescriptions for drugs. For example, if I could give
8 one example from my experience in the Senate, the drug
9 Lucentis cures -- or helps to cure or mitigate wet
10 macular degeneration, the main cure (ph) of blindness
11 in elderly people. It was regarded as a miracle drug
12 when approved by FDA in 2006, according to NIH.
13 Unfortunately, it costs $2,000 a dose. And many doses
14 are in need for an efficacious outcome, sometimes as
15 much as 20 or $30,000 worth of Lucentis.
16 Eye doctors found that the drug from which
17 Lucentis was derived, the cancer drug Avastin, is
18 equally safe and effective according to FDA with
19 compounded off-label use, which costs $50 a dose. And
20 many eye doctors felt they could not let their
21 patients go blind who had inadequate insurance or not
22 the financial means to afford Lucentis.
1 So I believe and I tried very hard as a
2 Senate investigator to get CMS to try to reimburse
3 more off-label Avastin. I was in favor of that
4 particular -- in that particular instance because,
5 according to the HHS inspector general, it would have
6 saved hundreds of millions of dollars to Medicare.
7 And according to FDA and the studies which were
8 performed by eye doctors themselves, both were equally
9 in safe and effective. And that was confirmed in the
10 NIH-sponsored clinical trial, which performed a head-
11 to-head comparison of those two drugs.
12 So certainly, there are useful examples.
13 But I just wanted to reiterate our coalition's overall
14 concerns about the fact that we believe this would
15 overwhelm the resource and ability of FDA to keep up
16 with such dissemination of off-label promotion.
17 MS. KUX: Yes, Rachel?
18 DR. SHERMAN: I'm interested in your
19 thoughts either in now or in writing and for the whole
20 panel, particularly anyone with communication
21 expertise.
22 So a companion initiative at FDA patient
1 medication information, the -- we had Part 15 on the -
2 - a couple years ago, the notion that a patient is
3 entitled to a, if you will, high-level readable,
4 actionable, and memorable summary of the risks and
5 benefit of their product. And we did -- we have
6 struggled with the idea of the indication.
7 So if the indication lists the indications
8 and the patient is then presented with that
9 information by their prescriber, how -- what would --
10 what, in your eyes, would be optimal? That -- the
11 fact that the -- what the use -- the problem they've
12 come to the doctor for is not listed? Is that, in
13 your eyes, enough? Or should there be some of that
14 precious space used to say if your condition is not
15 listed, please ask your prescriber?
16 Any thoughts you have on that would be most
17 appreciated not just for drugs and biological drugs,
18 but also for devices either that we would use
19 ourselves or someone would use on us.
20 Thank you.
21 MR. MITCHELL: If I may, that's another
22 question I'd like to take up with the coalition
1 members and make as part of our written submission to
2 answer your question and the other question that I
3 deferred because I think the fairest thing would do to
4 -- to be to communicate with the coalition
5 representatives who sent me up here today.
6 DR. SHERMAN: That'll be great. Thank you.
7 And then we can also make sure that the
8 people who are running that initiative would see the
9 same information. Thank you.
10 MR. MITCHELL: Certainly. Thank you very
11 much.
12 MS. KUX: Thank you.
13 Our next speaker is Dr. Diana Zuckerman from
14 the National Center for Health Research.
15 DR. ZUCKERMAN: Thank you very much.
16 I understand I have a few extra minutes
17 because Dr. Rebecca Jones is unable to be here today,
18 and I am going to be including her perspective in my
19 remarks.
20 I want to start out by saying I've been to a
21 lot of FDA meetings over the years, and this is
22 actually the best one I've ever been to in terms of
1 the questions that are being asked by the panel. And
2 I really appreciate the clear commitment that you have
3 to hearing everyone and making sure you understand
4 what they have to say. So thank you.
5 My perspective today is as someone trained
6 in psychology and epidemiology, ends up to be kind of
7 a good background for this because I'm going to try to
8 take the information that I have as a scientist, but
9 also the information that I have working with patients
10 to put those two strains together on this very
11 important issue.
12 My perspective also comes from having been a
13 researcher and faculty member at Yale and Harvard and
14 also a fellow at the Center for Bioethics at the
15 University of Pennsylvania. I'm also a board member
16 of the Alliance for a Stronger FDA and the Reagan-
17 Udall Foundation. So again, I'm going to combine
18 those perspectives in policy and science and also
19 working with patients.
20 The National Center for Health Research is a
21 think tank, and our focus is on a wide range of health
22 issues and, particularly, the quality of medical care
1 and how to prevent serious diseases as well.
2 I'm going to start out with a couple of
3 slides if I can figure out what I'm doing. Okay.
4 Here we go. So I just have a couple of slides just
5 because you've heard a lot of talking. And I think
6 sometimes pictures are helpful.
7 So I'm just going to give a small example of
8 INFUSE, which is a bone cement that's cleared for
9 adults 18 and over. Those of us with children might
10 wonder about 18 is actually an adult, but that's
11 another matter.
12 So bone cement sounds so benign, but it's a
13 very complicated material. And it has known risks for
14 children because they're still growing. So the
15 question is it's really contraindicated for children
16 what happens when it is used on children and,
17 particularly, on babies.
18 So here's a photograph of a two-year-old who
19 was treated with INFUSE at St. Louis Children's
20 Hospital. And this is from a 2008 published case
21 report in a medical journal. Because of cranial
22 damage that was being done from the INFUSE, he -- this
1 little boy needed a lot of surgeries. And this was
2 written up as a side effect of INFUSE -- 2008.
3 And yet in 2010, Haley (ph), a little girl
4 at Cincinnati Children's Hospital, got the same
5 treatment and had a very similar result, as you can
6 see.
7 So in both cases, the families did not --
8 were not told and did not know that this was an off-
9 label use, that this was a product approved for
10 adults. And it was being used not just in children,
11 but very, very young children. And obviously, it was
12 extremely upsetting to the family -- to Haley's family
13 when they eventually found out that there had been a
14 published article about this side effect. And yet it
15 was used for their daughter without their consent and
16 without their knowledge that it was not an approved
17 use.
18 So it took a while, and it took some
19 pressure from Haley's parents and from others before
20 the FDA was approached. Specifically, what kind of
21 warning are you going to put out? Now, the FDA is
22 great at putting out press releases when new products
1 are approved, but not so great at putting out press
2 releases when risks and dangers become apparent.
3 And in this case, the FDA finally eventually
4 put out a warning. But look what it says. The --
5 these are word for word. "Certain recombinant
6 proteins and synthetic peptides mimic bone growth
7 substances normally found in the body and may be added
8 to a carrier," and that's all -- I don't have to read
9 this whole thing to you. It doesn't say in anything
10 resembling clear language INFUSE and similar products
11 have been found to have dangers -- very serious
12 dangers.
13 So you can see I've put it in larger type.
14 You can see it says, "These products are not approved
15 for any use in patients under the age of 18 who are
16 still growing." But that's a pretty calm and
17 dispassionate warning without even specifically
18 mentioning the names of the products compared to a
19 picture, which I think would have had a lot more
20 impact.
21 Also, with that current FDA warning still on
22 the website, the FDA recommends against routine use of
1 these products in patients under 18, et cetera.
2 Consider the alternatives. Carefully consider the
3 benefits and risks.
4 Again, I understand that FDA likes to be
5 neutral and dispassionate. But when I look at press
6 releases for new products, they don't look so
7 dispassionate. They look a lot more enthusiastic.
8 And I think that warnings need to be a lot stronger.
9 So those are the end of my slides, but I do
10 have more I'd like to say.
11 I think a very important issue is why are
12 there -- why are you not hearing from more patients.
13 You've heard from a lot of industry folks and their
14 lawyers. You heard -- you -- and this is pretty
15 typical at FDA meetings. You hear from a lot of
16 industry people and not so many patients. And when
17 you do hear from patients, they're very frequently
18 recruited by companies to talk about how wonderful
19 their products are.
20 So we've worked with patients a lot. And I
21 think you probably already know that, you know, one
22 reason why patients aren't here more often and why
1 there aren't even more today is because patients don't
2 read the Federal Register. So they don't know about
3 the meetings. They're not that widely advertised. If
4 you don't read the Federal Register or if you're not
5 associated with some kind of -- within industry or an
6 industry-funded group, you're unlikely to know about
7 it.
8 Of course, the second reason is money.
9 Patients can't necessarily afford to come here at
10 their own expense. It's expensive to come here, and
11 it's not exactly conveniently located. So that's a
12 real difficulty for many patients.
13 A third issue is it's hard to talk about
14 these personal experiences. I -- you know, I think
15 Veverly is a really good example of a woman who
16 probably could talk to any group under any
17 circumstances and would do so. But not everybody
18 feels that way. These stories are hard to tell. It's
19 hard to talk about themselves.
20 And I think of Jeremy Lew, who spoke
21 yesterday, had a very moving story. I mean, Jeremy is
22 a screenwriter in Hollywood. His world is telling
1 stories. But telling other people's stories is so
2 much easier than telling your own story. He didn't
3 even remember to mention some of the tragic things
4 that happened to him -- the fact that he literally
5 lost his voice and had to have his voice box rebuilt -
6 - he now has a voice that's different from the voice
7 he used to have; the fact that he literally lost the
8 ability to use his hands because he was -- because
9 he's lost sensation in his fingers - -I mean, the
10 irony of a writer not being able to write, a
11 storyteller not being able to speak.
12 And so those are some of the tragic things
13 that happen and how hard it is to convey them in this
14 kind of setting.
15 Also, sadly, I know that some patients who
16 have spoken at FDA advisory committee meetings once
17 will never do it again. They didn't like having to
18 come at their own expense and be given only three
19 minutes or four minutes to speak. They've complained
20 to me about having their microphone cut off in the
21 middle of sentences. I myself have seen microphones
22 cut off while a woman was talking about her husband
1 dying on Christmas Day from the off-label use of a
2 typical antipsychotic.
3 So when people have this experience, they
4 share it with their friends, and they don't want to
5 come back. And they don't encourage other people to
6 do it. So I hope that's something that FDA can
7 consider -- how to make it a more welcoming atmosphere
8 for patients who want to talk about the experiences
9 and want to share with you the experiences that
10 they've had.
11 Another reason, as you've heard, is non-
12 disclosure agreements. Many patients who have been
13 harmed have had lawsuits. And sometimes they get
14 offered a rather small amount of money. But whether
15 it's a small amount -- whether it's, you know, $5,000
16 or $50,000 or $5 million, if they have a non-
17 disclosure agreement, they cannot talk about what
18 happened to them. They can't talk -- they feel that
19 they cannot come here to talk about it. They can't
20 talk to the media about it.
21 And as a result, I think FDA is harmed by
22 not having those voices. They can't have access to
1 voices of people who have been silenced. And as has
2 been pointed out, the irony of that -- the testimony
3 yesterday from these same companies saying free speech
4 is very important to them.
5 And then as has been mentioned by other
6 people today, many patients don't really know what
7 off-label means. They don't understand that FDA
8 approves products for specific indications and only
9 those indications. And the fact that just -- there's
10 this assumption that if it's FDA-approved it must be
11 safe and effective and not understanding that it's
12 safe and effective -- the benefits outweigh the risks
13 for some things, but not other indications.
14 So I just want to mention a couple of
15 things. Because the question has been raised can
16 journal articles be a good way to talk about what is
17 truthful and accurate information, I'm sorry to say
18 that I get about -- I literally get three emails a
19 week inviting me to submit articles into medical
20 journals, many of them I've never heard of. Sometimes
21 I'm asked to be an editor, a peer review editor, of
22 journals I've never heard of on issues that I really
1 know very little about.
2 But I am a peer reviewer for quite a few
3 journals, and I also submit peer-reviewed articles.
4 And I know, as many of you know, that some journals
5 are better than others. And there literally are many
6 journals now where just about anybody can publish
7 something if they're -- if they have the knowledge of
8 how to write such an article and the desire to do it.
9 So there are a lot of articles that are
10 published where the data are really questionable, and
11 I've reviewed some of them myself. And there's a huge
12 difference in quality.
13 But it's also an honor system. The FDA when
14 they look at data, as you all know, you scrutinize the
15 data. You look at it differently. You analyze it
16 differently. You reanalyze data.
17 As peer reviewers, we don't do that. We
18 pretty much take for granted that the data are
19 accurately analyzed. And unless there's an obvious
20 problem, we don't question it.
21 So for that reason, the fact that
22 something's published in a peer-reviewed journal
1 cannot be the basis of what's truthful.
2 Also, as you know, there have been studies
3 showing that many studies of clinical trials are not
4 replicated. So you have a study. One comes out. It
5 says something. And then there's no replication of
6 it, or efforts to replicate are unsuccessful because
7 the results look different.
8 And JAMA some years ago did a study also
9 showing that you could tell pretty much who's -- when
10 there were comparative effectiveness types of studies,
11 you could tell who paid for the study because who's --
12 whoever paid for the study, it was their product that
13 looked better.
14 And then I just want to add some
15 perspectives from Dr. Jones, who wanted to be sure
16 that I mention that it's her understanding as a
17 physician and how hard it is to explain to other
18 physicians and to patients that new doesn't
19 necessarily mean better and that it's not necessarily
20 a virtue that new products very often don't have the
21 kind of evidence that are available for older
22 products, that it should be looked at not as a great
1 advantage but rather a liability for patients as well
2 as for physicians and even for patients who have no
3 other options.
4 There's this assumption that anything is
5 better than nothing. But I think you all know at the
6 FDA and many people in this room and patients who've
7 talked that's not always true.
8 It's certainly clear that when doctors are
9 told about products, it makes light of the distinction
10 -- that off-label use makes light of the distinction
11 that certain patients may benefit, but not other
12 patients; that certain treatments might benefit, but
13 not other treatments; and that the entire idea of
14 changing and loosening the standards for the promotion
15 of off-label use compromises the FDA in a way that
16 frightens us greatly and frightens many physicians who
17 understand that.
18 I think that there's this assumption that
19 regulation is bad. We don't feel that way. We feel
20 that regulation protects patients. It doesn't deny
21 patients important treatments as much as it guarantees
22 some level of safety and effectiveness for treatments
1 that are available in the United States, but that the
2 widespread off-label use, as you've heard today,
3 compromises those guarantees to some extent.
4 I just want to quickly come up -- mention
5 two ideas that I have. I think that doctors need to
6 be trained to understand what FDA approval means in
7 terms of specific indications and why off-label uses
8 are not always a good idea. And I know that a lot of
9 FDA officials and staff talk to many groups, and I've
10 seen them at FDLI meetings and many other groups where
11 most of the audience are industry. And it would be
12 really terrific if there were more guest lectures or
13 grand rounds at medical schools to share information.
14 My experience with doctors is many of them really
15 don't understand the value of the FDA and don't really
16 understand why off-label uses aren't necessarily safe
17 and effective.
18 And as you've also heard, very strongly hope
19 that FDA can come up with some kind of standard
20 informed consent form that others can use. I
21 understand FDA can't require that they be used, but I
22 think you can help make it easier by providing some
1 kind of sample informed consent form, starting with
2 some of the most widely used off-label drugs. And
3 those would be atypical antipsychotics and
4 antidepressants, but also, apparently, spinal implants
5 -- and so devices as well as drugs.
6 And then just -- finally, just to say that
7 if the post-market surveillance system was better and
8 if you had more resources to do the kind of post-
9 market surveillance that I think we all would like to
10 see, that would help a lot. But it doesn't take the
11 place of having that information -- that patients
12 having that information before they take a drug,
13 doctors having that information before they prescribe
14 a drug or use a device -- that that's what's really
15 needed, is that premarket safety, not just relying on
16 post-market.
17 Thank you very much.
18 MS. KUX: Thank you, Dr. Zuckerman.
19 Panelists, any questions?
20 Lauren?
21 MS. SILVIS: Thank you very much.
22 You touched on this a little bit. And I
1 think for all the panelists from this morning it would
2 be helpful to hear more about the idea of effective
3 communication about off-label uses and data that might
4 be related to that use and how we should deal with
5 that for different audiences, both professional and
6 patient, and, you know, the ability of different
7 audiences to process that information and, you know,
8 just getting at the idea of effectively communicating
9 with the range of people about off-label information.
10 It would be very helpful to hear about -- you touched
11 on a little bit. But in your written comments, I
12 think it would be helpful to hear more.
13 DR. ZUCKERMAN: Thank you. And I won't take
14 a lot of time now.
15 But I would just start with using brand
16 names for patients, in particular, and a lesser extent
17 for doctors, that if FDA communications don't mention
18 the brand names, most patients aren't going to know
19 what you're talking about.
20 So you know, we understand, you know, the
21 need to use, you know, the proper name for drugs. But
22 if you don't mention the brand names, it's a huge loss
1 of information for patients.
2 MS. KUX: Dr. Califf?
3 DR. CALIFF: Thanks for your comments.
4 First, just to mention, I just finished a
5 college tour all around academic medical centers for a
6 variety of reasons. So just for the record, if you
7 could submit your ideas about the FDA academic because
8 almost everyone we deal with on the provider side gets
9 trained at one of these places. So your ideas would
10 be very welcome. I know there's not time today to
11 discuss it.
12 But I am very interested in your experience
13 and insights into this key thing that's come up today,
14 which is understanding why the prescription was
15 written or why the device was inserted. Do you have
16 information from physician groups about why it's so
17 hard to get that information and what the -- what
18 could be done about it? Because you know, if we link
19 it with Sentinel or with the NEST that we're
20 developing for devices, we'd have a lot of what you're
21 looking for.
22 DR. ZUCKERMAN: Yeah. And I appreciated
1 that question when you asked it before, and I can't
2 answer it, you'll be happy to know, right now. But it
3 is something that's important. But I guess our
4 experience is, you know, that there's a certain amount
5 of physicians feeling like they're making decisions
6 based on past experience, which might be quite limited
7 with certain kinds of patients or with certain kinds
8 of drugs. So they can prescribe something and not
9 actually know what happened to the patients after they
10 used it, especially off-label uses.
11 I'll just give one example. One of the --
12 some of the parents that I've talked to have daughters
13 who died from off-label use of birth control pills
14 where the girls or young women were using them --
15 actually, not just saying they were using them, but
16 actually using them -- to regulate their periods,
17 which is something that was quite heavily promoted
18 and, to some extent, still is promoted as sort of a
19 lifestyle choice. You know, you get your period.
20 You'll just get it, you know, on a regular calendar,
21 and you'll know when it is.
22 And these were young women who died from
1 blood clots. And you know, it's well known that birth
2 control pills can cause that and pregnancy can cause
3 that. So the benefits outweigh the risks compared to
4 pregnancy, but they don't outweigh the risks compared
5 to having an irregular period.
6 But the doctors just don't even think about
7 -- you know, that's just -- to them, this is
8 information that they have. This is a way you can use
9 the drug. And they aren't necessarily told very much,
10 apparently, about those off-label uses.
11 And I'll say. I did submit an article for
12 publication in a major OB/GYN journal. And the
13 pushback I got from the reviewers about, you know, of
14 course we know this and of course we consider this.
15 But the prescriptions tell us something very
16 different. There is very clear data on how frequently
17 prescriptions for birth control pills are given to
18 regulate menstrual cycle.
19 DR. CALIFF: I have one last question. It's
20 striking to me, reviewing the literature and from what
21 we've heard at this meeting, about the fields of
22 mental health and chronic neurologic disease being the
1 places where off-label prescribing is most common. Do
2 you have insights into why that's the case? Or what
3 might you think about to deal with that, specifically?
4 DR. ZUCKERMAN: Yeah. I guess, you know,
5 one thing -- you know, I'm sorry to say this as
6 somebody who came from the mental health field
7 originally. But if you go to an American Psychiatric
8 meeting, you can't tell the difference between the
9 presentations that are sponsored by drug companies and
10 the ones that are not. The -- it's so integrated now.
11 It used to be separate parts of the same meeting. And
12 now you can't tell the difference.
13 So the amount of money being spent is so
14 pervasive, and it's not helping because these are
15 difficult conditions to treat. And there's this sense
16 that psychotropic drugs are safe and not a very good
17 understanding of when they're not; and not a very good
18 understanding of the fact that, if they're
19 ineffective, maybe your patient should stop taking
20 them instead of just piling on additional psychotropic
21 drugs on top of the ones they're already taking until
22 they end up in a soup of, you know, somewhat toxic and
1 dangerous chemicals.
2 DR. SHERMAN: Leslie gave me a dirty look.
3 So for the record, maybe not to answer now,
4 two questions for the panel -- disclaimers -- we've
5 heard a lot about disclaimers. And I ask this
6 question. Is there any information you have on the
7 usefulness of the disclaimers or the lack of
8 usefulness? It would be extremely helpful to us.
9 There is a science behind it.
10 And then in terms of reaching out to
11 patients, as Ms. Kux stated at the beginning, we
12 always have a docket. We take it very seriously. We
13 scrutinize the docket. So is there a better -- is
14 there a way we can make that mechanism more accessible
15 to patients who can't travel or don't want to come in
16 person?
17 DR. ZUCKERMAN: Yeah. And I'll just mention
18 that I know some patients have asked can they
19 participate by video, you know, can they send in a
20 video. And that would certainly help on some of these
21 issues. I don't think it's the same as having them in
22 person, but it adds something.
1 MS. KUX: Thank you.
2 DR. ZUCKERMAN: Thank you very much.
3 MS. KUX: So our last presenter before a
4 break is Ms. Melayna Lokosky.
5 MS. LOKOSKY: This little button here?
6 Great. Okay.
7 Hi. My name is Melayna Lokosky. I am a
8 whistleblower who is a venture capital-funded startup
9 rep and in the industry for 13 years. My company,
10 Acclarent, sold $40 million worth of product, never
11 for its intended or cleared purpose, 100 percent off-
12 label, completely useless. So that is why I am here
13 today.
14 Innovation is being exploited and
15 manipulated to evade the law. How a venture capital-
16 funded medical device built a pathway to profits and
17 expense for -- at expense of patients, employees,
18 shareholders, and taxpayers, what's the problem?
19 Venture capital-funded medical device
20 industry is exploiting loopholes in the FDA to profit
21 from fraudulent over-evaluations of companies to sell
22 unsafe and ineffective products and hiding behind the
1 First Amendment and off-label to achieve the goals.
2 How did we solve that problem? There's two
3 simple fixes to this that will stop this fraud from
4 ruining the lives of innocent patients and prevent
5 knowingly and willingly exploiting the executives from
6 profiting from the public's expense.
7 Let's see here. The goals and motivations
8 of pharmaceutical companies and medical device
9 companies differ greatly. This is a point that the
10 DOJ was not familiar with prior to my case, but was
11 very regularly exploited within the medical device
12 industry.
13 The pharmaceutical company's goal is to get
14 the patent and to sell as much product as they can on
15 the patent during that seven-year time frame. There
16 are 1,500 reps that sell the same product. You have
17 seven years. You get a very big database to show
18 where the problems are.
19 On the venture capital side, the goal is to
20 get an IPO or acquisition. You have three to five
21 years. So the VCs want 8 to 10 times back their
22 original investment, and they want that in 3 to 5
1 years. So you don't have a huge database to pull from
2 as you do on the pharmaceutical side.
3 The scope is a lot different. You've got
4 maybe 15 reps selling. You're maybe doing one or two
5 cases a month, if that, in the beginning.
6 So the motivation is very different. The
7 companies come up with false projections to create the
8 appearance of hyper-growth. So the quotas are based
9 off of not what the market can actually bear
10 surgically, but what the investors want on the ROI.
11 That's the problem.
12 And what's happening is that shelves are
13 being overstocked and patients are having surgeries
14 needlessly as the result to try to meet this quota.
15 So this is where the fraud is.
16 The First Amendment is being dangerously and
17 illegally misappropriated by the medical device
18 industry for off-label promotion, using the same
19 guidelines as the pharmaceutical industry, despite the
20 very different pathways to the market.
21 The pharmaceutical industry pathway, again,
22 is a goal to get the approval, which is different than
1 what you're going to see on the VC side. The goal is
2 a clearance for a medical device.
3 But yet what the industry is doing is
4 misappropriating that. So medical device companies
5 exploit the FDA's lack of benchtop testing when they
6 knowingly and willingly select an ambiguous,
7 substantially equivalent product to gain clearance.
8 This allows the medical device company to place blame
9 on the FDA without taking accountability while
10 illegally using the First Amendment argument.
11 In the acquittal of vascular surgeon -- or
12 Vascular Solutions CEO Howard Root, a case in which
13 the company paid DOJ fines, Judge Lambert said that no
14 -- not a crime for a device company or its
15 representatives to give doctors wholly truthful and
16 non-misleading information about the unapproved use of
17 a medical device. Medical devices aren't approved.
18 They're cleared.
19 This is the difference in paths that negates
20 the off-label usage of medical device marketing. This
21 is where the FDA needs to intervene. Cleared medical
22 devices are not cleared on factual clinical data, but
1 based on something that a company decides is the
2 substantial equivalence, which means that they are
3 selling a device off-label. It can never be wholly
4 truthful, and that's part of the problem with this,
5 which negates the industry's manipulation of the First
6 Amendment to sell off-label.
7 Substantial equivalence in my industry is
8 making small, subtle changes to the 510(k) so it goes
9 unnoticed by the FDA, which is what happened in my
10 case. DOJ, FDA, federal judges were manipulated into
11 thinking that off-label in pharma is the same as off-
12 label in medical devices. And they have allowed this
13 industry to illegally use the First Amendment to sell
14 off-label.
15 How do VC-funded medical device companies
16 get away with this? They blame the FDA. When that
17 doesn’t work, they'll misappropriate the pharma
18 industry's pathway to acclaim off-label promotion.
19 They blame the employees.
20 We are threatened and intimidated into
21 underreporting adverse events. The very big topic
22 here is adverse events. And that's a means to protect
1 the company and not patient safety.
2 Employees are blamed for not training the
3 surgeons properly. The surgeons are blamed for user
4 error when it's usually the device error, or they're
5 blamed for not put -- not selecting the right patient
6 population. They blame the patients. They blame the
7 victims that they created when they put profits before
8 patients. They demean, insult, file motions to
9 dismiss, and appeal case after case as are lost and
10 further intimidates and demoralizes victims to remain
11 silent.
12 What should the FDA do to stop this abusive
13 practice? First, you have to stop the off-label
14 promotion of medical devices. This is not the same as
15 a drug. And the FDA's failure to recognize that is
16 exactly why I'm standing here today as a
17 whistleblower.
18 I lost my career over that, which is nothing
19 in comparison to what all these people in the front
20 row have lost. But it -- there is responsibility to
21 the FDA on this, and this device should have never
22 been approved. If there was benchtop testing, it
1 would have never gone through.
2 As a rep in the industry for 15 years, I did
3 not know that the FDA did not do benchtop testing. I
4 did not know that until I met with the DOJ and the
5 FBI. That's something that is not known in our
6 industry. That is not unique to me. I will tell you.
7 We need to establish a taskforce to
8 investigate innovation fraud. Innovation -- we heard
9 yesterday from all the attorneys from the industry.
10 They'll hide behind anywhere they possibly can,
11 whether it's wholly truthful. You cannot have wholly
12 truthful when you are using something that is
13 substantially equivalent. Substantial equivalence is
14 not the same thing as scientific data. And that is
15 where the fracture is in this, and that is the
16 loophole that they are exploiting. And they'll
17 continue to exploit. This is not unique to this small
18 company that sold to Johnson & Johnson for $785
19 million.
20 This is just kind of the overview of my
21 case. But I think some of the big things are that,
22 prior to this case, everybody in the industry thought
1 that medical device startups are too small. They go
2 unnoticed by the FDA. That changed in this case. And
3 that's where we have to make sure that we keep after
4 this and that the FDA really does intervene on behalf
5 of all the patients. It's bad for the employees who
6 are put in a terrible position, and it's bad for the
7 patients.
8 So that's it.
9 MS. KUX: Thank you very much.
10 Any questions?
11 Thank you. Thank you very much.
12 So we'll now proceed to our morning break,
13 and we'll be starting up again at 11:35 on the dot.
14 (Off the record.)
15 MS. KUX: -- will take their seats, we'll
16 get started. The speakers for the second part of the
17 morning could come on up. If they could come up from
18 Yale Law School. Thank you.
19 DR. MCCARTHY: I'm Margaret McCarthy, the
20 Executive Director of the Collaboration for Research
21 Integrity and Transparency, which is a joint
22 initiative of Yale Law School, Yale School of
1 Medicine, and the Yale School of Public Health.
2 Our mission is to promote health by
3 improving the integrity and transparency of biomedical
4 and clinical research, and we are dedicated to
5 ensuring that the evidence base for medical products
6 is complete, accurate, and available for scientific
7 and public inquiry.
8 I'm here with Jeanie Kim, research fellow
9 with CRIT, who will address the impact of off-label
10 promotion on the evidence base for medicines; and Amy
11 Kapczynski, law professor and faculty co-director of
12 CRIT, who will address the First Amendment challenges
13 raised by the pharmaceutical industry.
14 As for disclosures, CRIT is funded by a
15 research grant to Yale University from the Laura and
16 John Arnold Foundation. The sponsor had no role in
17 the content of our testimonies or in our decision to
18 testify. Our testimony also does not purport to
19 present Yale's institutional views.
20 My comments will address the risks that off-
21 label marketing by medical product companies has for
22 the patient-medical provider relationship. This risk
1 applies to both off-label communications to members of
2 the public and to healthcare providers.
3 CRIT encourages the availability of high-
4 quality, accurate, scientific information regarding
5 medical products. Consumers need access to accurate,
6 evidence-based information regarding medical products
7 so that they can make the best possible medical
8 decisions for themselves in partnership with
9 healthcare providers. Any marketing directly to
10 consumers by medical product manufacturers regarding
11 off-label use should be prohibited as contrary to this
12 principle.
13 The FDA's role in protecting the public by
14 ensuring that drugs, biologics, and high-risk medical
15 devices are safe and effective for approved uses
16 before they reach the market is key to the ability of
17 consumers to trust the medical products on the market
18 and to trust that the benefits of a taking a drug or
19 biologic for an approved purpose outweigh the risks.
20 Healthcare providers similarly rely on the FDA to
21 ensure that the medical products that they may
22 prescribe are safe and effective.
1 It is important to point out that medical
2 providers in the U.S. have always been able to -- been
3 free to prescribe medical products for off-label use
4 when they deem it appropriate. Indeed, in some
5 limited circumstances, evidence-based guidelines and
6 practice parameters have included recommendations for
7 off-label medical prescribing.
8 Off-label prescribing is appropriate where
9 there is informed consent, where the prescriber is
10 well versed in the condition for which the medication
11 is prescribed, where there is a robust literature on
12 safety and risk benefit analysis in the population
13 affected, and an adequate literature regarding
14 efficacy for the condition treated.
15 Where this evidence base is lacking,
16 patients run the risk of being exposed to unsafe
17 and/or ineffective medical products. This is
18 especially true for special populations such as
19 children and the elderly.
20 Concerns regarding the lack of evidence for
21 use of adult medical products in children, despite
22 extensive off-label prescribing, led to the passage of
1 the Pediatric Research Equity Act and the Best
2 Pharmaceuticals for Children Act so that medical
3 products for adults would also be evaluated for safety
4 and efficacy in pediatric populations.
5 Promotion by manufacturers of off-label uses
6 to medical professionals upsets the balance of
7 informed medical decision-making. The majority of
8 prescriptions in the U.S. are written in primary care
9 settings. It has been estimated that it would take
10 more than 600 hours per month for a primary care
11 provider to review all of the relevant new literature.
12 Additionally, a national random survey of
13 physicians reveal that they had difficulty
14 distinguishing between off-label use supported by
15 evidence and approved uses for medication and that 41
16 percent of those surveyed believe that an off-label
17 use with little or no evidence to support it was
18 actually an approved use.
19 Prescribing patterns are clearly influenced
20 by off-label promotion. In the past two decades, we
21 have seen large classes of medication improperly
22 promoted for off-label use, often with devastating
1 results. The off-label marketing of antidepressants
2 for children and adolescents that had only been
3 approved for adults and of atypical antipsychotics for
4 elderly patients with dementia are only two examples
5 of many that were associated with an increase in off-
6 label prescribing and well-documented increased
7 morbidity and mortality. Clearly, in these examples,
8 the risks of off-label use outweigh the benefits.
9 Allowing manufacturers to promote off-label
10 uses to consumers, whether on the internet or by other
11 means, will not provide consumers with high-quality,
12 science-based information to make truly informed
13 medical decisions.
14 Only the U.S. and New Zealand allow any
15 direct advertising of medical products to consumers.
16 Under current law and policy, such direct-to-consumer
17 marketing in the U.S. is limited to approved uses.
18 CRIT urges the FDA to reject any
19 modification of current policy that would allow direct
20 communication to consumers and expand communication to
21 medical providers regarding unapproved uses.
22 Indeed, the leading pharmaceutical industry
1 trade group, PhRMA in the U.S., has adopted guiding
2 principles that exclude off-label, direct to consumer
3 marketing.
4 In Europe, the pharmaceutical industry trade
5 group EFPIA opposes all promotion of off-label use
6 regardless of the audience.
7 We oppose any changes that would permit more
8 freedom for the pharmaceutical industry to engage in
9 communications about off-label uses.
10 We support the Agency's long-standing
11 authority to regulate such communications and
12 recommend that any changes that the Agency implements
13 will strengthen, and not weaken, its regulations and
14 policies.
15 Thank you.
16 MS. KUX: Thank you very much.
17 Panelists, questions?
18 Kristin?
19 MS. DAVIS: Thank you for your presentation.
20 I have a question about something that you cited, the
21 600 hours per month for a primary care provider to
22 review all the literature. And I think yesterday that
1 was brought up, not that exact number, but this idea
2 was brought up by members of the pharmaceutical
3 industry with this idea that they need an effective
4 way to communicate to providers because they can't
5 wade through all that literature.
6 And so I wonder if you have any thoughts
7 about if there is robust data for an off-label use,
8 whether there is a communication mechanism for
9 providers that you would support to make them aware of
10 that outside of the literature.
11 DR. MCCARTHY: Well, I think that there
12 already are mechanisms in place for that. And I think
13 a good example is practice parameters, you know, that
14 are evidence-based, and a number of medical societies
15 produce those already. And those are based on careful
16 review of the literature and also experience gained
17 from practice.
18 I think that the difficulty is, is that if
19 there were direct marketing allowed, more than is
20 already allowed, by the pharmaceutical companies
21 directly to physicians and other prescribers, that
22 they don't -- especially in the primary care setting,
1 that many prescribers simply lack the time to
2 accurately assess it.
3 They may not have access to the journals.
4 They don't typically have a subscription. Most
5 journal articles, other than those that are freely
6 available, most of them are protected by a pay wall.
7 And so a primary care provider -- let's say
8 a nurse practitioner, a physician's assistant. There
9 are many other providers in the U.S. besides doctors
10 and that can prescribe. And I think that professional
11 associations, conferences, are the more appropriate
12 way to convey that information.
13 MS. DAVIS: Thank you.
14 MS. KUX: Other questions?
15 MS. KUX: Thank you.
16 DR. MCCARTHY: Thank you.
17 MS. KUX: So our next speaker is Ms. Jeanie
18 Kim from Yale Law School.
19 MS. KIM: Thank you for this opportunity to
20 speak. My name is Jeanie Kim. I am a fellow at the
21 Collaboration for Research Integrity and Transparency.
22 I'd like to make three points here today.
1 First, allowing pharmaceutical promotion of
2 off-label uses reduces incentives for drug firms to
3 invest in rigorous clinical studies and produce strong
4 evidence for new indications.
5 Second, expanding or broadening the safe
6 harbor in the Agency's current guidance on off-label
7 communications will give companies greater freedom to
8 market off-label uses under the guise of disseminating
9 scientific findings.
10 And third, the Agency should strengthen, not
11 weaken, its current standards by requiring greater
12 research transparency when drug firms disseminate
13 information about-off label uses.
14 There has been increasing pressure on the
15 Agency to relax its stance on a company's ability to
16 communicate about unapproved uses. However, the
17 Agency's strong authority over this issue is a
18 critical component of its overall regulatory system, a
19 system that puts the burden on drug companies to
20 demonstrate a drug's safety and efficacy with respect
21 to each indication before marketing.
22 It's a system that has set forth the
1 framework for drug companies to design rigorous
2 trials, test the validity of specific drug claims, and
3 generate the evidence base for medical products.
4 By restricting companies from making claims
5 about unapproved uses and by requiring regulatory
6 review and approval for each intended use, the Agency
7 encourages companies to invest in research that
8 produces the evidence supporting new uses of medicine.
9 Off-label promotion undermines this
10 regulatory system. It undermines the production of
11 evidence that ensures high standards for clinical
12 care, and it undermines the independent scrutiny of
13 evidence by the FDA.
14 While off-label prescriptions are prevalent
15 and permissible in clinical practice, they are often
16 not supported by adequate evidence. This gap in
17 evidence has clinical and economic consequences for
18 patients, their families, and the healthcare system,
19 as many have already testified to through their
20 research findings and their personal stories.
21 If an off-label use is promising, then it
22 should be tested and validated with controlled
1 clinical studies and subjected to independent scrutiny
2 by the FDA. That's what's necessary to separate the
3 truly promising off-label uses from those that do not
4 live up to their promises. However, this gap in
5 evidence for off-label uses is less likely to be
6 filled if companies are permitted to make promotional
7 claims about off-label uses.
8 And if firms can increase sales and expand
9 the market for an improved medicine by promoting
10 unapproved uses, there is less incentive to invest the
11 time and the resources to conduct the trials necessary
12 for new use approval. In fact, drug companies may
13 have the incentive not to conduct rigorous trials for
14 off-label uses, as there is a real risk that the
15 evidence will not work in their favor.
16 And many have said this, and I repeat here
17 again, permitting off-label promotion encourages drug
18 companies to obtain approval for one narrow indication
19 and then widen the market for drugs without strong
20 evidence to justify the additional claims or without
21 demonstrating that the benefits outweigh the risks or
22 that there are even any benefits at all.
1 In addition to undermining companies'
2 incentives to test and validate off-label uses, off-
3 label promotion would reduce patients' willingness to
4 participate in clinical trials, which then further
5 compromises the production of evidence.
6 When off-label uses are widely promoted
7 without adequate evidence, thereby increasing demand
8 in prescriptions, those off-label uses then become the
9 standard of care, discouraging patients from joining
10 trials that do not guarantee access, given that
11 comparisons with placebos and alternatives are
12 critical for carrying out reliable clinical studies.
13 And it's not enough to address this issue in
14 terms of promotion. The Agency already allows drug
15 companies to engage in limited communications about
16 unapproved uses, and it does so largely by drawing a
17 distinction between promotion and scientific exchange,
18 an important distinction, but one that's become
19 increasingly difficult to draw.
20 Responding to unsolicited questions about
21 off-label uses is permissible as long as the responses
22 are scientific in nature and not promotional and
1 generated by medical or scientific personnel
2 independent from sales and marketing departments. And
3 drug firms can distribute peer-reviewed journal
4 articles that are based on adequate and well-
5 controlled clinical investigations.
6 But over the years, the Agency has shifted
7 the line between promotion and the dissemination of
8 scientific findings. For example, in 2014, the Agency
9 revised its guidance to allow companies to disseminate
10 non-peer reviewed clinic practice guidelines
11 containing information about off-label uses. And
12 here, with the request for comments, the Agency seems
13 to again be contemplating where and how to draw that
14 line.
15 And there has been a push from industry and
16 certain members of Congress for the FDA to broaden the
17 safe harbor categories for communicating about off-
18 label uses under the category of scientific exchange.
19 However, the Agency should be very careful
20 in permitting more ways for companies to communicate
21 about off-label uses under the guise of science.
22 Companies should not be permitted to circulate off-
1 label information on the basis of less, weaker, or
2 incomplete evidence. Already, the distinction between
3 promotion and scientific exchange is blurred by
4 widespread pharmaceutical practices such as seeding
5 trials, which are trials designed solely for marketing
6 purposes.
7 Broadening the categories for what
8 constitutes scientific exchange or weakening its
9 evidentiary standards will give firms more freedom to
10 disseminate information that distorts medical
11 literature -- marketing passed off as science.
12 Even with the current guidance, we urge the
13 Agency to add more safeguards to ensure that
14 information that drug companies are currently
15 permitted to disseminate about unapproved uses can be
16 scrutinized. Current safeguards, such as mandating
17 articles to be peer reviewed and published in medical
18 journals, do not always ensure that the underlying
19 studies were rigorously conducted and designed or that
20 the results are sound, nor are they sufficient when
21 taking into the reality of publication biases and
22 selective publishing.
1 Drug companies can selectively communicate
2 information to physicians, and the lack of
3 transparency makes it difficult to assess the evidence
4 in public literature.
5 While these problems exist regardless of
6 whether the use is approved or unapproved, the
7 problems are all the more keen when the dissemination
8 about information with unapproved uses because those
9 uses have not been independently scrutinized and have
10 not been determined by the Agency to be supported by
11 strong, aggregate evidence.
12 The Agency should require greater research
13 transparency by ensuring registration and reporting on
14 ClinicalTrials.gov and even encouraging greater data
15 sharing for studies underlying drug firms'
16 communication about off-label uses as well as any
17 studies involving that drug.
18 Drug firms seeking to distribute articles
19 under the banner of scientific exchange about off-
20 label uses should certify compliance with disclosure
21 requirements for all clinical studies concerning that
22 medical product and should be required to disclose
1 underlying clinical data so that investigators and
2 clinicians have access to results for a range of
3 trials and not just those that are selectively
4 published, disseminated, and communicated by drug
5 companies.
6 I emphasize the need for greater research
7 transparency, given the FDA's current guidance, but
8 transparency, while important, is not a replacement
9 for evidence production. It does very little when
10 there isn't evidence that's being created to begin
11 with.
12 And transparency should not be a replacement
13 for strong regulatory standards. Only the Agency has
14 full access to the complex data that's necessary to
15 make risk-benefit evaluations.
16 The Agency should maintain its restrictions
17 on off-label promotion, including the dissemination of
18 information about off-label uses that are
19 unsubstantiated or based on weak or incomplete
20 evidence, to ensure that each use that is promoted by
21 a drug firm has been demonstrated to be safe and
22 effective.
1 The FDA has an obligation to ensure the
2 safety and efficacy of medical products, a
3 determination that can only be made on the basis of
4 strong scientific evidence.
5 And the Agency would be failing its
6 statutory duty to protect patients and the public if
7 it voluntarily relinquished authority over off-label
8 communications, knowing that it would compromise the
9 evidence base for medicines.
10 Thank you.
11 MS. KUX: Thank you very much.
12 Questions, Panelists?
13 Tom?
14 MR. ABRAMS: You mentioned that we should
15 add more safeguards to insure the information that
16 drug companies are currently permitted to disseminate
17 and strengthen. And you noted, like, there could be
18 selective presentation of what studies the company is
19 actually giving out. You mentioned transparency --
20 MS. KIM: I didn't hear that last part.
21 MR. ABRAMS: What?
22 MS. KIM: I didn't hear your last part.
1 Sorry.
2 MR. ABRAMS: Yeah. You mentioned that one
3 of the flaws would be that the companies are selecting
4 what studies to be given out so they could take out --
5 just provide the positive results. You mentioned
6 transparency would be a help to safeguard this. Any
7 other thoughts that you could expand on what FDA could
8 do to --
9 MS. KIM: Yeah. I mean --
10 MR. ABRAMS: -- increase this?
11 MS. KIM: Yesterday, disclaimers were
12 mentioned by Dr. Kesselheim, but with the disclaimer
13 that they're not effective in impacting consumers'
14 understanding of health products.
15 So although disclaimers could help
16 strengthen the current evidentiary standards or the
17 current standards of the guidelines, they really
18 shouldn't be a replacement for evidence production.
19 There could be higher or stronger
20 disclaimers such as drug companies having to disclose
21 that the unapproved use was rejected by the Agency or
22 that they are seeking approval of the unapproved use.
1 There could be more specific demands made of those
2 disclaimers and disclosures. But again, I emphasize
3 Dr. Kesselheim's point that they just aren't as
4 effective in helping consumers and physicians
5 understand what's at stake.
6 MR. ABRAMS: Thank you.
7 MS. KUX: Any other questions?
8 Rachel?
9 DR. SHERMAN: Either now or in your
10 comments, could you expand -- your comments about
11 scientific exchange, do those apply only to healthcare
12 professionals, or also would you make the same
13 comments about formulary communities and payers?
14 MS. KIM: Yeah. I think that was one of the
15 questions I was presented by the Agency, and I can
16 address that more in the written comments.
17 I would like to say, I mean, the -- as
18 important as it is to maintain strong scientific
19 standards, whoever the audience is, what's most
20 pertinent with clinical care is who the audience is
21 when they're -- when it's clinicians and patients.
22 MS. KUX: Any more questions?
1 Kristin?
2 MS. DAVIS: And this can also be for any
3 follow-up written comments or if you want to address
4 it today.
5 So you mentioned a few times that
6 communication shouldn't be based on weak or incomplete
7 evidence. And so any thoughts on the criteria for
8 judging that and whether there should be any, you
9 know, kind of different considerations in areas, say,
10 for a rare disease where they might be a very small
11 patient population?
12 So doing something like a double-blind
13 controlled trial might be more difficult, you know,
14 than in other therapy areas -- if there should be any
15 considerations along those lines in weighing the
16 evidence or just any criteria for what would be the
17 hall markers of weaker versus weaker evidence.
18 MS. KIM: Yes. I mean, I think there are
19 some ethical issues with requiring randomized control
20 trials in every single instance. And I think the
21 Agency has the challenge of having to make some case-
22 by-case decisions.
1 So I would urge that in cases where it is
2 difficult to do a blinded control, a randomized trial,
3 especially in rare diseases, that the Agency is very
4 particular about how it allows more flexibility and to
5 ensure that whenever there is a lowering or a
6 weakening of standards that accommodate ethical
7 concerns or the reality, that those flexibilities
8 aren't expanded and they don't become the status quo.
9 MS. KUX: Other questions?
10 Thank you very much.
11 MS. KIM: Thank you.
12 MS. KUX: So our next speaker is Ms. Amy
13 Kapczynski from Yale Law School. Welcome.
14 MS. KAPCZYNSKI: Thanks very much.
15 So I'm Amy Kapczynski. I'm a professor of
16 law at Yale Law School and one of the faculty
17 directors of CRIT.
18 I share with my colleagues the view that
19 it's imperative that the FDA continue to strongly
20 enforce its existing approach -- it's historical
21 approach to off-label drug promotion.
22 And because I am a lawyer and a law
1 professor, I'm going to speak to what I suspect has
2 been on your minds, which is the question about how
3 recent developments in constitutional law implicate
4 the choices that you make.
5 So to begin with, it's important to
6 understand that commercial speech is not entitled to
7 the same degree of protection, constitutionally
8 speaking, as is political speech. So it is and it can
9 be much more heavily regulated than political speech
10 is, right?
11 So speech is not speech is not speech, all
12 right? This is a kind of principle, actually, of
13 First Amendment law. The kind of speech matters
14 tremendously to the amount of regulation that's
15 possible.
16 So for example, the government cannot bar
17 false political speech. But as you know, the
18 government can bar false commercial speech, right? So
19 extensive regulation is permitted in the commercial
20 speech area. That's a bedrock of American
21 constitutional law.
22 Second, I'll say that for decades no court
1 has indicated that the FDA's core restrictions on off-
2 label promotion were in any tension with the First
3 Amendment. This is a new development. As I know you
4 all know, in 2012, by a vote of two to one, a panel of
5 judges on the U.S. Court of Appeals for the Second
6 Circuit, where I once worked as a clerk, in a case
7 called U.S. v. Caronia, invalidated the conviction of
8 a drug company representative for promoting a drug
9 off-label.
10 So I want to stress the narrowness of that
11 opinion first. So this was a case where the detailer
12 had promoted a drug to treat narcolepsy -- or approved
13 to treat narcolepsy for off-label uses, including
14 chronic pain. The Second Circuit concluded that the
15 government couldn't prosecute the detailer simply for
16 making promotional statements about off-label uses.
17 But it was careful not to entirely strike down the
18 FDA's current approach.
19 So the Court said, well, maybe the
20 government can't penalize speech itself, but suggested
21 that you might prevail on a different legal theory,
22 the theory that you are penalizing conduct -- the
1 conduct of selling a misbranded drug and only using
2 speech as evidence of a crime, okay?
3 So this reflects a general rule in First
4 Amendment law that speech can be used as evidence of a
5 crime without implicating the First Amendment.
6 So if you consider, for example, the
7 category of hate crimes, this rule of law is what
8 authorizes the government to prosecute hate crimes
9 using a racist statement to show that a person had the
10 requisite element of a crime, a forbidden intent,
11 right? So the Second Circuit was careful to leave
12 open this alternative argument.
13 In the Amarin case, which many people have
14 mentioned so far, that is a District Court trial court
15 decision, which concluded, in fact, that the FDA
16 didn't have the authority to prohibit off-label speech
17 unless that speech was false or misleading. It
18 rejected the argument that its superior court, the
19 Second Circuit, left open. As you know, the FDA
20 settled that case, so there was no review of that
21 decision.
22 So I want to make a couple of simple points
1 about these cases. So first, they do not represent a
2 definitive legal resolution of this issue. So as I
3 mentioned, the Caronia decision was deliberately
4 modest in how it approached the legal question,
5 leaving open an alternative argument that could, in
6 fact, immunize the historical approach to off-label
7 promotion.
8 The evidentiary argument that the Court left
9 open is a powerful one. In fact, it's one that many
10 courts of appeal in the United States have accepted as
11 the very basis of the FDA's power to regulate
12 unapproved medicines, all right?
13 So if you market as a company an entirely
14 unapproved drug, you cannot argue that your treatment
15 claims are constitutionally protected speech and force
16 the Agency to disprove them, right? This is core to
17 the ability, in fact, to regulate the promotion of
18 unapproved drugs as well.
19 So the Court in Amarin disagreed with that,
20 but it's only a trial court decision. And it's
21 important for you to understand that trial court
22 decisions of this sort are not legally binding on any
1 other court, even within the same jurisdiction.
2 The FDA can also press other arguments in
3 future cases and in other jurisdictions and including
4 up to an appeal at the Supreme Court.
5 So as I described, the government is
6 permitted to regulate commercial speech. And one of
7 the grounds under which commercial speech can be
8 regulated is to ensure that the public is adequately
9 informed. Properly understood, the FDA's historical
10 approach, I believe, serves this end because it's well
11 tailored to a substantial need, the production of
12 high-quality evidence that can then be reviewed by
13 expert regulators.
14 So these cases, I will say, also illustrate
15 the second point that I wanted to stress, which is the
16 dangers of a legal standard that permits off-label
17 speech as long as it's not, quote, false and
18 misleading -- or misleading, sorry. This standard,
19 I'm afraid, will be interpreted by courts in a way
20 that's very different than how the Agency might
21 interpret it.
22 So judges may, for example, see any
1 evidence, including animal studies, anecdotal evidence
2 even, to be the basis of statements such as some
3 evidence supports the use of this drug for X
4 condition.
5 So in the dietary supplements context, where
6 these First Amendment arguments emerged many years
7 ago, I think this context provides a warning and a
8 useful warning. So in a 2001 case about folic acid in
9 the DC District Court called Pearson versus Shalala,
10 the judge concluded that the FDA could not prevent a
11 health claim as misleading, even though the Agency had
12 concluded that the -- that there was no evidence in
13 support of the claim because -- and I quote -- "The
14 mere absence of significant affirmative evidence in
15 support of a particular claim does not translate into
16 negative evidence against it," all right?
17 So you can make claim as long as there's no
18 evidence against it. That's obviously not how a
19 scientist would perceive that issue. But judges
20 aren't trained in science.
21 So if the FDA revises its approach, as some
22 have urged it to do, I think we could very well end up
1 with a drug industry that looks more like the
2 supplements industry.
3 So third, in its hearing announcement, the
4 Agency signaled that it may be considering changing
5 its approach not merely regarding marketing to
6 doctors, but also directly to consumers.
7 I just want to stress that neither of the
8 recent cases that I mentioned addresses promotion to
9 consumers. They only address promotion to doctors.
10 And in both cases, the courts were quite concerned
11 with, and their analysis turned on, the sophistication
12 of the audience involved and that they were speaking
13 to physicians.
14 I don't believe that those cases at all
15 stand for the proposition that the same approach need
16 be taken when you're talking about direct-to-consumer
17 speech, and I think that the state Agency has ample
18 room to restrict statements to consumers that even if
19 those statements might be permitted to doctors, given
20 the heightened potential that lay audiences would, in
21 fact, misunderstand marketing statements.
22 So I hope these will help to reassure the
1 Agency that the long-standing approach to off-label
2 marketing could well still be upheld in the courts and
3 also encourage incorporating the comments made by my
4 colleagues and others here that the Agency continue to
5 enforce its authority in this area and defend it
6 fully, including to the Supreme Court.
7 Thanks.
8 MS. KUX: Thank you.
9 Questions?
10 Oh, I actually have a question. You talk
11 about the Caronia case and the Amarin case. I'd be
12 interested either now or in your written remarks if
13 you could also talk about some of the more recent
14 Supreme Court jurisprudence that we heard sort of --
15 or saw up on people's slides, the cases like Sorrell.
16 MS. KAPCZYNSKI: Sorrell was actually pre-
17 Caronia. So -- but yeah. And Sorrell does -- Sorrell
18 was, I think, really the trigger for the Caronia case
19 in some of its language. And I can sort of say some
20 more about that in my remarks.
21 Because Sorrell didn't address the specific
22 off-label issue, it again would be something that
1 certainly lawyers would be thinking about but wouldn't
2 decide the question.
3 And for some of the reasons I'll describe
4 maybe at greater length in my remarks, it doesn't
5 dictate an outcome that would render the Agency's
6 historical approach unconstitutional.
7 MS. KUX: Any other questions?
8 MS. SCHIFTER: Hi. I think you addressed,
9 with respect to Caronia, that you believe it left open
10 the argument that speech can be used as evidence of
11 intent. But would you also criticize the Caronia
12 majority opinion on its Central Hudson evaluation and
13 think the Agency should take that on?
14 MS. KAPCZYNSKI: So I think that it was not
15 a good analysis of the Central Hudson test. I think
16 that the Agency has a strong argument on Central
17 Hudson grounds and that other courts might take more
18 seriously than this court did.
19 I will say one thing that I think that the
20 Agency -- sorry -- the court, the majority in the
21 Caronia decision, did particularly focus on and viewed
22 the Agency's interest primarily as about sort of not
1 keeping doctors from engaging in more off-label
2 promotion. I think that that's not the strongest
3 First Amendment argument for the important purposes of
4 the FDA's approach to off-label promotion.
5 I think that the Court should have focused -
6 - and the FDA raised both questions, but I think that
7 it's important for the FDA to stress that this play --
8 that the regulations that we're talking about play an
9 information production function, right? It's not
10 about suppressing speech. It's about producing data.
11 And I think that ground is a strong ground to defend
12 and that the Court should take seriously that as the
13 substantial interest at stake.
14 I think with respect -- when you frame it in
15 that way and you say this is essential for the way
16 that we produce data about off-label uses, then you
17 can also better understand that the second step of the
18 test where they say, well, how well tailored is the
19 particular approach. Then the fact that doctors are
20 allowed to prescribe off-label makes more sense
21 because doctors aren't the ones who are going to
22 produce the data, right? You don't have authority
1 over doctors, and doctors are not the entities best
2 situated to be able to, in fact, produce studies and
3 submit them to the FDA.
4 So I do think that the Agency has a good
5 Central Hudson case. I think the Court there didn't
6 perceive accurately some of what the interests the
7 Agency has in its existing approach and, therefore,
8 sort of misunderstood how the test applies.
9 MS. KUX: Any other questions?
10 Thank you.
11 MS. KAPCZYNSKI: Thank you.
12 MS. KUX: So our next speaker is Ms. Joy
13 Eckert from George Washington University.
14 MS. ECKERT: Good afternoon. My name is Joy
15 Eckert, and I'm the project manager for the Access Rx
16 Project in the D.C. Center for Rational Prescribing at
17 the George Washington University Milken Institute
18 School of Public Health. Both projects are supported
19 by the D.C. Department of Health.
20 We analyze and report annual pharmaceutical
21 marketing expenditures in the District of Columbia and
22 produce evidence-based and industry-free continuing
1 education for healthcare professionals.
2 This testimony was written jointly with Dr.
3 Ruth Lopert from the George Washington University
4 Milken Institute School of Public Health. Neither Dr.
5 Lopert nor I have any conflicts of interest to
6 declare.
7 Most of the speakers yesterday have focused
8 on promotion to physicians and payers. My testimony
9 will focus more on direct-to-consumer advertising and
10 promotion.
11 Pharmaceutical marketing and promotion
12 increase irrational prescribing for approved
13 indications. Promotion of unapproved off-label uses
14 will have even worse public health implications.
15 There is already substantial evidence of the
16 detrimental effects of direct-to-consumer advertising,
17 as well as market distortions in irrational
18 prescribing that are driven by promotion to
19 prescribers.
20 Studies have demonstrated the inability of
21 pharmaceutical advertising to provide appropriate and
22 balanced information and the deleterious effects of
1 direct to consumer advertising on healthcare
2 expenditures. Marketing and promotion focus on
3 creating demand for specific medicines. This
4 conflicts with the rights of patients to have access
5 to high-quality, independent, comparative information
6 on the risks and benefits of the available drug and
7 non-drug therapies.
8 The objectives of advertising and promotion
9 are to create demand and increase sales, which drive
10 up costs for both patients and payers.
11 DTCA has negative effects on patient-
12 clinician relationships. It adversely influences
13 patient-clinician relationships by adding additional
14 commercial pressure to prescribers, which can have
15 negative effects on trust, confidence, and clinical
16 practice.
17 Studies have also brought up patient safety
18 concerns with regard to DTCA. Promotion focuses on
19 newer medicines where long-term adverse effects and
20 rare effects are unknown, which inevitably puts
21 patients at risk. There are several examples of
22 heavily marketed medicines gaining significant market
1 share over well-established medicines, only to be
2 withdrawn when broader safety profiles are revealed.
3 DTCA also contributes to the inappropriate
4 medicalization of normal variations in healthy
5 populations. Industry promotes pharmaceutical
6 solutions over other available alternatives that could
7 assist people to adapt to changes associated with
8 normal health and aging processes.
9 The pharmaceutical marketing industry
10 creates new diseases, such as excessive underarm
11 sweating, excessive sleepiness, and pediatric bipolar
12 disorder by medicalizing normal variations of human
13 physiology and behavior as part of its strategy to
14 increase sales.
15 There is a lack of any credible evidence
16 demonstrating the claimed health benefits of DTCA,
17 even for approved indications. DTCA is already
18 heavily regulated and still results in adverse public
19 health effects. If the FDA allows for promotion to
20 consumers for unproved uses, these deleterious effects
21 will only increase.
22 As healthcare expenditure climbs towards 20
1 percent of GDP, why would we choose to reduce
2 regulation on a practice that will inevitably increase
3 cost? Industry would have you believe that off-label
4 and pre-launch promotion to payers will reduce cost in
5 the long-term, but there is no reliable evidence to
6 support that claim.
7 Years of research have shown that
8 pharmaceutical marketing increases the cost of
9 healthcare. And recent research using CMS's open
10 payments database provides even more evidence to show
11 that pharmaceutical promotion increases the cost of
12 healthcare.
13 Promotion of off-label use will inevitably
14 be heavily slanted toward new and more expensive
15 medicines. Off-label use of off-patent medicines will
16 only be promoted when these medicines are single
17 source and therefore lacking competition in the
18 market.
19 We already have a problem of manufacturers
20 exploiting the orphan drug provisions to gain rapid
21 and reduced-cost access to the market for products
22 with the potential for wider use. Given that
1 evidentiary standards for orphan drugs are lower, a
2 drug can be approved for a narrow indication and then
3 prescribed off-label for broader use. This makes it
4 easier for manufacturers to gain access to a wider
5 market based on inadequate data in a small population
6 that does not represent the larger market.
7 This exposes the population to unknown
8 risks. Allowing the subsequent promotion of off-label
9 uses of orphan drugs, or any drugs with a narrow
10 indication, for marketing approval effectively removes
11 incentives for manufacturers to submit full dossiers
12 for wider use.
13 Why would industry conduct Phase III
14 clinical trials which may or may not produce positive
15 results and pay the associated fees to the FDA, when
16 they can simply promote unapproved uses?
17 Creating an environment that encourages
18 industry to do small, low-quality studies for drug
19 approval while planning off-label promotion for wider,
20 unstudied populations would be catastrophic for public
21 health in this country.
22 The pharmaceutical industry often speaks of
1 its commitment to science-based communication. The
2 only way to ensure that communication is truly
3 science-based is for an independent regulatory
4 authority to evaluate whether benefits proven in RCTs
5 outweigh harms for a specific use -- in other words,
6 the current system for drug licensing or adding
7 labeled indications. To do anything less is to show a
8 complete absence of commitment to science and public
9 health.
10 We accept that the FDA does not and cannot
11 regulate off-label prescribing. However, it should
12 not permit the promotion of off-label uses -- permit
13 the promotion -- excuse me -- the promotion of off-
14 label uses. Off-label prescribing has a place in
15 medicine, but it should not be encouraged as a means
16 of circumventing well-established processes designed
17 to ensure that patients treated with a prescription
18 medicine are far more likely to experience benefit
19 rather than harm from that treatment. The interest of
20 public health must outweigh commercial interest.
21 Thank you.
22 MS. KUX: Thank you very much.
1 Panelists, any questions?
2 MS. KUX: Thank you.
3 So our next presenters are Ms. Kimberly
4 Dougherty and Ms. Cara Jones.
5 (Pause.)
6 MS. KUX: -- presentation. So if people,
7 like, want a seventh-inning stretch, or whatever the
8 right baseball terminology is, now would be a good
9 time to take it.
10 Thank you.
11 (Off the record.)
12 MS. KUX: Hey, folks. We're going to get
13 started.
14 MS. JONES: Hi. My name is Cara Jones. I'm
15 married with two children, ages six and four. And the
16 issues being discussed here these last couple of days
17 have directly impacted my family.
18 When I became pregnant with my first child,
19 I vowed, as I'm sure all mothers do, to make the best
20 decisions possible regarding my kids' health. I'm not
21 an individual that takes the idea of pharmaceutical
22 medications lightly. I'm the mom that wants to
1 discuss alternatives with my doctors for more natural
2 ways to handle illnesses. There are times, of course,
3 when medications are necessary and I have to put a
4 level of trust in my doctors, and that's where my
5 story begins.
6 My first pregnancy went smooth. I gave
7 birth to a beautiful, happy, healthy girl named Amaya.
8 My second pregnancy didn't go quite so
9 smooth. From the very beginning, I was sick. The
10 nausea seemed to never end. There were several-day
11 stretches were I would -- I was unable to keep down
12 food or water. Most days, the smell alone of food was
13 enough to make me sick. I tried each and every home
14 remedy I could think of to help ease the nausea.
15 I finally decided that I needed to seek
16 medical intervention, as I was dehydrated and I feared
17 for my baby. I remember sitting in the ER and the
18 doctor telling me they were going to give me some
19 medication to help the nausea.
20 They were going to give me fluids and Zofran
21 in an IV. My first reaction was panic. No one ever
22 said that it was off-label or would cause harm to me
1 or my baby. Had I known what possible risks were, I
2 wouldn't have taken it. That's just who I am.
3 But I got the IV. I felt better and was
4 sent home with a prescription for Zofran to take as
5 needed. I filled it. I got the generic form. It was
6 uncomfortable talking it. I used it very, very
7 sparingly.
8 I got through the rest of my pregnancy with
9 no other issues. Wanting to have a completely natural
10 childbirth, I delivered at a birthing center. After a
11 short labor, I gave birth to an amazing baby boy.
12 Three days later, we went to his
13 pediatrician for his first check-up. The doctor heard
14 a heart murmur and sent us to the children's hospital
15 for more testing.
16 While holding my baby during his EKG and
17 echocardiogram, I was confident that he was fine and
18 all this was just precautionary. It wasn't until
19 after the echo that I knew something was wrong.
20 We were told the doctor would need to see
21 the tests and he was going to want to talk to us.
22 They put us in a room, and we waited and waited. It
1 was the most two hours -- excruciating two hours of my
2 life. We had no idea what we were in store for.
3 The doctor finally came in and explained
4 that my precious boy had a hole in his heart,
5 specifically, a ventricular septal defect, or a VSD.
6 He explained that in a lot of cases, the hole closes
7 on its own. He let us know that we could wait and
8 watch until there were any negative side effects.
9 This would also be beneficial as the bigger he was,
10 the better he would be able to handle anesthesia.
11 If the hole did not close on its own and we
12 began to see negative symptoms, we would have to
13 discuss treatment options, which would most likely be
14 open-heart surgery to repair the hole. I was
15 devastated, but tried to remain hopeful that it
16 wouldn't come to that.
17 Over the next five months, we maintained
18 regular cardiology appointments to monitor the hole.
19 His heart was starting to enlarge due to blood flow
20 into the wrong chamber through the hole.
21 We had a little time before any permanent
22 damage. This was my time to make sure my boy was
1 growing. He was strictly breastfed and would eat a
2 little at a time every hour and a half. This led to
3 little sleep for me, but it was worth it to help my
4 boy be as big as he could be.
5 In November, we got the news we were hoping
6 to avoid. If we didn't do the surgery soon, there
7 would be irreversible damage to his heart. Couldn't
8 figure out how to make sense of what was happening.
9 Sebastian was a calm, chill baby. How is it possible
10 that he was this sick? I tried to do everything
11 right. I ate healthy. I exercised. We are a loving
12 family. Why us? Why him?
13 We scheduled his surgery for the middle of
14 January. My job in the meantime was to keep him
15 healthy. We tried to get through our holidays as
16 normally as possible. With the knowledge that your
17 six-month-old baby was getting reading for open-heart
18 surgery, some days were tough.
19 At the end of December, we got the call that
20 the surgeon had an opening and he wanted to move
21 Sebastian's surgery up to January 8th. We agreed and
22 started preparing.
1 We had to take our daughter out of daycare
2 for two weeks prior to surgery to avoid any
3 unnecessary germs or sickness in our household. The
4 night before his surgery, I gave him a bath in the
5 sink and took pictures -- one last picture before
6 getting the scar he would carry for the rest of his
7 life.
8 Being a military family, we never seemed to
9 have family local. So I had to fly my sister in from
10 Maine to stay to with my daughter while I was in the
11 hospital with Sebastian. My husband would go back and
12 forth between the hospital with Sebastian and home
13 with Amaya until he had to go back to work.
14 We arrived at the hospital very early on
15 January 8th. My husband and I got to be with
16 Sebastian while they got him ready to bring him back
17 to pre-op. When they said it was time to pass him
18 over so they could bring him to the back, I thought I
19 was going to lose control. Passing my son over was
20 the hardest thing I would ever do.
21 We watched the nurse walk away with our son
22 looking back at us having no idea what was going on.
1 There are no words to describe the feeling you have
2 when you pass your child to a stranger knowing there's
3 a possibility you might not get him back.
4 We met with the surgeon, and he explained
5 exactly what was going to happen in the surgery and
6 that he was going to take care of our boy as if he
7 were his own.
8 My husband and I sat in the waiting room for
9 what felt like an eternity. The hospital was great.
10 They sent someone out regularly to give us status
11 updates, and we finally got word that everything was
12 over and the surgery had gone smooth.
13 It wasn't until years later when I read the
14 medical records that I grasped the concept of how
15 large the hole really was and the fact that he was on
16 bypass for 58 minutes. For 58 minutes, machines kept
17 my baby boy alive.
18 When we were allowed into his room to see
19 him for the first time, I was nervous. We walked in,
20 and there were machines and tubes and foreign sounds.
21 And my baby was still unconscious on the bed.
22 He was covered in a blanket until we told
1 the nurse that we were ready to see his body. When
2 she pulled the blanket down, he looked scary. He had
3 tubes coming out of everywhere, and the incision was
4 huge.
5 The nurse explained everything, every tube
6 and wire that we were looking at. She let us know
7 that the first 24 hours were the hardest. She was
8 right.
9 The first night was horrible. He woke up
10 crying and in pain so many times I lost count. I felt
11 helpless. There was nothing I could do but sit by my
12 son's hospital bed and hope he had the strength to get
13 through this.
14 The next couple of days were the same
15 routine. He'd get a little better, and they'd take
16 another tube out. Nights seemed to be difficult.
17 Nobody was getting much sleep.
18 To make matters worse, I missed my daughter.
19 This is impacting our entire family. She was not
20 allowed in the hospital because she was only two.
21 There was no way I was leaving my son.
22 On day four, Sebastian was starting to feel
1 better. We knew because it was getting harder and
2 harder to keep him still. On day five, we were able
3 to go home.
4 We had to alter how we picked him up because
5 the bones needed time to heal, but he had no
6 restrictions. He went home with a couple of
7 medications to take for a week or two following
8 surgery.
9 The day we got home, his sister was so
10 excited. She'd missed her little brother and her mom.
11 We were just happy to get back to normal. We had to
12 have regular check-ups at first with the cardiologist
13 to make sure everything was healing right.
14 Thankfully, there were no complications with his
15 recovery.
16 We have a brand new baby. We didn't realize
17 until after his surgery the impact the hole had been
18 having on him. From the day we brought him home from
19 the hospital, he had not stopped moving. He started
20 as the calmest baby ever and has turned into the most
21 active four-year-old boy you'll ever meet.
22 While we're glad the surgery was behind us,
1 we still had to have regular cardiology appointments
2 to make sure the patch was holding up well and growing
3 with him. The visits went from weekly to monthly to
4 yearly. Every visit brings anxiety because you never
5 know what's going to happen. So far, so good.
6 My son is an active four-year-old boy with
7 no restrictions. We just live day by day and try not
8 to focus on what could happen. We've tried to be
9 positive and grateful because our story could have
10 ended much different.
11 January 8th holds a new meaning in our
12 family. Every year, we have a heart party for our
13 boy. He gets a heart-shaped cake, and we decorate the
14 house. It's our way to celebrate his strength and his
15 new happy, healthy heart.
16 With everything my family went through,
17 there was no anger until we heard that there was a
18 possible link between taking Zofran while pregnant and
19 heart defects in babies. We didn't even know about
20 off-label use of medications until a couple of years
21 after my son's surgery.
22 It's unfair that our family had to go
1 through this. I'm angry and I'm sad. I'm confused.
2 If I hadn't taken the medication, could I have
3 prevented it?
4 I trusted that the pharmaceutical companies
5 did their jobs and were honest about it. I trusted
6 that my doctors knew the risks of the drugs they
7 prescribed and made me aware of them so I could make
8 an educated decision. Whose responsibility is it to
9 keep people safe?
10 I truly hope that unsuspecting families
11 don't have to go through what my family has had to
12 endure.
13 MS. KUX: Thank you. Okay. All right.
14 Thank you.
15 Any questions?
16 Thank you.
17 So I want to thank all the panelists this
18 morning for their presentations and ask everybody to
19 come back at 1:30.
20 (Off the record.)
21 (Break)
22 MS. KUX: Welcome back, everyone. We're
1 gonna get started. So for folks who weren’t here this
2 morning who are speaking, I just want to give a little
3 bit of background. The -- this little box on the
4 podium is the timer. It'll turn yellow when you have
5 one minute and red when your time is up.
6 Each -- we have a little bit of time for
7 questions after each panelist, and we've been asking
8 questions, so be ready for that. And if -- we're not,
9 as you've noticed, running exactly on schedule, so if
10 you could be here a little bit before your time and be
11 prepared to stay a little bit after that would be
12 great.
13 So I think that's -- we'll just get started.
14 And I just -- again, thanks to all the folks who were
15 here this morning. This is sort of the last stretch,
16 and we're looking forward to everybody's
17 presentations.
18 Okay. So our next presenters are Dr.
19 Adriane Fugh-Berman and Dr. Alycia Hogenmiller.
20 MS. HOGENMILLER: Hello. I would just like
21 to clarify that I'm not a doctor. It's Ms.
22 Hogenmiller.
1 Thank you.
2 Hello. My name is Alycia Hogenmiller. I’m
3 the project manager of PharmedOut, a Georgetown
4 University Medical Center research project. We
5 examine how pharmaceutical and medical device
6 companies use marketing to affect therapeutic choices.
7 PharmedOut has a contract with the George
8 Washington University Milken Institute School of
9 Public Health to create industry-free, unbiased
10 continuing education to physicians, other clinicians,
11 and pharmacists for the D.C. Department of Health.
12 This contract funds part of both my salary and Dr.
13 Fugh-Berman's salary. We have no commercial conflicts
14 of interest.
15 In my testimony today, I would like to
16 address some points brought about this hearing.
17 First, industry has promised that if given permission
18 to promote products off-label, it will do so
19 responsibly. But what evidence supports this claim?
20 Lawsuits, bad public image, and large fines
21 have not deterred the industry thus far. Drug
22 companies have every incentive to push the limits of a
1 proposed ruling. Laws and regulations against off-
2 label promotion are a deterrent to only the worst
3 behavior. Even so, off-label sales are so profitable
4 for a company that laws against off-label promotion
5 continue to be ignored. Companies may even plan to
6 break the law, calculating fines of off-label
7 promotion as the price of business.
8 Despite several expensive high-profile off-
9 label promotion cases, companies have not changed
10 their practices. Repeat offenders, to name a few,
11 include Pfizer with 11 settlements, Merck with 9,
12 GlaxoSmithKline, Novartis, and Bristol-Myers Squibb,
13 all with 8.
14 A majority of cases, 58 percent, were
15 brought forward by whistleblowers, meaning the
16 government has thus far been insufficient in catching
17 these cases of abuse. Even when the FDA is able to
18 catch cases of abuse, they will be able to stop only a
19 portion of the most egregious cases.
20 The Office of Prescription Drug Promotion,
21 OPDP, is currently receiving over 80,000 promotional
22 pieces annually. They can only evaluate a tiny
1 percentage of these items.
2 Allowing off-label promotion will swamp OPDP
3 further and make it impossible for them to do their
4 job. Even when misleading campaigns are identified,
5 the damage is already done by the time enforcement
6 actions are taken.
7 Additionally, patients will be left without
8 protection of the government or legal recourse if they
9 are harmed by off-label promotion. This undermines
10 the core function of the FDA to protect consumers by
11 ensuring that benefits of medical therapies outweighs
12 harm.
13 Second, the idea that more information is
14 better. Physicians and patients don't need more
15 information. They need correct information,
16 especially information that is put into an appropriate
17 context.
18 You have heard that manufacturers know the
19 most about their drugs. That may be true. But you --
20 they cannot be counted on to provide accurate
21 information on competing drugs, generic drugs, or non-
22 pharmacologic therapies such as diet and exercise.
1 In fact, they have campaigns to battle
2 competing therapies. For example, Lipitor had a
3 campaign titled "Stop Kidding Yourself" that
4 discouraged patients from using diet and exercise to
5 lower cholesterol. And these are the companies we are
6 supposed to trust with providing appropriate context?
7 Industry given -- information given to
8 physicians and patients by industry will necessarily
9 be one-sided, the side of industry. Industry has no
10 incentive to emphasize harms of their products or
11 promote a superior product. That would go against
12 their shareholders' interests.
13 For people to be able to make informed
14 decisions, they need all the relevant information.
15 But what is relevant? To industry, that would only be
16 the benefits of the drug.
17 Industry, in their guidelines, has promised
18 a commitment to provide appropriate context about
19 data. In their guidelines, they have stated that they
20 will provide information about the limitations of the
21 data and the analysis conducted. This information
22 only applies internally to the materials provided.
1 Under their guidelines, they would not have
2 to compare their drug to other drugs. So even if
3 their drug is the worst in its class, companies will
4 not be required to disclose that.
5 FDA is charged with protecting consumers and
6 patients. Loosening restrictions on off-label
7 marketing abdicates that responsibility. Industry's
8 claims will always be misleading because the goal
9 isn't truth. The goal is selling as much of a product
10 as possible.
11 Third, allowing off-label promotion will
12 improve public health. This argument is based on the
13 claim that receiving more product information more
14 quickly helps public health. Again, what proof has
15 been provided that backs up this claim? I've heard
16 the phrase "real-world evidence" many times, but none
17 of the benefits of this so-called evidence has been
18 cited.
19 Here is some real world evidence. Americans
20 experience 2.1 million serious injuries from adverse
21 drug reactions every year. An estimated 128,000
22 people die from an adverse drug reaction. This
1 matches stroke as the fourth-leading cause of death.
2 People are asking for the FDA not to delay
3 drugs from reaching patients, but I have not heard
4 anyone ask for drugs to be taken off the market more
5 quickly, even after they have been proven to harm
6 patients. Taking bad products off the market would
7 improve public health.
8 Currently, industry chooses which studies to
9 fund, which studies to publish, and how to present
10 those studies. They do not do studies that compare
11 their drugs to competitors. They do not do studies on
12 long-term harms. As Dr. Califf said yesterday, in a
13 marriage, it is what you don't say that is the
14 problem. What industry chooses not to talk about is
15 harms.
16 Yesterday I did not hear any of the industry
17 representatives or the groups funded by industries
18 speak about the risk of drugs or devices, or they
19 actively dodged the question when directly asked.
20 Allowing off-label promotion of any kind will have a
21 cascading negative affect for drug regulation,
22 clinical practice, and public health.
1 The FDA is the protection for physicians and
2 patients. We have heard that regulation is impeding
3 the stream of knowledge. This is not a stream, but an
4 impending tsunami of bad, unreliable information. The
5 FDA is the dam protecting patients. I stand behind
6 the FDA in upholding the current regulation of not
7 allowing off-label promotion.
8 I implore you today to set forth the most
9 rigorous restrictions possible against off-label
10 promotion. Please do not adopt the standards set
11 forth by PhRMA and Bio in their guidelines. Please do
12 not let companies promote products off-label to
13 healthcare providers, payers, or to patients.
14 Thank you very much.
15 And I will answer questions after Dr. Fugh-
16 Berman speaks.
17 Thank you.
18 DR. FUGH-BERMAN: Good afternoon, and thank
19 you for having this hearing on a very important
20 subject. I'm a physician and associate professor in
21 the Department of Pharmacology and Physiology and the
22 Department of Family Medicine at Georgetown and direct
1 PharmedOut. And one of the things that PharmedOut
2 does is expose covert pharmaceutical marketing
3 practices.
4 I'm also a paid expert witness at the
5 request of plaintiffs in litigation regarding
6 pharmaceutical marketing practices.
7 My testimony's going to focus on three
8 points -- off-label promotion undermines public
9 health, industry education is always misleading, and
10 trust in pharma goes against the evidence.
11 Most off-label use is unsupported by
12 evidence. Studies shows that between 73 and 81
13 percent of off-label prescriptions are for conditions
14 for which there is little or no -- for which there is
15 no -- little or no scientific support for efficacy.
16 We know that promotion increases prescriptions. If
17 the FDA loosens restrictions on off-label promotion,
18 irrational prescriptions and associated harms will --
19 can be expected to skyrocket.
20 Off-label use increases adverse events. Dr.
21 Wolfe cited a Canadian study yesterday that found that
22 off -- that adverse effects were higher for off-label
1 use than on-label use. And for uses that had no
2 scientific support, it was even higher. There are
3 also studies that show that in children off-label use
4 of drugs is also associated with an increased number
5 and increased severity of adverse effects.
6 Off-label use of menopausal hormone therapy
7 caused breast cancer, heart attacks, strokes,
8 dementia, and increased deaths from lung cancer. Off-
9 label use of anti-psychotics in elders increases the
10 risk of cognitive declines, strokes, diabetes, hip
11 fracture, hypothermia, and pneumonia and death.
12 And the off-label combination fen-phen
13 caused valvular heart disease. Off-label use of the
14 analgesic Duract bromfenac caused liver failure. More
15 than half of prescriptions for fluoroquinolones, which
16 cause tendon rupture, are off-label as well.
17 Despite a black box warning and a lot of
18 adverse publicity between 2006 and 2010, more than 40
19 percent of prescriptions for erythropoiesis
20 stimulating agents were also for unsupported off-label
21 uses. ESAs increase the risk of death, serious
22 cardiovascular complications in renal patients, and
1 tumor progression in patients with cancer.
2 We know that most off-label prescriptions
3 are written for conditions that have no scientific
4 basis for their use. Well, harms are always going to
5 outweigh benefits when there are no benefits.
6 There's no overlap between off-label uses
7 supported by pharma and actual scientific support.
8 There is certainly some off-label uses that are
9 supported by multiple, randomized controlled trials.
10 For example, RCTs support the use of
11 bevacizumab or Avastin, as was mentioned by Jack
12 Mitchell earlier, in age-related macular degeneration;
13 Misoprostol in miscarriages or elective abortion;
14 Minocycline and doxycycline for rheumatoid arthritis.
15 Not one of these proven effective off-label uses has
16 been promoted by pharmaceutical companies.
17 In fact, pharmaceutical companies have
18 battled off-label uses that threaten profits.
19 Manufacturers of misoprostol refuse to apply for an
20 indication for Misoprostol for miscarriage or
21 abortion. Genentech fought off-label use of Avastin
22 in order to protect sales of its far more profitable
1 Lucentis. The company actually argued that no trial
2 supported the use of Avastin in macular degeneration,
3 but Genentech refused to do those trials.
4 It was great. Ophthalmologists fought back.
5 They knew that both of the products worked well. They
6 lobbied the national -- they started a registry. They
7 lobbied the National Eye Institute to fund trials.
8 There were eight trials that were done comparing the
9 two drugs. Not one dime of industry money went into
10 those trials, and they did show that the two drugs
11 were equivalent.
12 And tellingly, physicians who receive gifts
13 from pharma, ophthalmologists who receive gifts or
14 payments from pharma, are far more likely to use on-
15 label versions of bevacizumab. And the ones that
16 don't take money use the far cheaper and equally
17 effective off-label uses. So there are proven uses.
18 But off-label uses that have scientific
19 support will not remain a secret, even when industry
20 wants them to remain a secret. Off-label uses with no
21 scientific support are the ones that industry will
22 push because industry supports only that which
1 supports industry.
2 Industry education is always misleading. In
3 fact, pharma's most effective tool for selling
4 mediocre or dangerous drugs is education. Industries
5 already infiltrated every source of information that
6 prescribers rely on. Successful strategies include
7 ghost-written and ghost-managed articles that convey
8 marketing messages in the medical literature and also
9 consumer publications. Ghost writing has been
10 documented for Prempro, Lexapro, Paxil, Fen-phen,
11 Neurontin, Vioxx and Zoloft, among others.
12 Certainly, information on unapproved uses is
13 available from journals, professional societies,
14 compendia, and electronic communication platform, but
15 industry actively influences all of these. So it's no
16 surprise that off-label uses of branded drugs are
17 emphasized.
18 One analysis of compendia found that nearly
19 three-fold as many off-label uses were recommended for
20 atypical branded antipsychotics than for generically
21 available typical antipsychotics. It's also no
22 surprise that physicians are unaware of which
1 indications for a drug are on-label or off-label.
2 There -- the docs who -- and what -- the
3 study that looked at this found that the doctors who
4 used drugs off-label were less likely to know that the
5 drugs that they used were not for label -- were more
6 likely to believe that they were using the drug for
7 labeled indications, and they were not. So doctors do
8 not know the difference between on-label and off-label
9 use -- what's on-label and what's off-label. So it's
10 not just patients. It's doctors.
11 The fact that industry-driven avenues of
12 communication already exist is not justification for
13 dropping all barriers. Industry control of
14 information should be grounds for consternation, not
15 capitulation.
16 FDA needs to regulate off-label promotion
17 more, not less, including regulating industry-funded
18 CME as promotion. All industry-funded CME is a vessel
19 for marketing messages. We have demonstrated this in
20 published articles on continuing medical education,
21 how it was used to sell hypoactive sexual desire
22 disorder. We have several other papers in progress on
1 this.
2 Neither the ACCME, the accrediting body, nor
3 CME accreditors are capable of identifying these
4 marketing messages, especially when you consider that
5 marketing for a drug starts 7 to 10 years before a
6 drug actually comes on the market. They're not
7 marketing the drug specifically. They are marketing
8 the disease. Their pre-launch marketing messages are
9 different than post-launch marketing messages.
10 Three-quarters of the continuing medical
11 education that physicians see is commercially
12 supported.
13 Ghost-managed articles in the medical
14 literature should also be considered -- articles in
15 the medical literature should also be considered
16 promotion. This is a quote from an industry article.
17 "Peer-reviewed publications offer pharma companies
18 shelter from often stormy regulatory waters. FDA
19 views published articles as protected commercial
20 speech, so doesn't regulate their content."
21 Industry-funded studies exaggerate benefits
22 and downplay harms. A systematic review of 37 studies
1 found a significant association between industry
2 sponsorship and pro-industry conclusions.
3 Industry preferentially publishes positive
4 studies and buries negative studies. The medical
5 literature is highly influenced by the pharmaceutical
6 industry.
7 Industry insiders who work with PharmedOut
8 tell us that companies get a drug approved through a
9 small trial for an unusual or rare disease, while they
10 have an illegal off-label campaign for a large
11 population already planned. Ghost writing and ghost
12 management allows companies to ensure that their
13 marketing goals are supported in the -- in papers, and
14 that messages disadvantageous to their goals are
15 absent.
16 How things are written or how things are
17 spoken makes a difference. At this hearing for
18 example, there are several phrases used by industry
19 that we've heard over and over again by industry
20 vendors and industry-funded groups.
21 But what if we reframed some of those
22 phrases? For example, unmet medical needs could be
1 translated as untapped profit opportunity. Timely
2 means premature. Emerging evidence means hope. Best
3 evidence available equals rumor. And real world
4 evidence means non-evidence based.
5 Industry has long used third parties
6 including professional societies, consumer advocacy
7 groups and paid opinion leaders to promote products
8 off-label. But these are only a deterrent for the
9 worst behaviors. Despite repeated promises and
10 repeated finds, companies have not changed their
11 practices at all.
12 There's reasons that companies don't seek
13 labeled indications. They aren't willing to do the
14 trials because they're afraid the benefits of the drug
15 won't outweigh the risks, or they already did the
16 trial, their drug was ineffective, or too dangerous to
17 seek a labeled indication. What is to prevent a
18 company from promoting a drug off-label for a
19 condition for which the company already knows the drug
20 is ineffective?
21 There's two ways to market a drug in
22 industry -- performing the studies necessary for a
1 labeled indication or spreading rumors of benefits.
2 The -- that's called the publication strategy, which
3 systematically places articles in the medical
4 literature, and that's been very effective at both
5 selling drugs and harming patients.
6 Pharmaceutical marketing has already
7 distorted the discourse on off-label uses and
8 encouraged the unmonitored, potentially dangerous use
9 of drugs by patients who cannot benefit or for whom
10 the risks and benefits are unknown. You've heard from
11 industry that RCT's, randomized control trials, don’t
12 represent real world evidence. RCTs represent the
13 only reliable scientific evidence of benefit.
14 Observational studies cannot prove benefit.
15 Also, not a single person has mentioned the
16 placebo effect, or non-specific effects. Industry
17 hates non-specific effects because most of their drugs
18 don't actually do better than placebos. That's why
19 comparative control trials are done, to establish
20 whether a therapy is superior to placebo or superior
21 to a proven competitor.
22 Arthroscopic surgery helps knee
1 osteoarthritis. So does sham surgery. Many
2 observational studies mislead us into thinking
3 menopausal hormone therapy prevented cardiovascular
4 disease. RCTs showed us that the therapy doesn’t
5 prevent cardiovascular disease. It causes it, along
6 with strokes and breast cancers.
7 In the 19th century, physicians gave
8 dangerous and ineffective drugs to patients with no
9 regulation at all. Today, drugs have to be shown to
10 be safe and effective for specific indications.
11 Nothing prevents industry from submitting
12 articles to medical journals or discussing studies at
13 medical or scientific conferences. Discussion and
14 debate and the honing of ideas is what science is all
15 about.
16 But instead of risking public discussion,
17 peer review, or regulatory review of inadequate
18 studies, industry is asking the FDA's permission to
19 manipulate individuals behind closed doors into
20 believing questionable efficacy claims that would not
21 survive regulatory review. Industry wants to topple
22 the last, best barrier to promoting any therapy for
1 any condition.
2 Unapproved uses are sometimes necessary, but
3 they should always be undertaken with care and caution
4 because patients are being subjected to an experiment.
5 Valuable off-label uses should be discussed by
6 unbiased researchers in bona fide medical journals.
7 Truly useful off-label uses will not remain
8 a secret. Pharma wants to educate physicians and
9 payers through rumors rather than RCTs. Stand fast,
10 FDA. Promising therapies should be tested in clinical
11 trials and submitted for regulatory approval.
12 MS. KUX: Thank you very much to both of
13 you.
14 Any questions from the panelists?
15 Tom?
16 MR. ABRAMS: You outlined your concerns
17 about industry's dissemination of off-label
18 information. And you mentioned that off-label use
19 having adequate evidence is already known to
20 healthcare professionals, or there's ways of
21 healthcare professionals getting this information.
22 I'd like to explore that point a little bit
1 because a point that was brought up by some speakers
2 yesterday was industry can be a beneficial force in
3 this, getting data that a company may have, or helping
4 to get information to the healthcare professionals
5 that may be most relevant given the volume. There's
6 just so much volume out there it's hard to filter
7 through. I was wondering if you could comment on
8 those two -- points that were brought up by speakers
9 yesterday.
10 DR. FUGH-BERMAN: So the reason that there's
11 so much volume of information is that industry dumps a
12 lot of junk into the medical literature and really
13 fogs the environment in terms of information. We
14 don't need more information. We need good
15 information. We need unbiased information. And
16 unfortunately, most sources of information are
17 actually very tainted by industry.
18 There are already venues for new uses to be
19 discussed. They should be discussed in scientific
20 meetings. They can be discussed in medical journals.
21 They are trying to get -- industry is trying
22 to get around this to change the conversations into
1 one-on-one conversations that really can't be
2 monitored or regulated at all. And there are already
3 good and self-corrective venues for having these
4 discussions, and that's where it should be.
5 These discussions should be public. If it's
6 really scientific exchange, then it should be done in
7 a scientific format. And if they really have great
8 evidence of -- if they really have great evidence from
9 randomized control trials, then they should be
10 applying for an indication and a label change.
11 DR. KUX: Other questions?
12 Thank you.
13 MS. DAVIS: So just on that last point when
14 you were saying if they have great evidence they
15 should apply for a labeling change. You mentioned a
16 few situations where because the drug is no longer
17 single-source, or maybe it's just gone to generic,
18 that maybe there wouldn't be the incentives there to
19 apply for a labeling change. Do you have thoughts on
20 how the information should be disseminated in those
21 situations to make sure people are aware it?
22 DR. FUGH-BERMAN: Well, when they're proven
1 -- when there are proven uses of a generically
2 available information, I mean I'd like to say it's
3 never kept a secret. I will -- you know, I will say
4 that, in fact, often physicians don't know about the
5 data that are available that are done not by companies
6 because they don't -- they can't make a commercial
7 gain out of it, but of studies that are done by other
8 researchers.
9 So there does need to be a way to get that
10 information out to people, but it should be by
11 unbiased sources and not through pharmaceutical
12 companies. They are not capable of providing unbiased
13 sources.
14 MS. HOGENMILLER: And some examples of that
15 would be publically funded trials or publically funded
16 education for physicians and pharmacists or unbiased
17 newsletters. So there is information available.
18 DR. FUGH-BERMAN: Yeah. Great point.
19 Unbiased continuing medical education from the DC
20 Center for Rational Prescribing, for example.
21 MS. HOGENMILLER: Thank you.
22 MS. KUX: Our next speaker is Dr. Doyle
1 Stulting from the American Society of Cataract and
2 Refractive Surgery and the Alliance of Specialty
3 Medicine.
4 DR. STULTING: Good afternoon. My name is
5 Doyle Stulting. I'm testifying on behalf of the
6 American Society for Cataract and Refractive Surgery
7 and member organizations of the Alliance of Specialty
8 Medicine, a coalition of medical subspecialty
9 societies representing 100,000 physicians and
10 surgeons.
11 I have an M.D. and Ph. degree and past
12 president of the American Society for Cataract and
13 Refractive Surgery, founder of the Stulting Research
14 Center in Atlanta, Georgia, and Professor Emeritus at
15 Emory University. I've authored over 230 peer-
16 reviewed publications, edited the General Cornea for
17 10 years, was a member of the ophthalmic devices panel
18 for 10 years, and received the Food and Drug
19 Administration Citation for Excellence in ‘98.
20 This diverse exposure and unique training
21 gives me a unique perspective from which to comment on
22 today's topic. We believe the FDA's current
1 regulations unnecessarily currently interfere with the
2 dissemination of scientifically valid information
3 between healthcare professionals and manufacturers.
4 This interference ultimately denies
5 physicians access to vital current real world
6 experiences and adversely affects healthcare outcomes.
7 I and my colleagues in the Alliances Specialty
8 Medicine believe physicians have the ability to assess
9 and interpret clinical data appropriately and that
10 access to those data will result in measurable
11 benefits to patients to improve outcomes and new
12 cures.
13 Reasonable restrictions on the
14 communications would include notification that a
15 referenced indication is off-label as well as a
16 requirement that communications be truthful, balanced,
17 and not misleading.
18 Off-label use of drugs and devices is
19 actually very common in my practice and, indeed, the
20 practice of medicine. The off-label use is commonly
21 found in medical textbooks. In fact, failure to
22 prescribe medications or use devices off-label would
1 quickly place many of us, including me, at risk for a
2 malpractice lawsuit. Routine risk of -- routine use
3 of antibiotics after surgery, like cataract surgery,
4 is off-label. The use of antibiotics to treat severe
5 corneal life -- sight-threatening infections is also
6 off-label.
7 Would you like to have surgery without an
8 antibiotic coverage? Would you like to come into my
9 office with a sight-threatening corneal infection and
10 for me to have to tell you that I can't use a drug on-
11 label to treat you?
12 For certain populations such as children,
13 pregnant women, cancer patients, and patients with
14 rare diseases, FDA-sponsored clinical trials are not
15 feasible or too costly for any manufacturer to
16 undertake. This is especially true for patients with
17 rare diseases and those with conditions that may
18 exclude them from FDA clinical trials. For patients
19 such as these, off-label use of medical products is
20 our only option, one that may even be vision or
21 lifesaving.
22 Clinical trials designed for FDA approval
1 are rigid, well designed, monitored, appropriately
2 analyzed, and reliable. Obtaining FDA approval for a
3 particular indication is, however, slow, cumbersome,
4 and incredibly expensive.
5 In addition, the information upon which
6 approval is based often does not reflect the full
7 range of appropriate indications. It may not
8 accurately list all warnings and contraindications
9 either.
10 Data often come to light after approval that
11 expands the indications, supports modifications of
12 dosage, or even limits the indications for a
13 treatment. The quality of this information may not
14 meet the so-called gold standard of a randomized
15 double-blind prospective controlled clinical trial.
16 But my colleagues and I are capable of evaluation of
17 the reliability of scientific communications, and we
18 can appropriately apply this information to our
19 clinical practice.
20 The label on medical products represents the
21 results of clinical trials that are designed by the
22 manufacturer to obtain FDA approval in the most
1 certain and most expeditious way possible. These
2 motivations are not the same as our motivation to
3 provide the best medical care to our patients.
4 Clinical trial results, therefore, often do
5 not represent all appropriate indications for a
6 product. The product label not only reflects limited
7 clinical data influenced by business considerations,
8 but also represents a summary of knowledge that is
9 frozen in time.
10 Invariably, practitioners become aware of
11 new indications, dosages, complications, and cautions
12 about the use of medical products after the label is
13 created. And this off-label information is often
14 vital to the health of our patients. There's no
15 reason for our use of medical products to be bound by
16 outdated information.
17 Current FDA regulations impede our quest for
18 scientific knowledge and our ability to care for our
19 patients by interfering with the flow of information
20 from device and drug manufacturers to practitioners
21 and even among practitioners themselves. In reality,
22 many patients are harmed when treatment options are
1 taken off the table for lack of information.
2 Rising public awareness of off-label use,
3 and the stigma of FDA's regulations have attached to
4 it, even interferes with the doctor-patient
5 relationship. Not infrequently, my patients return
6 after an initial consultation having decided not to
7 take a prescribed medication on their own because of
8 outdated or poorly stated information that they read
9 on the product label.
10 Not only do they fail to comply with
11 appropriate effective treatment, but they also
12 question the clinical skills that their doctor who has
13 prescribed a medication based on valid scientific
14 evidence that might be against that on the label.
15 Before regulatory hurdles were erected, it
16 was not at all uncommon for a representative of a
17 manufacturing firm to be the first to call our
18 attention to important new information about off-label
19 use of a medical product. We had the opportunity to
20 evaluate this information critically before using it
21 to guide patient care. Now this kind of information
22 may go unnoticed by busy practitioners to the
1 detriment of our patients' health.
2 Provided that there is prominent disclosure
3 that the FDA has not approved a product for a certain
4 indication truthful, unbiased communications of data
5 should not be impaired. We urge the FDA to open the
6 lines of communication between manufacturers and
7 practitioners to help facilitate the development and
8 dissemination of accurate information about off-label
9 use. This will allow providers to make better
10 decisions for their patients, improve medical
11 outcomes, minimize the lack of patient compliance
12 caused by outdated label information, and improve the
13 good relationship that we strive to maintain with our
14 patients.
15 In fact, we believe it would be appropriate
16 to add a paragraph to all drug and device labels
17 stating something like the following. "The
18 indications, contraindications, warnings, cautions,
19 and other information contained in this label are
20 based on data generated by the clinical trial used to
21 obtain approval for marketing this product in the
22 United States. After marketing approval, additional
1 scientifically valid data may become available to
2 justify new usage, dosages, contraindications, or
3 other modifications of the information contained
4 herein. Your physician will take this information
5 into consideration when prescribing this product and
6 can discuss it with you."
7 This, or similar wording, would empower
8 physicians to utilize approved products for the
9 benefit of their patients on the basis of current
10 scientifically valid data without the stigma and
11 hampered professional communication created by
12 existing restrictions on off-label discussions.
13 Thank you for the opportunity to speak to
14 you today.
15 MS. KUX: Thank you very much.
16 Any questions, Panelists?
17 Lauren?
18 MS. SILVIS: You mentioned scientifically
19 valid data, and I'm wondering if you think that that's
20 something that needs to be further defined or a
21 concept that would be left up to physicians' judgment
22 with the disclaimer that for devices we do have a
1 regulation defining valid scientific evidence. But I
2 was just wondering if you thought it was something
3 that needed further define -- definition?
4 DR. STULTING: We as physicians in the
5 sciences understand the development of uncontroversial
6 scientific data. It begins with an observation,
7 perhaps the case report, a limited series, and then
8 progresses to a prospective controlled clinical trial.
9 All along the way, we use the information
10 that's available to us, tempered with the knowledge of
11 where it came from and how it was derived. We're
12 skeptical about a case report and sure about a
13 randomized controlled clinical trial.
14 But along the way, we still have to use that
15 information to the best of our ability for the
16 benefits of our patients. And we as physicians and
17 scientists hopefully are trained to do that. We can't
18 wait for a randomized controlled clinical trial for
19 everything we do. It just won't work. It's not
20 practical. It's the not the way we practice medicine,
21 unfortunately, in this country.
22 We have a quest for information, just like
1 many of the other speakers today. But we also have to
2 have that quest tempered by the consideration of who's
3 going to pay for it, how are we gonna generate it, and
4 what are we gonna do in the mid-time -- in the
5 meantime.
6 The unfortunate incidences of significant
7 complications from drugs and devices used off-label
8 have to be balanced by the benefit to patients who are
9 getting off-label uses and are doing well. Those
10 people are not at the meeting today.
11 MS. KUX: Additional questions?
12 DR. SHERMAN: Just one point of
13 clarification. You mentioned that you thought that
14 FDA was interfering with communication between
15 practitioners and that we were interfering with the
16 communication between the practitioner and the
17 patient. And if you could just expand a little bit
18 on, since we do not regulate the practice of medicine,
19 what you feel is creating those inhibitions.
20 DR. STULTING: Yeah. The designation of
21 off-label discussions with the -- let's see. You guys
22 published a guidance document for comment I believe in
1 January of 2011 or somewhere around in there. It was
2 about professional communications. It went out for
3 comment, and I haven't seen a final document.
4 However, most of the pharmaceutical and
5 device companies have implemented the guidance in
6 there, and it says if I am a speaker, for example, at
7 an industry-sponsored event, I am assumed to be an
8 employee of that company. And if someone in the
9 audience says, oh, what do you find when you use
10 cyclosporine off-label for the treatment of vernal
11 conjunctivitis, well, that's in the literature. But I
12 can't communicate and answer that question to the
13 group as a result of that guidance documents and the
14 off-label designation.
15 So communication between professionals is
16 being throttled by the off-label designation. And if
17 the paragraph that I suggested is off -- is added to
18 the label, then that will disappear to our benefit.
19 DR. SHERMAN: Maybe in your comments if you
20 could -- if you have any data or if you've done any
21 testing of the -- what's the right word -- the
22 communication specialist -- of the impact of such a
1 paragraph, that would be very helpful to us.
2 DR. STULTING: I'm sorry. I didn't catch
3 the question.
4 DR. SHERMAN: I'm blocking on the word.
5 Consumer test -- but there's another word -- when you
6 use a communication vehicle and you test it and you
7 see what the results of the communication are. Thank
8 you.
9 Perception. In other words, has there been
10 testing of the perception of a paragraph such as that
11 one?
12 DR. STULTING: Testing of what would happen
13 if the paragraph will be there?
14 DR. SHERMAN: Yeah.
15 DR. STULTING: Well, the effect will be that
16 there is -- it recognizes the fact that information
17 becomes available after the label is generated.
18 So in my view, it recognizes the fact that
19 we ought to be able to talk about those things without
20 them considered -- being considered off-label because
21 the label recognizes the fact that new data may
22 supplement or, indeed, replace what's on the label.
1 Did I answer the question?
2 DR. SHERMAN: Thank you.
3 MS. KUX: Thank you very much.
4 Hi. Our next speaker is Ms. Katherine
5 McGahey.
6 MS. MCGAHEY: Good afternoon. My name is
7 Katherine McGahey, and I'm here on behalf of The 1
8 Million 4 Anna Foundation, whose mission is to fight
9 Ewing sarcoma today, tomorrow, and until it's gone.
10 The foundation was formed by the Basso family,
11 following the loss of their beloved Anna at the age of
12 18 to Ewing sarcoma.
13 I have a Bachelor of Science degree in
14 physics with training in biology, physiology,
15 genetics, and chemistry. I am also an attorney for
16 the law firm of Strasburger & Price, headquartered in
17 Dallas, Texas. I have read and written extensively on
18 the First Amendment issues that have been discussed
19 here over the past two days. That is not what I'm
20 here to talk to you about.
21 My co-presenter, Ms. Lauren Brown, was not
22 able to attend today. First, I would like to thank
1 you for allowing me to also speak on her behalf.
2 Lauren is 22 years old and she's a senior at
3 Texas A&M University. She's pursuing two degrees, one
4 in international commerce, and the other in
5 statistics. And she hopes for a career in public
6 service. Lauren has been battling Ewing sarcoma since
7 she was 15 years old. Unfortunately, her disease has
8 recently taken a bad turn. Her pain is currently not
9 well managed, and that's why she was not able to
10 travel here today.
11 We wanted to address you on behalf of the
12 foundation and on behalf of the pediatric cancer
13 community at large to place one key piece of
14 information at the forefront of your minds. Whenever
15 you think about unapproved use of an approved drug,
16 you must think about pediatric cancer because that is
17 the world in which our children live and,
18 unfortunately, die.
19 Ewing sarcoma is one of 114
20 subclassifications under ICCC of pediatric cancer. It
21 is considered rare like all pediatric cancers. This
22 year, there will be somewhere between 300 and 400
1 children in this country diagnosed with Ewing sarcoma.
2 But pediatric cancer as a whole is not rare.
3 When you take all 114 classifications together, 43
4 children a day on average are diagnosed with cancer.
5 That's 1 in 285 children a year. When it comes to
6 disease, it is the leading cause of death in children.
7 The two days that we have the luxury of standing here
8 and airing our very differing opinions on the subject
9 of communication on off-label use of approved drugs,
10 between 10 and 14 children will die.
11 Since 1980, less than 10 drugs have been
12 approved for treatment in pediatric cancer and only
13 three for children in the first instance -- two in the
14 ALL and one in high-risk neuroblastoma. What this
15 means is from day one our children are treated off-
16 label. For those who advocate that no off-label use
17 should be allowed, you would be condemning our
18 children to death.
19 When a child is diagnosed with pediatric
20 cancer, if they are fortunate, they are either at or
21 they are quickly referred to a facility that is a
22 member of the Children's Oncology Group where they
1 will be treated under a standard COG protocol. But
2 COG protocols are still off-label. Ninety percent of
3 children are treated at a Children's Oncology Group
4 facility, and those protocols are proprietary, which
5 means the other 10 percent do not have access to that
6 information.
7 When the established COG protocol fails, a
8 child might be kept on chemotherapy or some other
9 treatment just to extend time. But the parent is told
10 there is nothing else the doctor can do, and the child
11 is sent home to die.
12 My daughter has been sent home to die three
13 times. The first time, she was a senior in high
14 school and we were told it was unlikely she would
15 graduate. We learned of a radiation technology -- a
16 radiation technique that was considered experimental.
17 We battled tumor board for two months because there
18 was no published data that showed that technique was
19 safe or effective in Ewing sarcoma. But it bought her
20 precious time. Today, that technique is part of an
21 established COG protocol for treatment of metastatic
22 Ewing sarcoma.
1 The second time she was sent home we pursued
2 clinical trials. I mean no disrespect to the
3 phenomenal oncologists who treat our children, but
4 they by and large do not have the time or the
5 expertise to research alternative treatments and
6 clinical trials for their patients. For the most
7 part, parents and caregivers are on their own.
8 With my educational background and the
9 extensive resources available to me, I found that task
10 daunting. The average parent, it is impossible. But
11 I would like for a moment for any parent in the room
12 to just stop and think what you would do if you were
13 told that your child is going to die.
14 For those of you who are not parents, I can
15 assure you, each of those parents are thinking they
16 would move heaven and earth to find something,
17 anything that might help their child. They'd turn to
18 the internet, websites, social media, list serves.
19 There are hundreds, if not thousands, of
20 groups out there dedicated to individual pediatric
21 cancers populated by warriors, survivors, parents,
22 caregivers -- excuse me. They share information.
1 Have you read this article? Have you been to this
2 website? Has anyone heard about this clinical trial?
3 What happens when your child took this? When happens
4 when you did that?
5 But these groups exist in a vacuum that has
6 been unintentionally created by FDA regulation because
7 our children live in an off-label world. The absence
8 of information creates that vacuum, and unfortunately,
9 because nature abhors a vacuum, all kinds of
10 misinformation and snake oil propagates.
11 Parents are told feed your child six quarts
12 of mushroom water a day. They believe that taking
13 proton pump inhibitors will cure cancer. I know a
14 father who took his child to Japan to get Coley's
15 toxin, which for those of you who are not aware is a
16 near-lethal combination of bacteria. My personal
17 favorite is dose your child with baking soda because,
18 of course, the highly alkaline baking soda will
19 counteract the acidic microenvironment in which tumor
20 cells live.
21 The absence of information is what fuels
22 this type of nonsense and harms our children. Despite
1 yesterday's debate, I will put to you no one has died
2 from too much truthful, non-misleading information.
3 We need the free-flow of information. We need
4 transparency. Transparency enables manufacturers to
5 work collaboratively with practitioners, patients, and
6 caregivers to improve treatment. But the information
7 must be able to flow both ways.
8 And under specific request, manufacturers
9 should be required to make disclosures when
10 practitioners, patients or caregivers need information
11 regarding the off-label use of approved drugs. There
12 has to be a mechanism by which those requests can be
13 made, and the information required to be disclosed.
14 It needs to be certified.
15 It needs to be released in a way that
16 protects the integrity of the data, and it must
17 include the appropriate disclosures that indicate the
18 relative reliability of that data because we know we
19 are asking for information that has varying degrees of
20 reliability. But while it's an interesting academic
21 prospect to debate what information is reliable enough
22 to disclose, these children do not have that luxury,
1 which brings me to the third time my daughter was sent
2 home to die, September.
3 My daughter has tumors in her lungs, and she
4 has tumors growing in the pleura of her right lung,
5 which any of you with medical experience will know is
6 incredibly painful. She also has a tumor on her
7 pericardium and a fairly significant pericardial
8 effusion.
9 She's pretty sick. And in September, the
10 doctor said, she probably only had a couple weeks. My
11 daughter had heard about a combination of drugs that
12 was taken by a Ewing sarcoma patient in another
13 country. In talking with this patient's mother, her
14 daughter was in liver failure before she began taking
15 these drugs -- liver failure due to the excessive
16 chemotherapy that she had received. After her death,
17 her mother requested an autopsy which showed that,
18 following treatment with this combination, all of her
19 cancer was necrotic. She died of liver failure.
20 My daughter has no more options, and she
21 cannot enroll in another clinical trial. So she asked
22 her oncologist to place her on this combination. Both
1 drugs are FDA-approved, but for other indications.
2 The combination is currently being tested in clinical
3 trial, but none of the data has been published yet.
4 Her doctor agreed.
5 Less than a week after she began treatment,
6 her pain began to subside. Four weeks into treatment
7 and scans showed some of her tumors were reducing in
8 size. Others were inconclusive, but they were not
9 progressing at the rate that they were prior to this
10 treatment.
11 Unfortunately, however, her heart function
12 has also declined. She had problematic
13 echocardiograms prior to starting this treatment,
14 which we presume was due to the pericardial tumor and
15 the effusion. But one of the drugs potentially causes
16 a particular heart defect, not the one that we are
17 seeing, but her doctor is concerned is it possible
18 this drug could be contributing or causing the heart
19 problems that they're seeing.
20 He decided to take her off the medication
21 for one week to see if anything improved. It did not.
22 So now he is in the position. He cannot get
1 additional information because she is being treated
2 off-label. My daughter has to make the horrendous
3 decision. Does she go back on this combination, which
4 is potentially reducing her tumors? And if she does,
5 does she risk almost immediate heart failure?
6 Promotion and communication are not the same
7 thing. To say that a drug company providing
8 information to a practitioner, a patient, or a
9 caregiver about the off-label use of an approved drug
10 so that the patient can make an informed decision and
11 a drug company advertising in a magazine off-label use
12 of a drug, to say that these two things are the same
13 is callous and insulting.
14 These children need access to this
15 information. Much of it is not going to be cleared
16 through clinical trial because these children are on
17 the bleeding edge of the current research. To use the
18 conflation of promotion and communication to advocate
19 for the reduction in the flow of information places
20 the most vulnerable members of our society at risk.
21 On behalf of the 1 Million 4 Anna
22 Foundation, I would like to thank the FDA for
1 soliciting our input. We in the cancer community, the
2 pediatric cancer community, want to assist you. This
3 is a very important first step, and we want to help
4 you move this forward. We only ask that you tell us
5 how we can do that.
6 But we want to be clear that we are talking
7 about the flow of information, not off-label use.
8 Off-label use is what doctors do. We're talking about
9 information, medical and scientific information of
10 varying degrees of reliability but, nonetheless,
11 vital. And when you impede the flow of that
12 information, our children die.
13 Thank you.
14 MS. KUX: Thank you very much.
15 MS. DAVIS: Thank you for your presentation.
16 So you emphasized the importance of having
17 access to all relevant information, but at the same
18 time that you need information where -- so you can
19 assess the reliability of that information.
20 Can you talk a little more either today, or
21 if you want to follow-up in any written comments,
22 about especially from the caregiver and patient
1 perspective where you may not have background and
2 training in clinical trial design or statistical
3 analysis or, you know, a degree in a health-related
4 field, but you're coming up to speed on all these
5 issues and you’re trying to assess the reliability,
6 what kind of information is most relevant and how it
7 can be presented in a way to make sure that patients
8 and caregivers can understand it, too?
9 MS. MCGAHEY: When you ask what kind of
10 information, do you mean what type of disclosure
11 should be included with the information or what
12 information we should have access to?
13 MS. DAVIS: I think it's more the first
14 thing because what I heard you saying -- and correct
15 me if I'm wrong -- is that you don't really have the
16 luxury of discarding any information. So it's
17 important that you have additional information so you
18 can understand the relevance and kind of reliability
19 of different sources of information.
20 MS. MCGAHEY: And as an example -- for
21 example, with the drug that my daughter is on, being
22 able to have access to what has been reported in any
1 type of heart issues, there we could evaluate the
2 information by understanding where it came from. In a
3 clinical trial we have the labeling information, but
4 that's not in any way related to the specific issue
5 that we're seeing.
6 But we know that in some instances, for
7 example, because the combination is currently under
8 test, there may be data that is currently available in
9 that clinical trial but has not yet been published.
10 We would understand if we were told we have this
11 information and it was derived in a clinical trial
12 that is currently ongoing. For example, if we know
13 where the data comes from, then we can assess its
14 reliability.
15 MS. DAVIS: Thank you.
16 MS. KUX: Other questions?
17 Rachel?
18 DR. SHERMAN: Thank you for your comments.
19 I'm curious and I also -- if the earlier speakers on
20 the panel could address this as well in terms of the
21 community.
22 So do you feel that the pediatric cancer
1 community being very small and tight-knit that there
2 are approaches that might work in that community that
3 perhaps wouldn't work in a larger less closely knit
4 community, if you will -- in other words, the intended
5 population for the communication?
6 MS. MCGAHEY: I would say specifically
7 within the pediatric cancer community, yes, it is very
8 close-knit because there is so little information on
9 the treatment of our children. By nature, we have to
10 band together. We have to share with each other. If
11 information -- for example, if information about a
12 particular drug is disclosed to one particular
13 patient, I think we can pretty much guarantee that
14 information's going to get propagated to other members
15 of that subset of cancer community.
16 That's why I think it's important that any
17 information that is disclosed, there has to be a
18 mechanism by which some form of certification can be
19 attached to it, so if the -- if that information is
20 further disseminated -- where it came from, something
21 that identifies its source, and its relative
22 reliability. Otherwise, information can be picked up
1 and misused.
2 So I do believe regulation needs to specify
3 a way in which that source and reliability can always
4 remain attached to the information, but it will be
5 disseminated.
6 I do believe other communities may be
7 different. I have wondered if it is a function of how
8 tight-knit the community is or if it is a function of
9 how life threatening the disease in question is. I
10 believe that for life-threatening diseases the
11 imperative is much greater, but I would not go so far
12 as to say it should be restricted to only life-
13 threatening diseases. The lupus example yesterday is
14 a perfect example of that.
15 DR. SHERMAN: That was very helpful. Thank
16 you.
17 And one additional thought, and again for
18 the earlier speakers, could you say a few words about
19 the payer community -- we heard from them yesterday --
20 either based on your own personal experience, the
21 foundations’ experience in terms of, if you will, the
22 information needs so that if, indeed, for example,
1 your daughter's physician is thoughtfully prescribing
2 off-label -- hurdles or lack thereof of reimbursement?
3 MS. MCGAHEY: I apologize. I did not hear
4 all of your question.
5 DR. SHERMAN: I'm curious what you think
6 about the payer community and how exchange of an
7 insurer.
8 MS. MCGAHEY: Oh, thank you.
9 DR. SHERMAN: Thank you.
10 MS. MCGAHEY: Sorry.
11 DR. SHERMAN: How -- again, it's a different
12 population, the cancer community, one population,
13 perhaps. I don't know. Antihypertensives is another.
14 But the -- and not the physician community, not the
15 patient community, now the payer community -- their
16 information needs and how that may or may not have
17 impacted your experience.
18 MS. MCGAHEY: In my experience, we have
19 worked with a case manager with our particular
20 insurance company since her diagnoses. That
21 relationship has been critical in moving her treatment
22 forward. There have been many instances where I have
1 needed to gather information, submit it to the case
2 manager, the case manager has worked with the medical
3 director in order to get authorization.
4 The first radiation treatment that she
5 received, even though it was experimental, our
6 insurance company agreed to cover it because we were
7 able to give them sufficient information to show that,
8 even though it wasn't documented to be safe and
9 effective in her cancer, it was still documented to be
10 a safe treatment for metastatic cancer in the lung.
11 Thank you.
12 MS. KUX: Thank you very much.
13 Our next speakers are Ms. Sarah
14 Christopherson and Ms. Christina Gerel --
15 MS. CHEREL: Cherel.
16 MS. KUX: Cherel -- from the National
17 Women's Health Network.
18 MS. CHRISTOPHERSON: My name is Sarah
19 Christopherson, and I am the policy and advocacy
20 director for the National Women's Health Network. And
21 I'll actually also be speaking on behalf of Ms.
22 Cherel, although I do not expect to use our full block
1 of time.
2 The National Women's Health Network is a
3 non-profit advocacy organization that works to improve
4 the health of all women. We are supported by our
5 members, and we do not accept financial support from
6 insurance companies, drug companies, or medical device
7 manufacturers.
8 Since the network's founding more than 40
9 years ago, we have brought the voices of women to the
10 FDA, advocating for medical products that meet women's
11 real-life needs and a drug and device development
12 process that reflects their lived experiences. We
13 look forward to working with the FDA to ensure patient
14 and consumer safety continue to be placed in the
15 highest regard.
16 As we've heard, off-label communication may
17 mean many things, including manufacturer-to-physician
18 communication, direct-to-consumer advertisements,
19 peer-reviewed journals, et cetera. All of these forms
20 of communication impact the care that patients
21 receive, even if subtly or unconsciously. And this is
22 significant because, as the FDA itself notes and as
1 we've heard from patients, you know, approval of one
2 intended use does not assure safety and effectiveness
3 for other uses.
4 The current regulatory framework already
5 provides significant flexibility and allows doctors
6 and healthcare providers to prescribe drugs and
7 devices off-label and exchange information. I think
8 the two previous speakers have talked about how we can
9 see this is already occurring in practice.
10 It's a common medical practice for
11 healthcare providers to do so, and I believe the
12 doctor mentioned that he'd be accused of malpractice
13 if he did not pursue this practice -- very common
14 already.
15 We recognize that off-label communications
16 can have real benefits for both individuals and the
17 public and, in specific circumstances, can promote
18 health and healthcare access. So for example, very
19 important to the National Women's Health Network,
20 before Mifepristone, which is medication abortion,
21 received an updated evidence-based label in March,
22 healthcare providers had used an evidence-based dose
1 that differed from the original approved use.
2 Providers were also able to prescribe Mifepristone to
3 women beyond the, what was then, the approved seven
4 weeks in states where this was not expressly
5 prohibited.
6 In these cases, off-label use and the
7 communication among providers about the off-label use
8 improved women's health. However, drug and device
9 sponsors should not be able to market their products
10 off-label when adequate safety and efficacy studies
11 were not conducted on those uses.
12 One example I want to mention, off-label
13 promotion of menopause hormone therapy persuaded women
14 and prescribers that drugs reduced the risk of
15 cardiovascular disease and could possibly reduce the
16 risk of Alzheimer's without well-designed, long-term
17 clinical trials to back up these claims.
18 Off-label promotion included direct-to-
19 consumer ads, both branded and unbranded, celebrity
20 endorsements, ghost-written articles in scientific
21 journals, pre-made slide sets for researchers, and
22 influence in shaping the content of CME courses. As a
1 result, hundreds of thousands of women developed
2 breast cancer, and many died.
3 The discussion of off-label promotion isn't
4 academic. We talked about that extensively. The
5 consequences have real world impact, including
6 disability and death for the women who were affected.
7 As we have heard, some drug and device
8 makers have argued that off-label communications are
9 free speech and that restricting those communications,
10 as long as they are truthful and non-misleading,
11 violates the First Amendment. The right to free
12 speech ensures that members of the public are able to
13 freely discuss their personal experiences on drug
14 informational science chat rooms and so-on. But when
15 a drug or device sponsor communicates to the public,
16 there is a heightened level of responsibility.
17 These First Amendment defenses should be
18 viewed in the context of a larger cross-industry
19 effort to undermine regulatory public health, safety,
20 and environmental protections, and they should be
21 rejected as such.
22 Drug and device manufacturers should not be
1 allowed to hide behind the First Amendment in order to
2 market their products in ways that undermine the
3 integrity of the FDA's regulatory role and review
4 process. We believe that with the right information
5 women can and do make the healthcare decisions that
6 are right for them.
7 But this depends on women having the
8 scientific evidence about safety and efficacy gained
9 through clinical trials, which are circumvented when a
10 manufacturer can turn to off-label communications.
11 Without these trials, women are left to play guesswork
12 when it comes to their health and how a drug or
13 medical device will act in their body.
14 We have spoken here at the FDA in the past
15 at length about the need for women, people of color,
16 the elderly, and other populations to have clinical
17 trials that represent them. Drugs and medical devices
18 react differently in different communities. Allowing
19 drug and device sponsors to communicate about their
20 products both to providers and patients eliminates the
21 incentive to conduct clinical trials and nullifies the
22 FDA review process.
1 And I want to echo a couple of comments that
2 were made earlier by Ms. Kim and Ms. Kapczynski that
3 it's about the data that we produce. It's about the
4 trials that we incent to have and the trials that we
5 incent to not have.
6 Women, people of color, the elderly -- these
7 groups are especially vulnerable. They especially
8 depend on the FDA to ensure that drugs and devices are
9 tested in populations like them. Allowing sponsors to
10 bypass this process harms the very populations that
11 are already most vulnerable to be excluded from the
12 clinical trials.
13 So in closing, we implore the FDA to reject
14 these attempts to undermine its own drugs and device
15 regulatory process to protect public health in the
16 American public. We've worked too hard and come too
17 far to retreat to the days when people could be easily
18 fooled by manufacturers' marketing gimmicks.
19 Thank you for your consideration of our
20 comments.
21 MS. KUX: Thank you very much.
22 Questions?
1 Thank you.
2 Our next speaker is Ms. Amy Leitman from MTM
3 Info & Research -- NTM Info & Research. Sorry.
4 MS. LEITMAN: Thank you. Good afternoon.
5 Thank you for the opportunity to speak here today on
6 an issue of great importance to patients, physicians,
7 researchers, regulators, and industry alike.
8 My name is Amy Leitman. I am the Director
9 of Policy and Advocacy for NTM Info & Research. We
10 are the sole patient advocacy group dedicated
11 specifically to non-tuberculous mycobacterial lung
12 disease. I am also a caregiver for a former patient
13 who passed away two years ago from this disease after
14 battling it for 18 years.
15 I'd like to start by telling you what it's
16 like to be a patient advocate in a rare disease space
17 where every single treatment, more than two dozen of
18 them, are unapproved or off-label. The official
19 treatment statement issued jointly by the American
20 Thoracic Society and the Infectious Disease Society of
21 America is 50 pages long and discusses the use of many
22 of these drugs to treat NTM lung disease.
1 Last year, our organization had a booth in
2 the exhibit hall at a large medical conference. We
3 saw this as an opportunity to reach out to the
4 pharmaceutical companies that make the treatments that
5 our patients use.
6 As I went to each of those industry booths
7 to speak to them, the representatives took me by the
8 arm and either led me over to the side or around the
9 back of their booth. These industry professionals
10 literally did not want to be seen talking to me for
11 fear of the reprisal they would have because they were
12 talking to someone about an unapproved use of their
13 medication.
14 This fear of speech is not acceptable. It's
15 particularly unacceptable when talking about life-
16 saving treatment. This fear of speech drove the
17 ultimate appellate result in Caronia. Speech can be
18 regulated, but significant limitations are placed on
19 its regulation, and those limitations must serve a
20 legitimate public interest and not be overly broad.
21 This is absolutely a legitimate public
22 interest to protect the public health. But we should
1 consider that the discussion of healing or life-saving
2 treatment is not the appropriate time or place to test
3 the constitutional limits of such speech and its
4 regulations.
5 It's also worth noting that a year later at
6 the same conference we actually had industry
7 representatives coming up to our booth wanting to talk
8 to our patients about their experiences as patients
9 with this disease. It is amazing what a difference a
10 year makes.
11 Doctors are already rushed to see patients
12 on a daily basis. To assume that they have the time
13 to research a condition that they may be completely
14 unfamiliar with is unrealistic. The opposite is
15 usually true, and the result is an overwhelming number
16 of doctors, including specialists, are unaware of
17 clinical guidelines that have been compiled by leading
18 experts and are based on decades of collective
19 experience and industry publications and research
20 publications by physicians and researchers.
21 We can help by clarifying greatly the rules
22 of communication between industry and healthcare
1 providers. By the metrics we've seen with our
2 organization, only about 20 percent of physicians with
3 NTM patients have been treating to or even consulting
4 with the existing guidelines.
5 This can lead to ultimately fatal errors.
6 Treating by monotherapy with certain drugs can confirm
7 mutated resistance to the drugs, and that then knocks
8 out an entire class of antibiotics that could be used
9 to treat this disease. This disease has to be treated
10 with a minimum of three antibiotics for a minimum of
11 18 months, usually.
12 If you knock out one entire class of drugs,
13 you significantly lower their success -- their chance
14 for successful treatment. Also by the metrics we've
15 seen, when physicians who were unaware of the
16 statement took a continuing education course in NTM
17 treatment, that number moves from 20 percent to nearly
18 80 percent.
19 Imagine the frustration of an expert
20 physician when a patient finally gets to them with
21 years of damage done and a much more difficult course
22 of treatment ahead due to an error born of ignorance.
1 Imagine how many more lives could be saved simply by
2 educating more healthcare professionals.
3 Right now, the average time between onset of
4 symptoms and initial diagnosis stands just under three
5 years. We've actually moved that needle in the 10-
6 plus years we've been around. That used to be nearly
7 four years.
8 This is actually where partnering with
9 industry could help us. The current regulatory
10 framework requires more detail and clarity that will
11 allow industry to help disseminate established
12 published treatment guidelines to healthcare providers
13 if those guidelines discuss off-label treatments.
14 Redacted guidelines are not an acceptable
15 substitute. Leaving out one key-piece of information
16 can lead to a fatal treatment error. Medical experts
17 compile guidelines. It should not be left to industry
18 nor anyone else to decide which information to omit
19 from them.
20 This is a starting point. It is not
21 applicable to every situation. But change starts
22 somewhere, and this is as good a place as any. If the
1 solutions were simple, none of us would be here today,
2 and this meeting wouldn't be necessary.
3 Technology has far out-paced regulatory
4 adaptation, and the patient voice has risen with a
5 continued growth of advocacy. Now is the time to
6 become more agile and discover new ways to incorporate
7 all the voices to best adjust this framework that has
8 shifted fundamentally but still needs adequate
9 guidance to protect the public interest.
10 Doctors are already using treatments off --
11 in off-label capacities. The risk is not reduced by
12 prohibiting communications outright. Regulating
13 communications so they are not deceptive is
14 understandable. Curtailing them so patients suffer
15 needlessly is not. The product will be used
16 regardless when the information is available in any
17 capacity that the off-label treatment does make sense.
18 It makes sense to destigmatize the discussion of data
19 and facts surrounding the use of the treatment.
20 A justifiable concern over patients being
21 confused or misled, particularly when those patients
22 are facing a difficult diagnosis and are scared, has
1 to be balanced against the fact that many patients,
2 particularly in the rare disease space, have no other
3 treatment options and often have no choice but to
4 become well-educated about their own healthcare. And
5 this is where destigmatized communications can help.
6 There are several potential benefits to
7 clarifying this area, the potential to capture
8 additional data about the results of such off-label
9 use, which may ultimately help justify approval for
10 additional uses.
11 We have nearly 100,000 patients in the
12 United States with NTM lung disease, and any of them
13 who are being treated are off-label. This amounts to
14 one of the world's largest clinical trials. But we
15 currently don't have a mechanism to capture this data.
16 Similarly, prescriptions can be tracked. If
17 there is an uptick in a prescription being written for
18 a certain diagnosis, that could signal the need to
19 look at a possibility and merit of a clinical trial.
20 Creating such a pathway might ease the burden and
21 expense of drug approvals and make drugs development
22 more attractive, particularly in areas where there is
1 a serious need for it.
2 Increasing communications with healthcare
3 providers could significantly improve the ability to
4 recruit for clinical trials, and identify potential
5 new clinical trial sites that would have gone
6 unnoticed.
7 A stronger argument that -- for patients who
8 need to advocate for insurance coverage of their off-
9 label medications, treatment guidelines or clinical
10 data that have been vetted and published according to
11 appropriate and accepted scientific standards should
12 carry more weight. These data are not mere guesses.
13 There are many other issues to consider
14 surrounding communications regarding unapproved uses.
15 It will take considerable time to shake them all out,
16 and unexpected problems will inevitably appear. Every
17 stakeholder's point of view should be weighed
18 carefully in these matters, and one key aspect of all
19 of this will be agility.
20 The Food and Drug Administration should
21 innovate in this area if we're going to deal with this
22 issue successfully now and the future.
1 Thank you.
2 MS. KUX: Thank you very much.
3 Questions?
4 Lauren and then Kristin.
5 MS. SILVIS: Thank you. And thank you.
6 You raised the issue of the, you know,
7 patient and caregiver input into regulatory decision-
8 making. And I had asked a little bit earlier about
9 some speakers to think about in their written comments
10 the ability of different groups to evaluate
11 information and data.
12 And I think it would also be interesting to
13 hear from these speakers, perhaps, in their written
14 comments about the needs of patients and caregivers
15 and receiving information, the different types of
16 needs, and how we might be able to evaluate that or
17 account for that.
18 MS. LEITMAN: Yeah. And actually, that's
19 something that we're in a particularly good position
20 to do. And I don't know how many other advocacy
21 groups have tried this, but we actually often survey
22 our patients on various questions. So -- and
1 sometimes we will get, you know, a doctor wondering or
2 research -- a researcher wondering about a particular
3 question. If there were questions that you had that
4 you wanted to pose to patients, we would send out a
5 survey to our patients and say this is what they're
6 wondering. This is why they're wondering it. This is
7 what it might lead to. Please take a few minutes to
8 answer this survey.
9 We actually get a -- really, a pretty good
10 response rate. We've done a number of these surveys,
11 and we've compiled a lot of data from it. So we have
12 really good patient-focused information. And we
13 actually -- we have a -- we have our own research -- a
14 little research consortium that's been funded by a
15 PCORI grant, and we do have patient input in -- at all
16 of our meetings, we always incorporate patient input.
17 MS. SILVIS: Yeah. I think examples of
18 those kinds of tools in the written comments would be
19 very helpful. Thank you.
20 MS. LEITMAN: SurveyMonkey. Really easy.
21 Very easy, very useful.
22 MS. DAVIS: Thank you for your presentation.
1 You mentioned with 100,000 patients in the
2 United States with NTM lung disease that, essentially,
3 this is one of the world's largest clinical trials,
4 but no one is capturing the data. And I'm just
5 curious, how -- so if medical product companies could
6 engage in increased communications, could you talk a
7 little bit about how that would lead to more capturing
8 of that data?
9 MS. LEITMAN: Sure. So what we would have
10 to do is figure out how we're going to centralize the
11 capture of data and harmonize the data itself. The
12 thing is, the kinds of tests that are required, the
13 sputum cultures, they really can only be done at a few
14 labs here in the United States. So we already know
15 that there's going to be a certain standard of
16 measurement.
17 We also know that these patients are being
18 followed regularly. They have to be. They have to be
19 monitored to see, you know, is the disease
20 progressing; is the medication working; if it is
21 progressing, how bad is the lung damage?
22 So we know that they're getting radiography.
1 We know that they're getting sputum cultures. And we
2 also know that survey tools now exist, and we're
3 actually in the process of developing one with a
4 researcher to measure patient input, you know, on
5 psychometric data -- how are they feeling; does this
6 treatment work -- from a perspective of things that
7 can't be captured in a lab. You know, are you less
8 fatigued kind of thing.
9 So this is all data that's already coming
10 out. We already -- you know, physicians have it. We
11 would just need to centralize it in -- somewhere. We
12 need to -- we would need to -- I mean, like I said,
13 it's almost like it's like the world's largest
14 clinical trial, but we're just not gathering that
15 information in. And it's such a tragic waste of data.
16 MS. DAVIS: And if I could just follow up.
17 And I don't want to put you on the spot, but if you
18 have any thoughts because some of what we've heard
19 from other speakers is how medical product companies,
20 given their financial incentives, could have
21 incentives to only present the positive data.
22 And so with the kind of data that you just
1 talked about being collected, I'm wondering if you
2 could talk about why it would be medical product
3 companies that would have the role in centralizing it
4 versus if --
5 MS. LEITMAN: It's not necessarily them.
6 MS. DAVIS: Okay.
7 MS. LEITMAN: Oh, yeah. No. We -- I mean,
8 the bronchiectasis research consortium is actually a
9 bunch of research institutions. It's -- you know,
10 it's like New York University and Mayo Clinic, et
11 cetera. And they have a research database. And so
12 that could perhaps be adapted to start collecting that
13 data.
14 The key is getting that data. There are
15 only 13 sites around the country. We'd have to figure
16 out how to get the data from, you know, local
17 physicians all around the country into that database
18 so that we could then pull it. But there are existing
19 mechanisms that are outside the purview of industry
20 that could easily be adapted for it.
21 There are organizations building PPRNs and
22 the PPRN model that the technical -- the technological
1 platform could be adapted to be used in a capacity,
2 you know, by research institutes that don't have, you
3 know -- that way, the industry doesn't have its hands
4 on the data. We wouldn't want industry influence on
5 the ultimate, you know, analysis of data.
6 One of the advantages of doing this kind of
7 study though, there are 160-plus species of NTM. Some
8 of the species that we know do infect humans have,
9 like, nine sub-species as well. And we're just --
10 this part where we are starting to, you know, identify
11 sub-species for treatment, it's a very nascent stage,
12 but we recognize its importance. We would actually be
13 able to take a better look at which treatments work
14 best for which strains. This would really be like
15 sort of the next iteration of precision medicine.
16 MS. DAVIS: Thank you very much.
17 MS. LEITMAN: Thank you.
18 MS. KUX: Other questions?
19 Rachel?
20 DR. SHERMAN: You mentioned looking at
21 uptake in prescriptions and linking it perhaps to
22 diagnosis. So if Dr. Califf were here, I know he
1 would ask you to please comment on how you would think
2 about incentivizing physicians to actually communicate
3 the diagnosis of the indication since that's generally
4 not information we have.
5 MS. LEITMAN: Well, I mean, there's always
6 an ICD code, right? When there's a diagnosis, there's
7 an ICD code for billing purposes.
8 We've actually done a number of studies
9 where we have pulled ICD data, and it's given us some
10 very good metrics on which strains are prevalent in
11 which areas of this country. I mean, we've done
12 geographic data, and we've done demographic data
13 studies.
14 So the fact that there are ICD codes being
15 used, it's possible that we could adapt that model. I
16 mean, I'm not certain. I'd have to go back and talk
17 to our researchers. But I mean that's certainly one
18 possible mechanism.
19 DR. SHERMAN: So any thoughts you have and
20 also more specific -- more specificity in the ICD
21 code, we'd really appreciate hearing that.
22 DR. LEITMAN: I think you'll be getting it.
1 Our research consortium is very anxious to hear about
2 the results of today's meeting. I think they'll have
3 a lot to say.
4 Thank you.
5 MS. KUX: Thank you.
6 We're going to have an afternoon break now,
7 and we'll reconvene at 3:15. Thank you.
8 (Off the record.)
9 MS. KUX: Hi, everyone. We're going to
10 start our last session for the public meeting. And so
11 we'll have a few scheduled presenters, and then we do
12 have a couple of folks who want to make public remarks
13 at the end.
14 So I'd like to call up Mr. Andrew Sperling
15 from the National Alliance on Mental Illness.
16 MR. SPERLING: My name is Andrew Sperling.
17 I'm with the National Alliance on Mental Illness. We
18 thank you for this opportunity and thank you for the
19 long two days that you've endured of these eight-
20 minute presentations. We're grateful to you for that.
21 NAMI is the nation's largest organization
22 representing and advocating on behalf of people,
1 children and adults, living with serious mental
2 illness in their families. We prioritize disorders
3 such as schizophrenia, bipolar disorder, major
4 depression, severe anxiety disorders, including PTSD.
5 I'm going to talk a little bit and delve
6 into a little bit of detail in some of the unique
7 issues we have in psychiatric medicine that we think
8 are unique to the way approved therapies are approved
9 off-label.
10 First of all are diagnostics. They are not
11 where they need to be. We are the only part of
12 medicine where diagnostics are rendered based on the
13 subjective rendering of symptoms to a clinician. We
14 wouldn't diagnose heart disease on the basis of the
15 severity of chest pains.
16 Unfortunately, that's where we are. Our
17 standard is the Diagnostic and Statistical Manual
18 published by the American Psychiatric Association.
19 And when you look at those diagnostics, you find it's
20 the patient rendering on a scale. These are evidence-
21 based scales, but they are still imprecise in terms of
22 what is actually going on with the patient. It could
1 be anxiety mixed with depression mixed with delusional
2 thoughts, and you come to a diagnosis.
3 It's very common when we talk to our
4 patients and their families that their loved one has
5 been through not one or two diagnoses, but five and
6 six diagnoses. And these aren't always consistent
7 with the label that a sponsor comes forward with the
8 evidence that you as an agency approve. So you will
9 have a medication that -- a manic psychotic that might
10 be approved for psychosis in schizophrenia, but not
11 psychosis in bipolar disorder.
12 And bipolar disorder is the most classic
13 case where we oftentimes find lots of off-label
14 prescribing. This is a complex disorder that is both
15 chronic and episodic. It's chronic in that we don't
16 have a curative intervention. But at the same time,
17 there are episodes of mania, episodes of depression,
18 episodes of rapid cycling, and that often requires a
19 complex array of medications to manage all of those
20 complex symptoms, many of which are off-label.
21 The second thing we're facing in our field
22 is a workforce shortage. And it's at crisis
1 proportions, particularly in areas such as child and
2 adolescent psychiatry. So we have many primary care
3 doctors, pediatricians, gerontologists, that are out
4 there prescribing medications, treating people for
5 serious mental illness simply because of the shortage
6 of psychiatrists.
7 That inevitably leads -- when that is done
8 off-label, there is a deficit there. These people,
9 these clinicians, have not necessarily been trained in
10 detail in psychiatry. They haven't done a three- or
11 four- or five-year residency in geriatric psychiatry.
12 And we want to make sure to the extent that
13 they are prescribing off-label, that it be informed by
14 the best science we have out there, which is
15 oftentimes far beyond the label that the FDA has
16 approved.
17 And there is strong evidence out there. We
18 have peer-reviewed, respected, published, robust
19 treatment guidelines published by bodies such as the
20 American Psychiatric Association, the Academy of Child
21 and Adolescent Psychiatry, that actually validate and
22 provide strong scientific basis for what is often off-
1 label prescribing.
2 And these treatments are desperately needed
3 by patients, and we need to recognize that they are
4 palliative in nature. They are not curative
5 interventions. But they're the state of the art of
6 what we have right now, and we want to make sure the
7 extent they are being prescribed by primary care
8 physicians that they are being done in the most
9 appropriate way.
10 I will remind you again. Eighty percent of
11 the prescriptions written for SSRI's are written not
12 by psychiatrists but by primary care doctors,
13 internists, and other physicians. We want to make
14 sure that they have the science when they do that and
15 that FDA does everything in its power to overcome
16 legal and regulatory barriers to make sure that the
17 best science is made available and provided to these
18 clinicians when they prescribe off-label.
19 Off-label is common. It happens. We just
20 want to make sure it's informed.
21 So NAMI would urge the FDA to provide
22 greater clarity as to how this scientific literature -
1 - be it treatment guidelines, peer-reviewed articles,
2 bulletins, et cetera -- can be lawfully disseminated
3 to prescribing physicians. The FDA needs to develop
4 and define a process for communication for truthful
5 and non-leading information.
6 NAMI would also urge that it be appropriate
7 to the prescriber in their particular level. The kind
8 of information that needs to be rendered and accessed
9 by a primary care doctor who doesn't have any
10 specialty training in psychiatry is different than a
11 child and adolescent psychiatrist who has been through
12 a five-year residency program, for example.
13 So it needs to be tailored to the audience
14 for which it's intended. And greater clarity from the
15 Agency to clear up the ambiguous areas would allow
16 that communication to take place so that when off-
17 label prescribing is done, which, unfortunately, is
18 common in our field, that it's informed by the best
19 science.
20 Thank you very much for this opportunity to
21 offer input, and we look forward to supporting the
22 efforts of the Agency to provide that clarity to the
1 field. Thank you.
2 MS. KUX: Thank you very much.
3 Any questions, Panel?
4 UNIDENTIFIED SPEAKER: (inaudible - off
5 mic).
6 (Laughter.)
7 MS. KUX: You don't get to speak.
8 Tom?
9 MR. ABRAMS: You mentioned that the
10 information should be tailored to the audience it's
11 intended to. Could you expand on that?
12 MR. SPERLING: Yes, absolutely. So -- and
13 again, we're talking about within the realm of
14 physicians because that's where we believe this
15 information needs to be communicated.
16 NAMI believes strongly, particularly in
17 rural and frontier areas where there is an internist
18 or even potentially a cardiologist, any other type of
19 medical professional that has no psychiatric training,
20 the kind of information that's going to be useful to
21 that prescriber is very different than the kind of
22 information that is going to be useful to someone who
1 has done a four-year residency program in psychiatry.
2 The level of knowledge of managing
3 psychiatric symptoms of how the drugs are prescribed,
4 of the varying -- I would also add, at least
5 particularly with antipsychotics, the side effect
6 profiles and mechanisms of action for each of these
7 medications is very, very different.
8 And the level of knowledge of all of that,
9 of dosing and side effects, for someone who has
10 actually done a four- or five-year residency in
11 psychiatry is very different than the experience of
12 someone who is trained in internal medicine.
13 So the information that goes to each of
14 those needs to be tailored to their knowledge and
15 their working knowledge of prescribing these
16 medications.
17 MS. KUX: Other questions?
18 Thank you.
19 MR. SPERLING: Thank you very much.
20 MS. KUX: So our next speaker is Mr. Jon
21 Furman from the USA Patient Network.
22 MR. FURMAN: Good afternoon. Hopefully
1 everyone can hear me here.
2 I'd like to thank Diane Zuckerman for
3 helping me get here and the FDA for having me.
4 I'm going to test the clicker.
5 I'm here representing USA Patient Network.
6 As it was said, my name is John Furman. The USA
7 Patient Network is an independent group of patient
8 advocates from across the country. We are working to
9 ensure medical products are safe and effective for all
10 patients.
11 We are concerned that so many drugs and
12 devices are used off-label. We are concerned that the
13 patients are rarely told by their doctors when they
14 prescribe a drug or use a device off-label. This is
15 happening too often now when this type of promotion is
16 not completely legal. And these problems will
17 increase if the FDA loosens the rules for off-label
18 promotion.
19 Many patients don't know that the FDA
20 approves medical products only for specific
21 indications. Many patients don't know what off-label
22 use means or what the implications are for whether the
1 risks outweigh the benefits. Most patients don't know
2 that adverse events are higher with off-label use.
3 Patients need to know all of these things.
4 Doctors don't always understand the
5 implications of off-label use. They assume that if it
6 is FDA approved, a product is safe. I've heard this.
7 I've had friends that have heard this from physicians.
8 It is a big issue here.
9 Doctors may not weigh the risks and benefits
10 the same as patients do. Doctors are already
11 receiving published articles of questionable merit
12 regarding off-label uses. And we don't want the
13 situation to get worse.
14 What patients need and should be able to
15 expect from the FDA, the FDA should do more to protect
16 patients, requiring informed consent for off-label
17 uses of any medical products with possible serious
18 risks. FDA should not loosen the rules regarding off-
19 label promotion.
20 Specifically why I'm here, this has to do
21 with my experience with a class of antibiotics known
22 as fluoroquinolones. Off-label use changed my life
1 and not in a good way.
2 I received fluoroquinolones for a minor
3 infection -- for minor infections 5 times over the
4 past 15 years. These antibiotics were given as a
5 first-line of treatment, which is off-label since they
6 were only approved for use when other antibiotics
7 failed. I now suffer from diverse symptoms -- this
8 has been going on since 1999 and continues to this day
9 -- that are considered complications of these drugs.
10 This includes muscle soreness, heart rhythm
11 abnormalities, depression, suicidal thoughts, tremors,
12 akathisia, seizures, neuropathic pain, chronic
13 fatigue, memory loss. I could go on. It's
14 unbelievable -- well established, serious harms from
15 these drugs.
16 The damage -- the potential for damage was
17 first started to be acknowledged in the early 1990s to
18 the early 2000s. Some drugs have been pulled off the
19 market -- fluoroquinolone drugs. Others quickly took
20 their place.
21 Black box warnings were added in 2008 and
22 2011 and 2016. Notably, this was decades after
1 original approval. The issues were not caught.
2 A safety announcement in 2013 regarding
3 serious and sometimes permanent nerve damage -- this
4 mostly discussed peripheral nervous system damage.
5 These drugs can significantly damage the central
6 nervous system, and we really haven't dug too far into
7 that yet in the medical community.
8 Currently, 56 percent of prescriptions are
9 for off-label uses when it comes to fluoroquinolone.
10 The best-selling antibiotic of 2010 was Levaquin, a
11 fluoroquinolone. However, Levaquin ranked third and
12 Cipro ranked fifth in adverse event reports submitted
13 in 2013. Cipro has been linked to 79,000 adverse
14 event reports and 1,700 deaths in the last decade.
15 Too many people were harmed by these drugs while it is
16 illegal to promote off-label uses. Many more will be
17 harmed if these uses can be promoted.
18 I wanted to cover briefly, as I started to
19 develop symptoms back in 1999/2000, what I was told by
20 the physicians is that I -- you know, had -- either
21 prescribing the drugs or were specialists that I
22 sought advice from, the PCP told me there's no way
1 these antibiotics could be causing the symptoms that
2 you're describing.
3 In 2012 when it came to my attention what
4 had been causing my problems, I called a local
5 tertiary research hospital begging for help because I
6 felt like I was going to die. And they tell me these
7 drugs don't do what you're saying has happened. And
8 if they did occasionally, we wouldn't know anything
9 about it. The best we can do is schedule you for an
10 outpatient psychiatric evaluation in six months.
11 This is a big problem. Physicians cannot
12 recognize the side effects of the drugs that they're
13 prescribing, and a lot of things are kind of swept
14 under the carpet and categorized as mental health
15 issues. And none of this is recognized or treated
16 appropriately. It's oftentimes the answer, and it was
17 for me previously, is prescriptions of more
18 psychiatric medications like SSRI's or
19 benzodiazepines, which can lead to a snowball effect
20 of health issues. But there's a big problem there.
21 In the case of the quinolones, post-market
22 surveillance mechanisms, to the extent that they
1 exist, failed. It took decades to identify the harms
2 caused by these drugs. And we’re still nowhere
3 finished identifying all of them, I'm sure.
4 Post-market studies are rarely conducted for
5 off-label use. And who would pay for those studies?
6 What incentive do companies have to complete required
7 post-market studies quickly?
8 The FDA does not enforce requirements, and
9 companies face no penalties for delaying studies or
10 not completing them appropriately.
11 Will the FDA become irrelevant? This is a
12 big question as we move forward into the future here.
13 As part of the FDA approval process, FDA is assigned
14 to scrutinize company data to see if they agree that a
15 product is safe and effective. What incentive do
16 companies have to submit applications to the FDA for
17 approval for new indications if the companies can
18 promote them without approval?
19 Conclusions. Based on our experiences as
20 patients, it is reasonable to conclude that any policy
21 changes that could broaden the use of the
22 pharmaceutical without a vast improvement of informed
1 consent and monitoring of outcomes is not in the best
2 interests of patients. We need to know the outcomes
3 off-label and on-label because we're not doing a good
4 job on-label either.
5 A solution in search of a problem? Patients
6 are not missing out on safe and effective treatments
7 due to restrictions on promotion of off-label use. On
8 the contrary, many patients have been harmed, even
9 though it is currently illegal to promote off-label
10 uses. Many more will be harmed if these uses can be
11 promoted. Many patients have similar stories.
12 Instead, the FDA should provide training in
13 medical schools to explain the risks of off-label uses
14 in the absence of solid, scientific evidence that the
15 indication is safe and effective. They should provide
16 model informed consent forms for commonly used off-
17 label products.
18 FDA's mission -- and I would like to see you
19 all uphold this mission. The FDA is responsible for
20 protecting the public health by ensuring the safety,
21 efficacy, and security of human and veterinary drugs,
22 biological products and medical devices. And allowing
1 off-label promotion does not help the FDA protect us.
2 These are grave dangers, and there is a very real
3 possibility and likelihood of tragedy.
4 And that's it. Thank you.
5 MS. KUX: Thank you very much.
6 Any questions, Panelists?
7 Kristin?
8 MS. DAVIS: Thank you for your presentation.
9 I have a question, and this is both for you
10 and for anybody who's still in the audience who
11 brought this up, too, about this idea of informed
12 consent when a prescriber is going to prescribe a drug
13 off-label.
14 If you could either address today or in any
15 follow-up remarks what the elements of that informed
16 consent would be, you know, what something like that -
17 - you talked about a model informed consent form. So
18 any more specifics, too, on what could be included in
19 that and what would be, you know, useful information
20 for the patients in that setting, that would be
21 helpful.
22 MR. FURMAN: Sure. Of course, this is going
1 to come from my point of view, based on my experience
2 with fluoroquinolones.
3 It turns out that, you know, this class of
4 drugs is tremendously powerful -- very, very effective
5 at killing bacteria and pretty much everything else.
6 It does this by altering bacteria's ability to
7 reproduce by tinkering with DNA mechanisms. It turns
8 out it does to the host as well.
9 When I was first prescribed these drugs, you
10 know, it wasn't even 100 percent sure I had an
11 infection. And you know, I was prescribed a drug that
12 alters DNA. I had no idea. I should have been told
13 something.
14 This goes to the risk-benefit analysis that,
15 you know, we would hope physicians would be trained
16 and have the kind of judgment to handle that well.
17 It's come to my attention and a lot of other people's
18 attention that this is all too often not the case.
19 But a patient should have some kind of reasonable
20 representation of what the risks are for a particular
21 kind of medication and a choice as to whether or not
22 they want to pursue that rather than be completely
1 trusting. We can do a lot better.
2 I could follow up more later if you'd like
3 me to.
4 MS. DAVIS: Thank you.
5 MR. FURMAN: Sure.
6 MS. KUX: Other questions?
7 MR. FURMAN: Thank you.
8 MS. KUX: Thank you.
9 Our next speaker is Dr. Megan Coder from the
10 Pharmaceutical Care Management Association.
11 DR. CODER: Hello. We'd like to thank the
12 FDA for taking up this manufacturer issue -- issue of
13 manufacturer communications regarding unapproved
14 medication uses and for keeping this discussion
15 focused on the promotion and protection of public
16 health.
17 My name is Megan Coder. I am the Senior
18 Director of Industry Programs with PCMA, the
19 Pharmaceutical Care Management Association. PCMA
20 represents PBMs, and PBMs help more than 266 million
21 Americans access safe and affordable prescription
22 drugs. As drug utilizations and costs continue to
1 increase, payers rely on PBMs to develop strategies to
2 improve the safe use of medications and lower costs
3 for patients and payers alike.
4 Due to recent court decisions,
5 administrative actions, and other factors, the system
6 of communication among manufacturers, providers,
7 patients, payers, and regulatory agencies has become a
8 bit confusing and inconsistent, as highlighted by the
9 recent settlement.
10 Quite simply, we encourage manufacturers to
11 share information regarding the off-label use of drugs
12 with payers and healthcare providers, but we do not
13 believe that manufacturers should be sharing this type
14 of promotional information with patients.
15 In response to Question 1(a) in the Federal
16 (ph) Register, payers would appreciate more
17 communication from manufacturers regarding preliminary
18 and even inconclusive information about the unapproved
19 uses of medical products as long as it is done in an
20 appropriate way.
21 As payers, health plans, and PBMs work
22 together to create formularies that best serve patient
1 needs, it is critical for them to have access to all
2 available outcomes and information. Increased data
3 sharing will allow payers and PBM's to identify
4 appropriate treatment options for patients while
5 better preventing unintended harm and injury.
6 The FDA should consider establishing clearly
7 defined standards around the quality and completeness
8 of information that manufacturers will provide to
9 payers and clinicians. Some things to consider may
10 include the current compendia system is often
11 inadequate and unworkable where evidence of vastly
12 different quality can justify coverage decision for
13 off-label use.
14 It is important to develop a system that
15 prevents the dissemination of non-reproducible
16 evidence and data that has inherent conflict of
17 interest biases.
18 Studies and clinical information regarding
19 off-label use of drugs should be complete and not
20 cherry-picked by the manufacturer. Studies showing
21 unfavorable results should be reported alongside those
22 showing favorable outcomes.
1 Information supporting off-label use should
2 also be shared with the FDA. The Agency or another
3 independent qualified body could judge the quality of
4 the evidence and incorporate it into the compendia
5 system. For example, as probably mentioned before, a
6 1,000-patient double-blind study should carry more
7 weight than a 10-person case study. It may also be
8 worthwhile to reference the Institute of Medicine
9 guidelines for evidence trustworthiness when
10 developing this model.
11 We believe that manufacturers must disclose
12 all known risks associated with off-label usage. We
13 encourage the Agency to consider whether manufacturers
14 should maintain some degree of liability if they have
15 not disclosed risks adequately and their drugs
16 continue to be used off-label.
17 In response to Question 2(a), to be
18 systematic here, the high cost of specialty drugs have
19 already begun challenging employer's, union's and the
20 government's ability to deliver high-quality benefits
21 that still fits within their budgets. Payers and PBMs
22 are, therefore, using every tool at their disposal to
1 manage expenses and enable access to these innovative
2 therapies. Payers will and want to pay for high-value
3 treatments.
4 The use of drug formularies enables payers
5 and PBMs to promote value and produce positive patient
6 outcomes by using clinically sound, cost-effective
7 medication therapy outcomes.
8 By providing P&T (ph) committees with high-
9 quality data on off-labeled uses, manufacturers can
10 help introduce competition into non-competitive
11 categories. Providers in this case will then have
12 more options in selecting appropriate treatments for
13 patients, while payers would have more flexibility in
14 negotiating with competing manufacturers for better
15 prices.
16 Manufacturers should have sufficient
17 incentive to produce high-quality, off-label data and
18 share with payers under the appropriate circumstances,
19 especially since they have already shown a willingness
20 to produce this type of data and share with the FDA to
21 secure approval for new indications on existing
22 products.
1 Lastly, Question 5(e). While we must ensure
2 that doctors and payers have sufficient information on
3 any off-label medication use that could pose a risk to
4 patients, we feel very strongly that manufacturers
5 should never engage consumers in off-label promotional
6 activities.
7 Discussions of off-label use should stay
8 between patients and their doctors so that solid
9 evidence can appropriately be weighed with a potential
10 risk. It is important to prevent patients from being
11 exposed to ineffective and even harmful treatments.
12 Despite current FDA rules on direct-to-
13 consumer advertising, researchers have found that ads
14 often exaggerate the benefits of a drug's use while
15 downplaying the risks. Since a product that's
16 considered safe and effective for one disease or
17 patient population, cannot automatically be considered
18 safe and effective for all patient populations, we are
19 concerned that manufacturer marketing of off-label use
20 to patients could result in misleading information and
21 even inappropriate prescribing.
22 Direct-to-consumer advertising appears to
1 medicalize symptoms that have previously not been
2 defined as medical conditions. We cannot allow these
3 trends to be exacerbated by allowing direct-to-
4 consumer advertising of off-label uses.
5 Manufacturers' behavior with respect to
6 violating off-label communication policies
7 demonstrates that penalties may not be enough to deter
8 violation of the current policies. This may have
9 already been discussed, but an example, in 2014, Endo
10 Pharmaceuticals paid just under $182 million to settle
11 Department of Justice prosecution for its illegal
12 marketing of Lidoderm for uses that the FDA had not
13 approved.
14 In recent years, other firms have settled
15 similarly for $2.2 billion, $2.3 billion, and then GSK
16 had $3 billion. We, therefore, question whether
17 current penalties have the intended deterrent effect.
18 The FDA may wish to reconsider current penalties and
19 enforcement actions with respect to off-label
20 communications by manufacturers.
21 So in conclusion, we do not believe that
22 manufacturers should promote off-label use to patients
1 at any point in the prescribing or diagnosis process.
2 But there is great value in communicating this
3 information to payers and PBMs.
4 In an era where biosimilars and other
5 complex treatments are flooding the market, it is
6 important for the FDA to proceed carefully in forming
7 their off-label communication polices, to present
8 unforeseen consequences that harm patients, payers,
9 and the tools they rely on to deliver high-quality,
10 affordable therapies.
11 And with that, I turn it to you.
12 MS. KUX: Thank you very much.
13 Panelists, any questions?
14 Kristin?
15 MS. DAVIS: So you talked about -- that one
16 thing the companies could do is sharing the data with
17 FDA. And it sounded like maybe in an advance of uses
18 being included in compendia. Could you talk a little
19 bit more about how you would see FDA's role playing
20 out there in that setting outside of the drug approval
21 process?
22 DR. CODER: Sure. In the comment process, I
1 will make sure to have our members weigh in on this
2 more formally, so this is noted as such.
3 From what my understanding is, it seems that
4 there are multiple compendia and multiple ways that
5 individuals or payers can go about trying to determine
6 the effectiveness (ph) and quality. So I think what
7 our members were trying to just pose a suggestion of
8 having the FDA or another independent body be able to
9 house this and bring this together and be able to
10 better define what an off-label use is that's
11 appropriate and the right ones to be possibly being
12 considered for patients.
13 So having the FDA take an increased role I
14 think would be of interest, at least to pursue as an
15 idea of trying to bring more standardization and
16 harmonization to the compendia.
17 MS. DAVIS: Thank you.
18 MS. KUX: Other questions?
19 Rachel?
20 DR. SHERMAN: Could you either now or in
21 your comments comment on whether it would be useful
22 for you to know if the indications off-label use was
1 an indication that the company was actively pursuing
2 development of, presumably, ultimately seeking as an
3 indication or not -- in other words, whether there was
4 a development plan and, if so, what that was?
5 DR. CODER: For? Sorry, if I miss -- I
6 think the goal would be -- and I apologize if I'm not
7 answering the question as stated. But the goal would
8 really be to make sure that the people who need the
9 information have the information at their hands. And
10 that patients aren't being promoted to for off-label
11 uses. So that way, payers and PBM's work together to
12 create formularies. They work with physicians in the
13 health systems to figure out what is best for each of
14 those individual populations.
15 So I think it's to find a systematic way of
16 going down the line and make sure every single person
17 who needs information has it. But making sure that
18 those who it may not benefit immediately are -- for
19 those who may not benefit immediately will be able to
20 have that information delivered to them in the most
21 appropriate manner and the most appropriate vehicle.
22 And what we see right now would be that
1 would be their physicians in their health systems and
2 providers on the ground. But that's after a funnel-
3 down effect having gone through these different P&T
4 committees and other clinical bodies that really are
5 addressing all possible off-label and on-label uses to
6 make sure that treatment is pursued in the appropriate
7 manner.
8 MS. KUX: Other questions?
9 Thank you very much.
10 DR. CODER: Yeah.
11 MS. KUX: So our next speaker is Ms. Madris
12 Tomes from -- sorry if I got your name wrong -- from
13 Device Events.
14 MS. TOMES: Okay. Bear with me a moment.
15 All right.
16 My name is Madris Tomes. The reason that
17 I'm here today is probably not what most of you would
18 expect. If this meeting had happened five years ago,
19 I would probably have had a very different opinion and
20 you would hear a very different story.
21 I had previously worked at CMS as a fraud
22 contractor looking for problems with medical device
1 reimbursements. And I went to the FDA to work about -
2 - I guess about five years ago on post-market
3 surveillance in CDRH, and what I learned there changed
4 everything I think about medical devices.
5 I worked in the drug space for a little
6 while, but most of what I'm going to talk about today
7 has to do with the medical device side and what my
8 fears are about how the labeling is affecting
9 patients.
10 Next slide. Or do I do that? I do that?
11 Okay, great.
12 So I am not a physician. I'm not a
13 scientist. I'm not a lawyer. I am a data person, and
14 I look for patterns and problems with medical devices.
15 And I look for, basically, the reason that a problem
16 is taking place.
17 And one of the things that I've been finding
18 is that when you have these patterns of problems that
19 are coming in, it's taking the FDA between two months
20 and two years to do a recall or to recommend a recall.
21 And so my concern has to do with the amount
22 of data that's coming in and how that's being
1 disseminated and when it's being disseminated and what
2 effect that has on whether physicians have the
3 information that they truly need to give the best
4 advice to their patients. And I think if they're
5 fully informed and are informing their patients,
6 that's one thing. But I'm concerned that they're not,
7 that they simply don't have the information.
8 One of the things I want to stress about the
9 way that I pulled this data -- this is all public
10 data. When I worked at the FDA, I never had access to
11 actually see the adverse event reports.
12 I knew the structure of the report. I knew
13 how they were processed. I knew that sometimes it was
14 a death report. And occasionally a malfunction or an
15 injury report would mention a death, but the wrong box
16 was checked. Those were the things that I knew.
17 And when I left the FDA, I decided to build
18 a system that could help find these problems with
19 these patterns of the data. And I didn't know exactly
20 what I would find. I knew that there were issues.
21 When I started looking at the data, I
22 started seeing the people and the patients behind the
1 data and really starting to worry because I truly did
2 not have that viewpoint when I was at the FDA. I was
3 thinking, okay, we've got 70,000 reports. How many
4 analysts are there? How fast can they review these?
5 Are they going to only look at the deaths first? But
6 you look at it differently when you start to meet the
7 patients that have been harmed.
8 I broke out the data into two different
9 areas for our discussion today. I put the off-label
10 use separately from contraindicated use, and I'll
11 explain why in a little bit. I think that confusing
12 the two can be a big mistake.
13 One of the things I want to point out is
14 that, as of the end of September, I searched on
15 adverse events in the public data and found 23,809
16 adverse event reports referencing off-label use of a
17 device; 777 of these patients died. And that's not
18 counting malfunction and injury reports that may have
19 been deaths. I didn't have the time to look through
20 them all like that.
21 There was an Office of the Inspector General
22 report back in 2009, and that stated that only 14
1 percent of adverse event reports were actually being
2 submitted to the FDA or being reported.
3 And so when you look at the data like that
4 and you think, okay, you know, the MOD data, anybody
5 who's looked at it, it's overwhelming. You know that
6 there's a lot there, but you can only see 500 reports
7 at a time.
8 So there's no way to really identify
9 patterns. All you can really do is look through one
10 report at a time. And that's what's available to the
11 public.
12 So my goal was to take that data and put it
13 in a format where you could actually look at, you
14 know, okay, well, how many adverse events does
15 Medtronic have. It's over 800,000. How many does J&J
16 have? It's even more. And many of these reports come
17 in with many different company names. And so there's
18 no way to identify, looking 500 at a time, that these
19 are really happening.
20 So I wanted to point out that over 1,100 of
21 the adverse events that referenced off-label use were
22 pediatric use. And the -- a lot of times, I hear, you
1 know, device companies are stating that a lot of the
2 reports are coming from patients now and they're
3 skewed. But you can also look at the physician
4 reports. You can look at healthcare provider reports.
5 So I don't like to see this data discounted
6 because I think all these reports really show the full
7 story of what can be going on with a device, at least
8 from the adverse event arena.
9 If there's a device that isn't in my system,
10 that doesn't mean it doesn't exist. It doesn't exist
11 in my system or in the MOD system until something gets
12 reported about it.
13 And so I broke out those reports for you
14 just so you could see the injury and malfunction,
15 death. And Other used to be a box on the form. It's
16 not on there anymore.
17 And one of the things I wanted to do was
18 also to show that there are some trends with the
19 devices that are using this off-label use. And you
20 can see the adverse events for those.
21 I don't have the denominator data for these.
22 I wish I did. I'm working toward getting that. So
1 it's hard to tell, well, how many invasive glucose
2 sensors have been used. I see 3,342 adverse event
3 reports, but it could be out of a million. It could
4 be out of 5,000. I know it's not 5,000, but just to
5 give you an idea of, you know, the struggles with
6 using this data. I just have to make the most of what
7 I can get and communicate it.
8 One of the things that I've mentioned for a
9 moment was that there are devices used against
10 contraindication. There was an example yesterday that
11 was presented about a device that contains a bone
12 morphogentic protein that was contraindicated for use
13 in the cervical spine. And so I had been curious
14 about how many instances that occurs. And I did a
15 search today during lunch, and I found over 2,000
16 adverse event references to cervical use with that
17 BMP. That's not in my slides because I did it today.
18 And so I'm putting up these numbers to give
19 you an idea of when a device has a contraindication.
20 That's when the FDA -- at least my understanding of it
21 is that they're saying not to use this device for this
22 use. And I think that that's different than off-
1 label, and that's why I completely separated these.
2 And this is to give you an idea that
3 physicians are reporting adverse events when these
4 things happen. They're not doing it enough. And just
5 to let you know, 99 percent of the reports from
6 physicians go through the manufacturer first and then
7 come to the FDA. And one of the things I'd really
8 like to see change is have those physicians reporting
9 directly to the FDA so that the message can't change.
10 The device names that were often reported
11 with contraindications, I've listed those. I haven't
12 picked on any companies. I hope that's appreciated.
13 And if you have any questions, though, I'm
14 happy to, you know, fill you in on what I have.
15 So one of the things that I think is really
16 important and that I want to stress is that, you know,
17 I've been a patient. I've been one of the patients
18 that had six years before they were diagnosed with
19 something. And if there was a drug that could fix it
20 tomorrow, I would probably want to be in the clinical
21 trial.
22 But I also know that when 70,000 adverse
1 event reports come in to the FDA each month, that
2 there's no way that physicians and scientists and
3 device companies even can comprehend how many problems
4 there are with these. And so I think more
5 transparency is vital because I'm not getting shoulder
6 surgery until I know all these things are fixed. And
7 I'm not taking a new drug until I know that if they
8 start to see adverse events that that's going to be
9 available and that they're going to be honest about it
10 and tell me how many injuries, how many deaths. And
11 that's what I'd like to see.
12 Thank you.
13 MS. KUX: Thank you very much.
14 Panelists, do you have any comment -- any
15 questions?
16 Thank you.
17 So we do have a couple of folks who signed
18 up for the open public comment. So I'm just going to
19 call you by name. And if you could come up to the
20 podium, I'd really appreciate it.
21 I've got Arman Oruc, and I'm really sorry if
22 I mispronounced your name.
1 (Side conversation.)
2 MR. ORUC: My name is Arman Oruc. I'm with
3 a small company in San Diego called Samumed. We're, I
4 guess, what you would call a small biotech, to use the
5 politically more benign term, as opposed to a small
6 pharmaceutical company.
7 Although, we do have -- just to give you the
8 context of why I'm speaking and why you should listen
9 to me, I think I'm the only person from that side of
10 the industry, the smaller start-up side of the
11 industry. Some would argue -- and I think I'm one of
12 them -- that a lot of the innovation in the industry
13 comes from companies like ours.
14 I happen to be an early investor in the
15 company, in addition to being the chief legal officer.
16 And that's a fact I'm proud of, unlike most other
17 lawyers maybe.
18 The voice of -- or the considerations, the
19 policy considerations, for the innovation industry are
20 often overlooked partly because we're small. It's
21 rare for a company our size. We only have about 150
22 employees, give or take, and most of those are recent
1 employees.
2 So for somebody like me to show up at a
3 meeting like this is extremely rare. And it only
4 happens because I'm a creature of Washington, D.C.,
5 and I understand the importance of these things.
6 Now, with that, let me give you a little bit
7 of background. We have a platform technology that's
8 applicable to many potential indications. It's in the
9 -- we use small molecules to regenerate tissue.
10 That's our aim. That's our target.
11 With that, I'm sure there will be a lot of
12 issues around off-label use if and when, hopefully,
13 one of our products gets approved. We have programs
14 in osteoarthritis, IPF, pulmonary fibrosis, alopecia,
15 of all things, and the list goes on. And those are
16 the clinical programs.
17 Now, I want to -- with that background, I
18 want to make two points that are critical to start-ups
19 like us. The first one was mentioned by a lot of
20 payers, ironically, maybe not that ironic. But the
21 notion of communicating with the payer community early
22 and often as we're going through the drug development
1 process is critical to our ability to survive.
2 And I don't say that lightly. It's critical
3 for our funding ability, which is a humbling
4 experience, if any of you have ever done that, trying
5 to raise money to get a start-up going and then
6 continue to develop drugs in this regulatory
7 environment.
8 So getting that input from the payers as to
9 how to develop the drug, how to position it, is a
10 critical issue. And we should be allowed with as
11 little restrictions as possible to have those
12 communications with the payer community pre-approval.
13 So that's the first point I wanted to make.
14 The second point is the tougher issue, and that's
15 really the main purpose of this meeting. And I have
16 very little to contribute other than to urge you to
17 consider the consequences of your next actions in this
18 area on how it affects incentives to innovate.
19 Specifically, you've been urged to stand
20 fast on off-label communications. I urge you not to
21 not because I want more liberal rules around off-label
22 communication. I want rules on off-label
1 communication. We need rules.
2 We're a small start-up. When we get
3 approved, I need to have now. I need to know what the
4 rules of engagement will be if and when we get
5 approved. I need to know those.
6 So the lack of clarity is disturbing to us.
7 And what I see is what the medical information working
8 group sees, which is maybe unfortunate for those who
9 want to stand fast on this current regulatory regime
10 on off-label communications. The law is moving. And
11 whether we like it or not, it's going to change. And
12 I urge you to find a regulatory regime for off-label
13 communications that are clear and would be consistent
14 with the constitutional law as it is developing.
15 The alternative would be to roll the dice
16 and continue to litigate. There are other agencies
17 that have tried that approach -- some with success;
18 some without success. I think here, given some of the
19 benefits in having clearer rules, clearer than rules
20 such as unsolicited versus solicited distinction
21 which, as a newbie to the industry, I still don't
22 understand.
1 Instead of rules like that, I think,
2 especially the start-up community would be happy to
3 see clearer rules that actually make sense on the
4 ground.
5 So with that, I'll conclude my remarks.
6 Thank you.
7 MS. KUX: Thank you very much for your
8 perspective.
9 Does anyone have questions?
10 Thank you.
11 Our next speaker is Kristina Gehrki. And
12 again, I hope I got your name right. Thank you.
13 MS. GEHRKI: Good afternoon. I wasn't
14 planning on speaking today, but I appreciate your time
15 and attention.
16 I want to first say that NAMI, if NAMI is
17 still in the room -- Mr. James, what was your name,
18 the speaker for NAMI?
19 I really appreciated NAMI's comment that
20 they urge, and I use the word urge to match NAMI's
21 verbiage, really appreciate that NAMI says they urge
22 the FDA to encourage clear and open communication with
1 patients and doctors.
2 And I would just ask NAMI if they would
3 maybe on their website be clear about their
4 communication with people who go to their site for
5 information and if NAMI would clearly disclose the
6 pharmaceutical money they take for their "research"
7 because if I'm going to NAMI's website for
8 information, I expect NAMI to do that clear
9 communicating.
10 And, oh, by the way, I have a masters in
11 communication. I actually specialize in risk and
12 crisis. And before my beautiful daughter, who you see
13 here at age 10, before she was chemically tortured for
14 eight years and then killed by telephone, I used to go
15 around the country and talk about how to communicate
16 crisis and risk.
17 So NAMI, please work with me so we can make
18 sure the FDA makes it a requirement and not a
19 guideline that when you're given a black box drug and
20 you are covered by the FDA black box warning that says
21 that drug can and does create suicidal thoughts and
22 suicide itself -- if that's important, Panel, why
1 don't you make it a requirement, not a guideline?
2 Because my daughter was given a black box drug, and we
3 were never told that it was an off-label use. And we
4 were never told that it could cause her death.
5 And guess what? When she was suffering from
6 akathisia, the doctor, who was probably told by NAMI,
7 paid no attention to those black box rules. They're
8 just silliness. The doctor, over the phone, increased
9 the toxin Zoloft to 200 milligrams, the maximum dose
10 allowable by law.
11 And because the doctor was told by the FDA
12 that the guidelines were so unimportant, that you
13 might suffer from akathisia and you might end up dead,
14 but it's just a guideline.
15 And let me read to you your guideline. I
16 know it by heart now. This is what the FDA states
17 about black box drugs, many of which, like my
18 daughter's, were given off-label.
19 "Patients, families, and caregivers," should
20 be closely who -- "should be informed when a black box
21 drug, SSRI," -- in this case, Zoloft, just like
22 Woody's -- "patients and caregivers should be informed
1 when a drug is changed by dose increased, decreased or
2 stopped, to," quote, "closely monitor and watch for
3 and report any unusual changes in behavior."
4 But when my daughter's doctor was called and
5 said that my -- and I told her my daughter died
6 because it was increased over the phone without ever
7 seeing her and she died 28 hours later, at 200
8 milligrams and 104 pounds, the doctor started
9 screaming because the FDA and NAMI discount those
10 black box warnings.
11 And I want to tell you what a doctor says
12 when she finds out that her patient, a 19-year-old and
13 5-week daughter, 105 pounds, who over the phone had a
14 drug doubled for an undiagnosed, unspecified illness,
15 takes their life in a violent fashion.
16 And here's what the doctor screamed. Oh, my
17 God, oh, my God. I can't believe it. Oh, my God. I
18 just saw her. She wasn't depressed. Guess what?
19 That's my daughter, Natalie. Look at her closely
20 because when you have a daughter and you go home and
21 hug your kids, I don't think anybody on this panel --
22 anybody -- is going to wish that you are not informed
1 of whether you're given a drug off-label or you're
2 given a drug that has a black box warning.
3 I travel a lot. And when I go to the
4 airports in Greece or Turkey or Sweden, guess what?
5 When you go to the airport, you see the cigarette and
6 the tobacco ads, and they are large. And you can see
7 them from the hallway of the duty-free shop. And it
8 says it can cause your death.
9 Well, let me tell you. If a drug has a
10 black box warning and it can cause your death, your
11 ego-dystonic suicide, which is not a suicide at all --
12 it's actually called prescripticide -- and the FDA
13 itself knew in 1993. Before my daughter was even
14 conceived, the FDA knew that the drug my daughter
15 would get 19 years later for an unspecified,
16 undiagnosed illness, off-label, you knew before my
17 daughter was conceived that that drug can and did
18 cause suicide among healthy people who had no history
19 of any anxiety or depression.
20 So all I can do today, in summary, is to say
21 I'm sitting out there and I'm thinking the last
22 speaker talked about the adverse drug reports and how
1 few people report adverse reactions.
2 How many of you on the panel right now are
3 sitting on data or don't know you're sitting on data?
4 Or maybe the pharmaceutical companies haven't given
5 you the data. Maybe you'll get it when the revolving
6 door comes back and they come back and work for you.
7 How many people in the FDA right now are sitting on
8 data or haven't looked at the data yet because they
9 don't have enough manpower? How many of you are
10 sitting on data right now that some of these products,
11 some of these off-label uses of these medical devices,
12 have already not only proven to be ineffective, but
13 caused deaths?
14 I want to tell you before I close. Let me
15 tell you a little bit about akathisia. You only die
16 from akathisia-induced suicide by getting a drug. My
17 daughter had no chemical imbalance. She had nothing
18 wrong with her. The doctor said over the phone that
19 she increased the drug because my daughter was focused
20 on dieting and exercising.
21 What really happened, quickly, is that the
22 doctor increased the drug over the phone without ever
1 seeing my child, because she didn't understand -- NAMI
2 listen up -- she didn't understand akathisia.
3 And so she assumed my daughter when she said
4 she was too sick to come in -- and my daughter was
5 coughing up blood -- and you can see that in the movie
6 about my daughter. You can actually see her note
7 where she says I keep coughing up blood because she
8 took her life, because as the FDA itself states --
9 this your quote, by the way, "Patients suffering from
10 akathisia don't take their life in a way that
11 traditionally depressed patients take their lives."
12 Rather -- please, FDA, if I'm incorrect, put in on
13 your website and correct my quote. "Rather, patients
14 suffering from akathisia take their lives because the
15 symptoms of akathisia are so overwhelming that
16 patients believe death is a welcome alternative."
17 So I'm going to say to you today. If you
18 want to see about my daughter's death and understand
19 why the blood is on your hands because you believe
20 that a black box suicidal warning is so
21 inconsequential that it should be a guideline for a
22 doctor and it should be printed in small print tucked
1 inside the envelope -- my daughter had no clue -- no
2 clue -- over the phone at 19 and 5 weeks that the drug
3 she was prescribed and doubled over the phone had a
4 suicide warning. But you guys did.
5 So I'll just say this. What medical devices
6 today do you know have already caused avoidable
7 deaths? And why would you want to do anything, NAMI?
8 Why would you want to do anything to reduce
9 communication about patients and providers? Because I
10 can tell you, my daughter's doctor wasn't happy that
11 she caused my daughter's death, and she was very, very
12 surprised.
13 Thank you.
14 MS. KUX: We appreciate your remarks.
15 So that closes our public hearing. And I
16 want to again thank everybody who spoke today for
17 their presentations over the last couple of days and
18 to you in the audience, both here in the room and on
19 the web, for all of your attention.
20 We're looking forward to comments to the
21 public docket, which closes on January 9th.
22 We -- the presentations we've heard today
1 have been -- and yesterday have been incredibly
2 thoughtful and insightful. So we expect more useful
3 information in the docket.
4 I'd just like to wish everybody a good trip
5 home and a good holiday tomorrow, if you have it off,
6 and adjourn the hearing. Thank you very much.
7 And before I leave, I do want to just say
8 thanks to Kristin again and to all of the other folks
9 behind scenes who have been helping. Four of them are
10 sitting at the table over there -- but the folks out
11 in the lobby as well who have been registering folks
12 because we wouldn't have been able to put on such a
13 great hearing without them either.
14 So a round of applause for all of them.
15 (Applause.)
16 MS. KUX: Thank you all very much.
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1 CERTIFICATE OF NOTARY PUBLIC
2 I, Nate Riveness, the officer before whom the
3 foregoing proceeding was taken, do hereby certify that
4 the proceedings were recorded by me and thereafter
5 reduced to typewriting under my direction; that said
6 proceedings are a true and accurate record to the best
7 of my knowledge, skills, and ability; that I am
8 neither counsel for, related to, nor employed by any
9 of the parties to the action in which this was taken;
10 and, further, that I am not a relative or employee of
11 any counsel or attorney employed by the parties
12 hereto, nor financially or otherwise interested in the
13 outcome of this action.
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16 Nate Riveness
17 Notary Public in and for the
18 State of Maryland
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1 CERTIFICATE OF TRANSCRIBER
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3 I, Wanda Burdick, do hereby certify that this
4 transcript was prepared from audio to the best of my
5 ability.
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7 I am neither counsel for, related to, nor
8 employed by any of the parties to this action, nor
9 financially or otherwise interested in the outcome of
10 this action.
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14 11/15/2016 Wanda Burdick
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