U.S. DEPARTMENT OF HEALTH
AND HUMAN SERVICES
ADVISORY COMMITTEE ON HERITABLE DISORDERS AND GENETIC DISEASES IN NEWBORNS AND
CHILDREN
Fourth Meeting
Thursday, April 21,
2005
Rotunda Room, 8th Floor
Ronald Reagan Building
and International Trade Center
1300 Pennsylvania
Avenue, N.W.
Washington, D.C.
IN ATTENDANCE:
Committee Members
William J. Becker, D.O.,
M.P.H.
Medical Director
Bureau of Public
Health Laboratories
Ohio Department of
Public Health
1571 Perry Street,
P.O. Box 2568
Columbus, OH 43216-2568
Amy Brower, Ph.D.
Executive Director
Medical Informatics
and Genetics
Third Wave Molecular
Diagnostics
502 South Rosa Road
Madison, WI 53719
Peter B. Coggins, Ph.D.
Senior Vice President
PerkinElmer
President
PerkinElmer Life
and Analytical Sciences
549 Albany Street
Boston, MA 02118
E. Stephen Edwards, M.D.,
F.A.A.P.
American Academy
of Pediatrics
Past President
2700 Conover Court
Raleigh, NC 27612-2919
Gregory A. Hawkins, Ph.D.
Assistant Professor
Department of Internal
Medicine
Center for Human
Genomics
Wake Forest University
School of Medicine
Medical Center Boulevard
Winston-Salem, NC
27157-1054
R. Rodney Howell, M.D.
Committee Chairperson
Professor
Department of Pediatrics
(D820)
The University of
Miami School of Medicine
P.O. Box 016820
Miami, FL 33101
Jennifer L. Howse, Ph.D.
March of Dimes Birth
Defects Foundation
President
1275 Mamaroneck Avenue
White Plains, NY
10605
IN ATTENDANCE:
Piero Rinaldo, M.D., Ph.D.
Professor of Laboratory
Medicine
Mayo Clinic College
of Medicine
Department of Laboratory
Medicine and Pathology
Chair, Division of
Laboratory Genetics
Mayo Clinic Rochester
200 1st Street, S.W.
Rochester, MN 55905
Derek Robertson, J.D.,
M.B.A.
Powers, Pyles, Sutter
& Verville, PC
1875 I Street, N.W.,
12th Floor
Washington, D.C.
20006-5409
Ex Officio Members
Duane Alexander, M.D.
National Institutes
of Health
Director
National Institute
of Child Health and Human Development
31 Center Drive,
Room 2A03
Mail Stop Code 2425
Bethesda, MD 20892-2425
Coleen Boyle, Ph.D., M.S.
Centers for Disease
Control and Prevention
Associate Director
Science and Public
Health Team
National Center on
Birth Defects
and Developmental
Disabilities
1600 Clifton Road,
Mail Stop E87
Atlanta, GA 30333
Denise Dougherty, Ph.D.
Agency for Healthcare
Research and Quality
Senior Advisor, Child
Health
540 Gaither Road
Rockville, MD 20850
Peter C. van Dyck, M.D.,
M.P.H., M.S.
Health Resources
and Services Administration
Associate Administrator
Maternal and Child
Health Bureau
Parklawn Building
5600 Fishers Lane,
Room 18-05
Rockville, MD 20857
IN ATTENDANCE:
Liaison Members
Joseph Telfair, Dr.P.H.,
M.S.W., M.P.H.
Secretary's Advisory
Committee on
Genetics, Health,
and Society
Department of Maternal
and Child Health
School of Public
Health
University of Alabama
at Birmingham
1665 University Boulevard,
Room 320
Birmingham, AL 35294-0022
Executive Secretary
Michele A. Lloyd-Puryear,
M.D., Ph.D.
Health Resources
and Services Administration
Chief, Genetic Services
Branch
Maternal and Child
Health Bureau
Parklawn Building
5600 Fishers Lane,
Room 18A-19
Rockville, MD 20857
C O N T E N T S
PAGE
Call to Order, Opening Remarks, and Welcome
R. Rodney Howell, M.D.
Committee Chairperson 6
Update on the American College of Medical
Genetics (ACMG) Report to HRSA
Peter C. van Dyck, M.D., M.P.H.
Associate Administrator
Maternal and Child Health Bureau
Health Resources and Services Administration 9
Discussion 11
Public Comments 100
Parental Education Session
Survey of States for Policies and Procedures
for Public and Professional Education
Donna Williams, M.S.
National Newborn Screening and
Genetics Resource Center 141
Parental Education Project
Terry C. Davis, Ph.D.
Louisiana State University at Shreveport 154
Sickle Cell Disease Newborn Screening
Education Project
Janet Ohene-Frempong, M.S.
President
J.O. Frempong and Associates 181
Discussion 204
P R O C E E D I N G S (9:10 a.m.)
DR. HOWELL: Ladies and gentlemen, let me welcome you to the fourth meeting of the Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children. We still, I might point out, are looking for a wonderful, easy way to name this committee, which remains complicated, and most of the monikers that have come forth were not appropriate for polite company. So we're still looking for ideas. So if you have one, please let us hear.
Let me thank the members of the committee for their very hard work, and also the HRSA staff that's been working very hard behind the scenes since we met last, and particularly Peter and Michele to my right for their excellent work.
The first thing on the agenda today is a minutes approval. Unfortunately or fortunately, the minutes that were in the binder of the members was not the final version that had been signed and sent forth. They were very, very similar, and I know people have read them carefully, but the thing is we will not approve the minutes until the official ones arrive, and they surely are on their way.
In the book of the members is the new charter for this group that was signed on February 3rd by Secretary of HHS. The charter is very similar to the original charter. There are a couple of important changes that I will simply mention. It's great that Jennifer Howse and Steve Edwards are now voting members, which is a nice change and so forth, and we appreciate that. There are certain other aspects to the charter about some organizations and representation that will require HRSA to look at and consider and come up with some ideas and policies about how to implement some of those changes. Again, those are decisions that will be made within HRSA, and they will have to think about that.
Since our last meeting, Secretary Leavitt has indeed been appointed and confirmed. I think you're all aware of that, but he is the person to whom we respond and to whom the report was sent. If you look at the agenda, it's very clear that we're going to spend a good bit of time on the ACMG report. The final report now has been in the public arena for some time. It's been on the HRSA website. I know that all the members have read it with great care, all 300-plus pages of the document, and I'm confident that many of the people in the audience have also read the report and so forth.
During the course of this meeting, we're going to have public comment today and tomorrow. We've historically had it on only one day, but you will notice that there are two days for public comment. In order to make public comment, one needs to sign up at the front desk, and if someone is here and wants to make a public comment, remember that you need to do that.
The second thing is that if you are interested in actually sending a formal comment about the ACMG report that would be appended to the material that goes forth to the Secretary, you need to either send that as an email or a letter, and those should be addressed to Dr. Puryear at HRSA. So if you want to make a formal comment, et cetera, to have that go forth.
You will notice also on the agenda today that there are subcommittee meetings. At the last meeting you'll recall that there were three subcommittees that were established, and those subcommittees have been working away on their areas of responsibility. Those subcommittee meetings are open to the public, as are the rest of the meetings. So if there's one area that's of great interest to anybody in the audience, you should feel free to go to those subcommittee meetings and so forth.
The original agenda, which I think many of you did not get, had some changes tomorrow, but the agenda as it is currently in your book today, the Guidelines for Newborn Screening and Follow-up, that order has been modified somewhat such that Drs. Vogt and Tuerck will start off with the newborn screening follow-up activities and quality assurance, and that will be followed by Brad Therrell's report on the performance evaluation and assessment system.
I think that those are all of my general comments, and we will come back to the minutes as soon as the individual members of the committee have had those and have had a chance to look at them, and we'll ask your comments about approval.
The major activities today are focused on the report. We would like to have that discussed. Dr. van Dyck will make some opening comments about that, but the plan that we have is that members of the committee will ask questions and comment about the report, and Dr. Watson, who has been responsible for overseeing the preparation of this report, has been able to modify his schedule in California to be with us today, and he will be able to answer some of the questions that other members will have from that.
Are there any other comments before we get under way?
(No response.)
DR. HOWELL: If not, why don't we move to the first item, which is the report.
DR. VAN DYCK: Thank you, Rod.
Good morning, everybody. It's a pleasure to talk about the report briefly this morning.
Just to make sure everybody is in the same place, the American College of Medical Genetics was specifically asked to develop recommendations to address five different areas for HRSA under a contract, and those five areas were to look at a recommendation for a uniform condition panel, including implementation methodology; model policies and procedures for state newborn screening programs, with consideration of a national model; a third, model minimum standards for state newborn screening programs, with consideration of national oversight; four, a model decision matrix for consideration of state screening program expansion; and five, the value of a national process for quality assurance and oversight.
HRSA did accept a final copy of the American College of Medical Genetics report, which is now in the public domain for public comment. The public comments are available for 60 days. The final comments must be received by May 7th, May 8th. Comments must be received by May 8th. The ACMG report is available, if you want to download it, at mchb.hrsa.gov/screening. Be prepared to wait a while for the download because it is a large document, but it is broken up into sections, and you can download sections.
Public comments — and this is important — may be received at a special fax number in the Maternal and Child Health Bureau, and that fax number is 301-443-8604, or you can send the comments by email, and the email address is screening@hrsa.hhs.gov. These are the only ways that your public comments will be accepted. You can send them by fax, send them by email, and you can send them by mail.
So if you want to send by the postal service, the address is the Maternal and Child Health Bureau at 5600 Fishers Lane. I'll go through this twice quickly. If you want the address, you can come up afterwards. Maternal and Children Health Bureau, 5600 Fishers Lane, Parklawn Building, Room 18A-19 in Rockville, Maryland, 20857.
We are soliciting and encouraging public comment. If you have anything you want to say about the report, please submit the public comments. It's very important to us to receive a wide range of comments and to hear from everybody.
Rod, I think, unless there are specific questions about the process, I think that's what I'd like to say.
DR. HOWELL: Thank you very much, Peter.
We're now open for the committee to comment about the report and have any questions about the report.
Dr. Howse?
DR. HOWSE: Can you hear me?
DR. HOWELL: Yes.
DR. HOWSE: Thank you, Dr. van Dyck and Dr. Howell. I actually just wanted to raise a question about what happens after May the 8th, which is the date by which all the public comments are, as I understand it, required to be received, to be considered.
Just, I guess, a couple of questions. One is will HRSA make available, downloaded please, in convenient print-out form copies of the comments to all the committee so we can look at the whole array of comments that have been received from the public? I realize it will be a magnum opus, but it's a very important magnum opus to us.
Secondly, could you explain to us and help us understand, so we know how to be helpful, what is the HRSA process for the review of these comments and the digestion of the comments? What's the internal process that you all have in mind?
Thirdly, what's the next step with respect to communicating the comments to the Secretary's office as was promised, Dr. Howell, in your letter to the Secretary, that these comments would be appropriately reviewed and passed along? I just thought it might be useful if we could understand the whole process so that the committee knows how to place itself and how to be helpful in the whole thing. Thank you.
DR. VAN DYCK: Well, I can answer the parts I can answer, and that is the comments will be public and so will be available. They probably will not be available in a downloaded form because so many are being written, but they're available on paper as well. Now, we'll have to look at whether we can scan them all and get them in the process, and it just depends. This is a massive workload, but I can report on that the next time. But the comments will be available to the public. So that's number one.
Two, the process. The process is that the Department will review the comments and will make recommendations to the Secretary, and that's as far as I know what the process will be. It will be up to the Secretary to decide what to do with the comments and the report.
Third, the comments are certainly, as in Dr. Howell's letter to the Secretary, wishing to comment on the public comments, the committee is welcome and I think it's advisable and important for the committee to comment on the public comments as well, and they will be available to the committee to do that.
DR. HOWELL: It would certainly seem to me — two things. One is that the committee members should have access to all the report; and secondly, we should then discuss those in this setting and then make comments and/or recommendations that would go forth to the Secretary from this committee. I would think that would be essential, because, number one, we said we were going to do it, and I think we should look at those and so forth, look at all of them and make comments about them. I would imagine, having not seen the comments except for the handful that people have sent me as a courtesy along the way, it would strike me that many of the comments are going to be in a similar vein as far as things that would be very important to do in the future in newborn screening and things of that nature.
So I would imagine, although it's going to be voluminous, it's going to be fairly readily digested and commented on, would be my guess. I may be wrong.
Anybody have any comments about what you would like to do with all of this stuff and how you'd like to handle it and comment about it?
DR. RINALDO: Can we have an idea how many comments have come in so far?
DR. VAN DYCK: I'm not sure they've been counted. The comments just come.
DR. RINALDO: Dozens? Hundreds?
DR. VAN DYCK: Michele, do you have some gross idea?
DR. LLOYD-PURYEAR: Dozens. Close to 100.
DR. HOWELL: So it's not an overwhelming number at this point.
DR. HOWSE: Could I just be a little more persistent on the availability of a compilation of these comments to each member of the committee? I mean, rather than us chasing down what's been faxed and what's on the website, et cetera, can we just ask that you all, when the comment period is over, you assemble the comments, you print them out for us, you send them to us in a chunky folder or a less chunky folder, depending on how many show up, and then we've all got the same thing that we are looking at so that, Dr. Howell, to your point, the committee members are assured that we're all reading the same thing, we're all looking at the same comments, and then we also have the valuable comments, Dr. van Dyck, that you and your team and whoever else on HHS is going to weigh in on these comments, we could have those as well, so that when this committee reviews, we know what we're talking about?
DR. VAN DYCK: Yes, that's no problem.
DR. HOWSE: That would be great.
DR. VAN DYCK: That's no problem.
DR. HOWSE: I'm not clear about the timetable for the next steps. When do you pass along — when does the Secretary get the final letter from Dr. Howell? I don't know whether you do a separate one either from HRSA. But when does the Secretary have what he has about the report and about whatever the public wants to say about the report? So that at least it's all in and it can be considered, then. What's our role? When are we going to have something at the Secretary's desk so that at least we've discharged our responsibility to look at comments, review comments, and get the final take? I'm just not clear about that timetable.
DR. VAN DYCK: Well, you're talking about two different processes. One is the committee's process, and the committee has direct access to the Secretary. So whenever you get — whenever we get, I should say, as the committee our comments finished, then they're sent to the Secretary. So that's a matter of committee business and is up to the committee as a process.
The other process is the internal Department process of reviewing the comments and forming some document that goes forward, and I don't know what the time period for that will be. Clearly, it's an important process and we'll move as quickly as we can.
DR. HOWELL: Our next meeting is in July, and certainly we should be able to get the material from HRSA and review it and discuss it and come up with some conclusions at the July meeting. Is that fair?
I think it would be helpful to also have a little understanding about how the federal agencies will weigh in on this document, because the federal agencies will also weigh in on this document in some way, as I understand it. Is that correct, Peter?
DR. VAN DYCK: Well, the federal agencies can certainly comment during the public comment period, but there will be an internal Department process where the agencies are officially asked to comment and weigh in on both the report and the public comments.
DR. HOWELL: Do you think that's workable, Jennifer, as far as the time frame? In other words, to get the material to us in May, that will allow a considerable period of time before we meet in July to review it so that we should be able to come up with a document.
DR. HOWSE: I think that's up to the committee members to comment. I mean, that seems appropriate, and I think Peter has been very clear that that's a committee process and we have to be responsible for setting our internal deadlines. But I can't speak for the committee about what they do for fun reading.
DR. TELFAIR: Dr. Howell, first of all, I want to just say that I appreciate the work that has gone into that report. It's pretty extensive.
The suggestion or thought that I have about how this committee could work with the report in terms of just making it a little bit more realistic in terms of timing and work is that there are three committees, subcommittees, and I don't know whether or not there's ability to triage some of the comments into those groupings for the committee in some way, for the subcommittees in some way, so that the subcommittees can take responsibility, at least for their part, and then come together with a larger report, even though that still leaves the option open for everybody to look at it as well. I'm just trying to think of how to expedite the work, make it a little bit more digestible, and coming up with a way that's more relevant to what we can do in terms of passing that on to the bureau.
DR. HOWELL: Did everybody hear Dr. Telfair's comments? I guess it depends on the nature of the comments about whether or not they might logically fit into one of the subcommittees. I don't have a clue about how that's going to fall out.
DR. TELFAIR: I understand that, and that's why I was saying maybe we can consider a triaging way of getting it done. I mean, all the comments will be reviewed as they come in, and if they fit into one of the categories or one of the purviews of one of the subcommittees, we could do that, knowing that there may be some overlap, and we can just make that a judgment call. All I'm saying is for the ability of the committee to actually get us some substantive comments back or some substantive input and come up with a mini-report or whatever. It would be a little bit more realistic to divvy the work up, instead of having everybody on the committee be responsible for — and we can all discuss it. It doesn't eliminate the option for discussion. It just makes it a little bit more digestible, I think.
DR. HOWELL: Well, that's interesting.
Amy has a comment.
DR. BROWER: I appreciate that. I think for me, for my own education, I'd like to read all of the comments and consider them all and not have them subdivided into the committees. I think that if we're worried about the workload or anything, we could consider having a conference call of this committee prior to the July meeting so that we come to the July meeting with some understanding of those public comments and of people's initial impressions of those.
DR. HOWELL: So your suggestion would be for everybody to look at everything and then have a conference call maybe to comment about them. The ones that I've seen — and again, I've not seen the documents because HRSA gets those, but that people have sent me as a courtesy or something — have been very similar. I mean, they basically said the same thing, and those that have had particular issues have had the same issues, not surprisingly, the same as many of the issues in the report.
Any further thoughts about the public comment?
(No response.)
DR. HOWELL: But the bottom line, we will get it soon, after May the 8th, and we will get them all, and I sense that there's an interest in the group of seeing them all. Is that right? I see nodding of heads. So perhaps we'll have a conference call, and it's possible that if there are specific issues that fall within one of the subcommittees, we can ask the subcommittee at the conference call to please think about a response to that.
Coleen?
DR. BOYLE: I guess I'm a little unclear about today's agenda, then, because will we be discussing this again in the July meeting? I feel like we're doing duplicate work without all of the information. Obviously, the public comments are an important consideration for our comments today. So it's just more of a comment than anything else. I feel like we don't have the whole package yet. That's all.
DR. HOWELL: Well, we don't have the public comment, but I think that the purpose today is to discuss the ACMG report. The public comment period is not over, so we can't get them until it's over. That's just a timing issue.
DR. BOYLE: I realize that, but the report is a final report. So we're not changing the report. It's already been delivered to HRSA. So in a way, we're sort of putting together our own thoughts about what we're sending forward to the Secretary. Part of that compilation is obviously the public comment piece. So again, I feel like maybe we're doing our July-related meeting.
DR. HOWELL: What comments do we have from the group about the report as it is here? In other words, we've got the final report from the ACMG, and we've been waiting for a long time. People have read it and so forth. What thoughts have you about it?
DR. VAN DYCK: Rod, can I just clarify Coleen's comment a little bit?
DR. HOWELL: Yes.
DR. VAN DYCK: I thought the purpose of today's meeting and discussion on the report was to comment within the public comment period on the report from the committee.
DR. HOWELL: Yes.
DR. VAN DYCK: And that the July meeting, then, would be to make additional comments related to the public comments that you would then have that would supplement your comments that you submit today.
DR. HOWELL: We're going to later comment on the comments I guess it's fair to say.
(Laughter.)
DR. HOWELL: Today we're commenting on the report and so forth, et cetera. I think we can say we think these comments are wonderful or we think they're out to lunch or whatever the group happens to think about it.
What about the report? We've been talking about this report forever, and you now have it. Jennifer, what do you think about the report? You've obviously thought a lot about it.
DR. HOWSE: We're on record, sir, with what we think.
DR. HOWELL: Steve?
DR. EDWARDS: I want to raise a question not so much about what I think about it as to some of the comments that have been raised by an organization that I represent, because I think that unless we can dispel this question, that we can't really move on to any further substance, and that question is this, and that is related to the scientific validity of the study. So I think we need to lay that out. We've got Mike Watson here today to help us with that. We've got a bunch of people around this table who are all more scientists than I am. But I think unless we're clear on the scientific validity of the material that's been presented to us, this basic foundation of the work that we're doing, that unless we're all totally clear and in agreement on that, then it's hard to move ahead, and that is one of the considerations that I have heard.
So it may be, Mike, like asking you to prove you don't beat your wife, but I wonder if we could go through, and I would appreciate discussion from colleagues at the table, too, who are scientists, because I think that that's the foundation of what we're discussing. Unless we have true belief and consensus on that, then it's hard to go any further. Is that too much to ask?
DR. HOWELL: I don't think so. I think one of the questions has been focused on the methodology of the report and some comments about the methodology and how that evolved, the substance behind that and so forth, and I think that's a perfectly valid question for Mike. Joe and you and Coleen have some additional questions that would ride on top of that?
DR. TELFAIR: Yes, actually, I did, a little bit more about the final decision-making process and the algorithm that went into that, because that was not as clear to me as the initial algorithm in terms of the decision-making. But when the final tabulation was done, that was not as clear in the report. So I, too, have similar questions, and that would be really helpful if that was explained.
DR. HOWELL: Coleen, would you like to amplify that?
DR. BOYLE: Well, I guess I feel like I'm on record with my concerns about the report, and they remain. I guess I feel similar to Joseph, that it was very difficult in rereading this version of the report. Again, I want to applaud the authors in terms of the development of the report. I think this represents an enormous amount of effort, and it was a very challenging project. But I still think, based on what's in the report, what we had asked for back in September was a clearer development of the methods and the results and the discussion around that, and I feel like it's still very unclear to me how the final product was arrived at.
DR. HOWELL: Maybe Dr. Watson could come up and sit at the table and respond. I think that for many people who are moderately close to this report, the decision that went into it and the evolution went on for a very long time, and a tremendous discussion about how do you make decisions about extraordinarily rare conditions, some of which have a lot of material to allude to, some that have little and so forth. Mike has certainly spent a very large amount of time with a group of very smart people answering, working on these questions.
DR. WATSON: I'm not sure I have a specific question yet. I mean, it's quite general, and I'm not sure exactly what kind of response to start with. I suppose I can — I guess as I think back over the course of the deliberations of the expert group, one of the things that was strongly taken into consideration was the fact that we were, to a large extent, at least in many of the new disorders that were being evaluated, we had to rely on expert opinion. We acknowledged that expert opinion is not the highest quality of evidence base that one can work from, but at the end I think it was felt by those who were experts in the diseases that were recommended that the message was so clear that we had to accept the likelihood that the observations were correct in the expert literature.
Where there was higher levels of evidence available, either because there were clinical trials around therapeutics or in more common conditions like hyperbilirubinemia and such, there are certainly a large number of very strong evidence reports, the Cochrane reports and others in some of the more common conditions. But I presume that the question is about many of the rarer disorders that are included in our list.
DR. BOYLE: I feel like I'm sort of on the spot here, because I feel like maybe I'm the one dissenter on this report, and I feel like I have expressed my opinions. I guess what I'm talking about more is in terms of the actual methodology we used. We all acknowledge that the methodology was on the committee, so there was the expert opinion methodology. My problem with the report is that it's somewhat disguised, and I don't want to say this in a negative way, but it's sort of disguised as being a systematic review.
There is a whole science around systematic reviews and how to conduct a systematic review. Unfortunately, Denise isn't here, who is sort of an expert in that area. I agree with many of the rare conditions, there is no literature, and that's acknowledged. But I felt like the way the report was done, we started with the expert review, and then as sort of an end process we brought in the scientific literature as a sort of a complement to that expert review. In a systematic review, you would do just the opposite. You would start with the science and then fill in the gaps, what information you don't have, with expert review.
Again, I feel like the merging of those two pieces or those two lines of evidence in the report is a little bit muddy. It's not quite clear how those two were brought together and the final decisions were made. Part of it is just acknowledging, and I think you tried to do that in the Limitations section, acknowledge the gaps in the literature. The other thing you could have acknowledged in the gaps in the literature is, again, there's a science base about expert review and the challenges of using expert review information only, and that really wasn't brought in in terms of the biases that are introduced through that methodology.
To me it's those kinds of things. I feel like I have written comments, or we have written comments as an agency that we'll share with you. But that's really more the issue with the report, and the clarity of the process.
DR. WATSON: I'm still not quite — I mean, there's a lot of questions there, and I think one of the presumptions is that I've actually been at all the meetings and have heard your comments, and I haven't. Whatever comments have been submitted from you and other organizations I've never seen. So I suppose I have to wing it.
I think a lot of the way that we approached developing the evidence and the approach to the survey was somewhat driven by two of the international groups that presented to us. Rodney Pollitt, who had done one of the first health technology assessment reports, argued rather strongly against being overly bogged down in the criteria and those sorts of things, acknowledged that there was a significant component that rarely gets recognized in these sorts of evidence-based processes, and that was that there's a value aspect to newborn screening conditions that is realized by the public that doesn't necessarily get acknowledged in the approaches taken in some of the more common evidence-based approaches to analyzing the literature.
We wanted to give, and in fact our contract required that we actually give strong credence to the opinions of the public, the consumers, scientists from state health laboratories, a wide range of people. Given that fairly direct charge to us in the contract, we chose to start by soliciting that broad perspective from the wide range of people so that we would be able to factor it into our decision-making from the start. I will admit that I was uncomfortable by starting with the survey because we acknowledged that there were certainly components of it that are objective and that ultimately one could not use a survey to determine the incidence of a disease, that you had to ultimately fold in that evidence base and confirm anything that was presumed from the surveys to have been reflected, and justify it based on the evidence base itself, and we did that secondarily.
I'm not sure what would have happened had we flipped the order of those two processes around by first developing the evidence base which, for most of the conditions in question, is largely expert opinion based. So we acknowledged that we would be beginning with a relatively weak level of evidence quality based on the types of studies that develop that evidence, and then overlay the views of all those other constituencies. I'm not sure we'd have ended up in an entirely different place.
DR. HOWELL: Dr. Rinaldo has some comments because he was involved in a lot of these efforts early on.
DR. RINALDO: Coleen, I would like you to clarify something, because as you bring up the issue about the muddy methodology, now I think it's for me necessary to understand. Are you questioning the end product? Because this was a process to generate specific recommendations for new overarching principles and the recommended panel.
Now, I would like to understand, is your problem with the process that led to actually a correct product, or you have a problem with the final product? And if so, specifically. Because we're looking at specific criteria and specific conditions. So perhaps we can take any specific issue that you have a concern and try to analyze what happened there and perhaps what is wrong, because I think this discussion, as far as it remains on a very general level, it really is strictly subjective. It's either you like it or you don't. But I think the real question is, is it right or wrong?
So perhaps you can elaborate a little bit and give us specifics.
DR. BOYLE: I guess in terms of the final product, understanding how one arrived at the final product is understanding the process and the evidence that went into that. So although I can't say I have exceptions with the final product, again my expertise is in epidemiology, and part of that understanding of the final product is understanding how that evidence was derived. That's more my issue.
Another one sort of following from that as a committee work, I would like us to arrive at a process, because obviously we'll be considering other conditions that would be amenable for newborn screening. I would like us to arrive at a process that we all feel comfortable with in terms of how to evaluate these conditions as they come up.
DR. RINALDO: If I can respond, the process is actually clearly outlined in here. So again, what I'm trying to get is something tangible that I can analyze or review and try to really debate the pros and cons. So there is a flow chart that specifically addresses the issue of how we will deal with additional conditions that certainly will come up and should come up. So I really think to have a productive discussion, we need to have something specific to talk about. So give us a few examples.
DR. WATSON: I would actually expand on that a little bit and say that one of the fundamental difficulties in this whole process was that a committee of 20 people with a wide range of background and expertise, not all of whom really — and frankly, I'm not an expert in more than a handful of the conditions ultimately in our list or that we reviewed, and we had to rely, because we acknowledged it on the front end that it's expert opinion. We ultimately did have to rely heavily upon experts in providing the information on which we based the evidence, on telling us whether or not they felt the evidence was strong or weak. For 78 diseases ultimately analyzed, it would have been extremely difficult or costly or something to bring all of those experts to our meetings.
There were two or three experts for every single disease on the back end of the evidence base, and a different set of experts on the front end in the survey process. We acknowledged that the survey does include a wide range of opinion, but we also state in the report that we sorted out experts within all of that survey to determine that they were consistent with all of the final results of the broad group that participated in that part. There is some overlap between the experts in those two parts of the report, but I think as an ongoing process, I actually think it's going to be much easier than what we had, because you can focus on a handful of diseases at a time and bring together a core group of experts who can deal with those conditions.
That was very much more difficult for us because we had 78 conditions and a couple of hundred experts around the world who provided the evidence and validated our evidence base for us. I think that probably underlies a lot of the difficulty, the fact that we had to and we did rely upon a lot of people outside of our committee because we, I think, acknowledged that if you're left with expert opinion — I mean, I think what evidence-based medicine likes to be able to do is to develop an evidence base that hopefully has lots of those well-controlled studies that somebody that doesn't understand the diseases can step back from it and say, okay, these are all very wonderful studies, and on that basis alone I can accept this answer.
When you have to go with expert opinion, you're not in the position for everybody to step back and really react that way to the final result. I'm not sure that it's even possible to get out of that problem. Of the few comments I've seen, I know that the Committee on Genetics at the AAP acknowledged right off the bat that expert opinion is certainly a valid type of evidence, and it is what we have to work from. We would welcome national collaborative studies that allowed for aggregated data and all of the kind of information we'd like to see collected in an organized way. But we don't have it.
DR. RINALDO: Does it exist?
DR. WATSON: Well, it could exist if we had a children's oncology group model through which we aggregated all patients into a structure that was funded by which we could actually understand this wide range of patient outcomes that are possible. A lot of things we don't really have until we move to large-scale population studies. That's one of the banes of our existence in genetics, that we're always going from that which we have, which always starts with the most biased view of a disease based on those people who came to you, usually the most severe versions of anything. Gradually you work back through families, and you find it's a little bit broader than you thought it was. Then you move into targeted phenotypes and you begin to get a broader sense of the condition.
But in our world, it's not until you really get to that population level that you begin to really understand the full breadth of the condition. I think FDA has recognized this in much of what it's been doing with rare diseases, and CMS is moving in the exact same direction. If you look at the way FDA has dealt with therapeutics for rare diseases, they've acknowledged that a clinical trial with 50 patients is compelling enough to say let's approve this as a Phase III clinical trial. However, now they start to really push the back end, which is Phase IV surveillance, to make sure everything that you thought was the case remains the case.
I think that's going to be one of the fundamental issues that we have to build into this whole process, an ongoing monitoring of what's happening with those identified in the programs. We need to find ways of collecting that data in a uniform way.
DR. HOWELL: Dr. Alexander?
DR. ALEXANDER: Mike, I'd just like to pick up on those comments and say that in a perfect world, we would have gathered this information ahead of time in these rare disorders, but there's really been no organized way to do it. Only with implementation of screening for these disorders in a broad way, in a manner that we will be able to identify larger numbers of patients even with rare disorders and enter them with their parents' permission into studies of the available therapies is it ever possible to gather the size of population that we need to get the evidence that we're all asking for.
In the meantime, we have to deal, bad as it may be, it's the best there is, with expert opinion. That happens in medical practice all the time. We try to get away from it as much as we can and gather the information as quickly as we can through controlled trials, and that's the way we're learning to do things.
The only way we're ever going to get to that point in these disorders for which we're talking about screening, because they're so rare, is to do the screening for them, gather the patients into groups where we have trials going for each of these disorders of interventions that we think are effective based on that expert opinion, test that intervention, and whether it's 10, 15, or 20 patients, and gather that data. The impediment to gathering that data is the lack of screening, and until we do that screening and gather these patients as a population for study, we will still be in the realm of expert opinion.
We have to be able to start this screening, gather the population that we need, with studies planned ahead of time on these rare disorders, approach the parents about getting their permission to enroll their children in planned studies of these interventions so that we can change expert opinion into evidence base, and that's what we have to do. But we can't do it until we start screening in an organized way.
DR. HOWELL: Coleen, do you have any further questions or comments? I think that the committee meetings that were involved in the preparation of this report that I was in echoed a lot of Dr. Alexander's comments, and also a tremendous interest in developing a system whereby every child identified in the country with a rare disorder is entered in a study with, again, the parents' permission, to learn about the condition, because some of the conditions are so rare that we don't know a lot about them. We know that sometimes lack of treatment might lead to sudden death or damage, but we really don't know much about the effectiveness of the treatment or what might be improved and so forth.
Let me ask a question of the group. One of the key issues of this report is in the beginning in the area of overarching principles. Again, those were derived over a long period of discussion with a variety of people. You say, well, gosh, this is very much like the principles that I've seen over the years, and I might point out that the Wilson and Jungner principles that are reported commonly — most people have never read Wilson and Jungner's report. I have. It was derived to look for treatable diseases in adults in developed countries. It had nothing to do with newborn screening but screening for disease and so forth.
But the one thing that's clearly different in these recommendations that the committee I think felt strongly about is to broaden the definition of potential benefit from newborn screening, with the idea that there are broader benefits than have historically been recognized and that benefits to families and so forth might accrue when there's not a curative treatment at the current time. I'd like the group's comments about the so-called overarching principles, because that's the basis on which this report I think will be used in the future.
Does anybody want to comment about that? Does anybody disagree with the concept that there might be a broader benefit to people in society than just direct treatment but knowing about a condition early and the possibility that such a condition might have treatments, such as early childhood intervention or something of that nature? Those are not yet proven. But any thoughts about that, comments about that?
DR. BECKER: Rod, I agree that, certainly, given the limitations that we've discussed about the expert opinion versus the traditional rigorous evidence-based review, certainly it's a paradigm shift, and I think that's really what Coleen is talking about. It's not the traditional well-controlled evidence-based study that I think we're used to seeing or maybe our clinical colleagues wish to see. For all the reasons that we've talked about, it just doesn't exist, and this is probably the best product that we could put out at this point in time, keeping in mind Duane's comments that it can get better with enhanced surveillance.
I think from the overarching principles, it also represents a little bit of a paradigm shift in that traditional public health screening programs don't just collect data or don't just collect information without a specific benefit or intervention that's been shown to either be effective at the personal level or effective at the financial level to society as a whole. So I think we have to acknowledge that there again maybe a slight change in the perspective that communities or society as a whole are going to have to get used to thinking about if that's what we decide to endorse.
I'd be interested in hearing Steve's comments. Steve actually brought up the original question about the scientific validation and, from his organization's perspective, if this conversation has been enough to fill in some of the gaps or questions that he had.
DR. EDWARDS: Well, you said what I was looking for, and that is I think that's the question that I was raising, not is this a perfect instrument, but I think that this committee has to look at it not necessarily as the perfect instrument but the best available, and I think those were the kinds of words that you used, and that was very assuring to me. I guess the question shouldn't have been directed so much at Michael as at the rest of the committee, especially those of you who are involved in the research arena.
But I think that this is a fundamental question that I have been comforted by, and then as these questions have arisen, then I was discomfited by. But I'm not asking if this is a perfect study. People talk in pediatrics, my field, all the time about doing things on the basis of evidence, which is wonderful, except that there are very, very few conditions that you can study on an evidence base. I mean, evidence base is a goal. It's out there. We're all working towards that. But if you wanted to look at the practical now for most pediatric conditions, you don't have evidence-based information.
So I'm not asking that we operate in a perfect world, but I would like to be reassured by those who are scientific investigators at this table that they feel that this methodology is maybe not even the best that we could come up with but among the best, that this is very good information, because I think that's basic to the work that we have to do as a committee. If it's not, then we're at the wrong discussion. We need to be comfortable about that before we move on.
So again, I'm not asking if this is a perfect study. I'm just asking if this is close to the best that we can come up with.
DR. HOWELL: Amy?
DR. BROWER: As a scientist, when I read the report, I actually thought that the approach was elegant and that starting with the survey was a great thing to do in addressing these types of rare disorders. So actually, as I read through it, although it's not a standard methodology, I really thought that there are some things that we can model other surveys and other things like this on, because it's really a different paradigm. We're really talking about addressing a different set of issues, and so we need to think about it in a different way. So I didn't have scientifically any problems with the report, and I actually thought it was put together very well.
DR. RINALDO: I think these are all valid issues, but my goal is to force a discussion of the specifics, because if we have a problem or we perceive there is a problem with how this was done, then I would like to know. Were we asking the wrong questions, or were we asking the wrong people? Because you can have the perfect set of questions, and you ask the wrong people and whatever comes out of it is pretty much not very useful. On the other hand, you might have an array of the best experts in the world, which I believe were involved in this process, but if we're asking them the wrong questions, then again, we really don't make much use.
So again, I would like to know what was wrong. Were we asking the wrong questions? Didn't ask enough questions? Should the questions have been different? Again, I really need to get to the root of the problems, real or perceived. We've got to focus on something specific. Clearly, being involved in that process, I obviously have a bias. I really believe, though, that the effort that was put into involving everybody who could possibly have something to contribute to this was unprecedented.
If you look really at the list of names of the people who appeared and served on our committees, including many of us, and we met I don't know how many times, and then the external review group, and then the steering committee, we really reached out in every possible way. So again, tell us, please. I understand and respect your expertise. As epidemiologists, you might look at this and say these are the problems, but I really would like to have a better idea or a specific idea of what the problems were.
DR. HOWELL: Joseph?
DR. TELFAIR: Well, I guess I can't answer your question because that's not what my comment was going to be, because I think it has been covered very well. The questions that I had have been asked very eloquently and have been answered very eloquently. My question is in sort of the next level of this, which is taking the information, particularly the way the decision-making was made, and I was wondering because that's one thing I kept looking for, how would this be used by those who have to use this information to make decisions. In other words, I was looking for a little bit more of a structure.
Given the way states and given the way municipalities have to make decisions about allocation of funds, involvement of others in these processes, how would they use this information? Is it going to be something that comes out of that? Which is why, when I was thinking about comments and structuring this, maybe that's something this committee can do next, or not, but that was my next step besides just clarification on what was done. So I'm not speaking to problems, you understand. It's more the utility issue here.
DR. RINALDO: Absolutely. I think, though, that we have to really recognize the reality and the impact that the report has already had. We're hearing almost daily — the last was two days ago, that Arizona has decided to pursue and approve a bill. So it's becoming, in the newborn screening arena, the concept of this panel I think is now pretty well established. So people are actually working to reach that level.
So I think that's the first phase of a response, how people will respond, and I think, from what I've seen so far, the reaction is that people say, well, we have to catch up with this panel. It seems very interesting that when I talk to people in state newborn screening programs, they are almost fearful of the March of Dimes report card.
(Laughter.)
DR. RINALDO: I can tell you that next week in Minnesota, the newborn screening advisory committee will meet, and there was all this discussion about the things we have to add so we are complying and we get an A in the report card. I don't want to discuss that too much.
There is one disease that was excluded, and I think correctly, and that's Wilson disease. I can tell you that in our little county in southeastern Minnesota now, we're screening on a voluntary basis, a research program. But it's actually very helpful that once we collect the data, we can actually go back at the state level and physically modify it, and I believe it was included in the survey. We'll use a survey, and this time we'll have a way to score this condition and compare it to what has happened historically for all the other established conditions.
I think that is actually another tangible product, because before — and I don't know if anybody can make a strong argument against the fact that most of the decisions made in the past were very subjective. Again, I don't think perfect really exists in this world, but if I look at this report and what it has forced to happen, I think we have made some significant progress, going from a totally subjective criteria — we were discussing with Brad earlier that there is one state that has one particular condition not included in the panel, and they had adamantly opposed any discussion of why it's there, because they have one member of the advisory committee that says so.
So if we can move from that stage to a stage where it's somewhat muddy, I agree, but it's certainly a sizeable step in the right direction, I think we should be somewhat happy about it, feel that something has been accomplished, and now work on it and improve it.
I just want to add one final comment about what Dr. Alexander said, which is absolutely right, because we have this definition of rare diseases, but remember that 4 million babies are born in the United States every year. So a disease that's 1 in 100,000 means that it will take five years, and we might have between 150 and 200 patients. Even if not all agree to be part of a research project, how many rare diseases you can think of in a population study with a denominator of 100? That will be phenomenal progress and I really think what this whole process is shooting for, trying to create an evidence base for things that now don't have one.
DR. BOYLE: I don't disagree with anything in what you said. As a matter of fact, I'm right there with you, and I'll follow up on Mike's comment earlier about the Phase IV studies and the fact that part of our responsibility as a committee is to really drive home that message, the fact that we need to follow up on these children and we need to develop the evidence base. So I'm not at all arguing with that, and I do feel that we have moved the field forward in terms of trying to be much more analytical about the approach in terms of trying to decide which conditions should be included in the newborn panel.
I think that the survey and the criteria that were outlined really do help a state think through all of the different aspects of that, and they can take it at their level and sort of pull that apart and weight things differently with the criteria they feel in their own advisory committees are most important, not that our judgment or this committee's judgment or the director's judgment is the most appropriate one.
DR. HOWELL: I think the Phase IV thing is critical and is of great interest.
We have a number of people. Start with Bill, and Mike, and Greg.
DR. EDWARDS: And may I suggest that the chairman address this, too?
DR. HOWELL: The report per se? Let me make a comment about one specific area, and that is that in considering the individual rare conditions, one of the questions that obviously arose is how do you have expert input, which is a key part of this study, and that was quite systematically done, basically looking at who has published on the thing. In other words, people that have written about the conditions and are recognized in the literature as being the experts are the people that weighed in on the expert opinion, and I think that you can be very comfortable with the fact that it may not be everybody in the area, but it's certainly a strong representation.
Interestingly enough, at certain times that I remember, particularly one problem that came up with hypothyroidism, the group looking at it felt that they had not had all the input that was needed, and so specifically people were actually solicited and said, you know, we need you to look at this particular condition because you're a known expert in hypothyroidism and so forth. So I think that the expert opinion, which I think is a very important part of this — the literature is there. You can see what it is. But the expert opinion I can assure you was very carefully done and is probably as good as you could get. It's not perfect, but it's probably as good as you could get.
Now, one of the problems we've dealt with — and I'll be very candid as the chair of the committee — we've had some people that have said, oh my goodness, you didn't have this group represented and so forth. We did not necessarily have the complainant represented, but we had strong representation from that area of expertise.
Bill?
DR. BECKER: I don't think I could say it any better than Rod did. It's the best evidence that's available to us at this point in time. As Coleen said, it's a model. As Piero also suggested, it's a model that can be improved upon as we gather more information about this. Having worked with a number of colleagues on the expert group and now on this committee, I think, as Coleen said, it does advance the field in a very substantial way, and I'm very pleased with the report and the conclusions that the report came to.
DR. HOWELL: Mike?
DR. WATSON: I'd add the fact that I think the charge to this particular committee extends well beyond newborn screening. It's heritable diseases and genetics disorders of newborns and children, and getting newborn screening to the point where we're actually able to collect the best data because we're collecting it at a population base level is — I mean, you've got problems coming like you don't know in the world of genetics. The lysosomal storage diseases are coming down the pike very quickly. The therapeutics may very well be there before the newborn screening test is. Fabry's is already approved as a therapeutic, yet we have not gotten to the point where we're identifying those people in a large general population to really understand the breadth of the condition.
So I think you need to think broadly as you look at how you're going to collect information in the long term and not just focus on newborn screening but extend to the entire world of genetics. Right now, every time I read something about clinical trials, they're taking another year longer because nobody can get the patients to really run the clinical trials in an appropriate way. They're getting very many fewer patients and they're much less comfortable with the data they get from those patients.
We know that the next set of conditions, as I look at the lysosomal storage diseases and think about what's coming down the pike there, this is a group of disorders where every time I turn around the proportion of patients who are adult onset versus infantile, what we really thought used to be the classical form of the conditions, is shifting to these adult forms. So we've got huge problems to sort out in the future as we identify people in screening programs who may not have what we thought was the classical infantile form of the disease but may not have onset until their 20s, 30s, 40s, yet may come up positive in a newborn screening test. We need to capture these patient populations now so that we've got them to have enough statistical power to really do these things in a reasonable time frame so that we don't go too far too fast yet have the information to inform us about where we ought to be going, but get it in a quick way.
So I would think much more broadly in developing programs by which we're going to monitor this stuff beyond just newborn screening, where we're talking about 50 some-odd conditions and think about those other 800 or 900 that we're dealing with.
DR. HOWELL: Let me comment briefly about that. I think if you look at the way the report reads, a number of conditions as therapeutics are available on the market will "fit" these criteria for newborn screening once you have a test and so forth. Certainly, the lysosomals are an excellent example of things Mike talked about. For example, one of the conditions that a therapy is in trials right now that looks very encouraging is Pompe's disease. Again, it's focused on the acute infantile form where you have rapid death. However, most patients actually have a late onset. As we move to newborn screening, we will obviously detect those people, which means initiating the follow-up programs and so forth is just going to be absolutely key.
This report suggests a huge amount of research agendas as far as if you look at the output and you look at the follow-ups. You've got a huge array of research that's going to be needed to answer the questions.
Greg, you've been waiting patiently.
DR. HAWKINS: Yes, and I may be digressing a little bit because I've had to wait. So many different comments have been made. I want to make a comment on about five conversations back. But I have a unique perspective because, first of all, I don't do research in childhood diseases, and there are a number of experts here at this table that I can glean a lot of information from. Second of all, I'm here as a parent representative as well, because I have kids and how this would affect me or affect my children in the future.
But just coming at it from the scientific point of view, I do genetics in a different realm. I do it with adults, and you talk about the type of evidence-based studies, and one of the things that I see in my field and one of the areas I look at is asthma, severe asthma and COPD. We sometimes get paralyzed by the evidence that's out there and we tend not to move forward by not contacting people and not talking to people. I mean, that's why we go to research meetings and that's why we talk with experts and have meetings behind doors, so the experts can get together and make decisions, because lots of time in the evidence-based studies, things you read in the literature, you have to remember that a lot of that has been processed and has gone through a review process that has been reviewed again, and the information is there, and the journals may not be the evidence that we actually need to move on and to do a scientific study.
Lots of times, the studies that we see are conflicting, and when we see that evidence conflicting, like you say, it paralyzes us and we don't move forward. To be able to know that there was a group of people that got together and talked about this type of information with regard to knowing what's in the literature and having the evidence to look at this information, but that they can come up with some different perspectives based on what they know, their experience, especially in some of the rare diseases where there's nothing on them — I mean, what if there was just one paper published on a rare disease? That just paralyzed everyone from looking into that disease further.
But the experts who have experience can come in and give information, and I think that's one thing that as a parent — now I step back as a parent and look at this, and the people out here in the audience or the people who may get online and comment about this type of study, they're not so much interested in the evidence base but what's going to become of this report when it's done. They're interested in what we're going to do about the problems that we have with not having a uniform panel of diseases to actually test for.
So from the public point of view, I think they want us to get beyond the scientific arguing that maybe goes on behind doors, whether the information is right or wrong and whether we should move on it. They really want the experts to say we really need to do this, we need to do this type of testing.
Steve poked me over here and said do you want to hear my comment? Maybe my comment was kind of rambling, but it was going through hearing everybody talk along the way. I kind of had to reformulate my thoughts again. I don't know if that kind of gives you a perspective from two different angles, but I think the report was a good report from what information we had available. It was a difficult one to put together. I'm glad I wasn't involved.
DR. HOWELL: Let me comment that there was a tremendous interest in getting parents' input into this, particularly parents who have these conditions, because that input is extremely important in making these decisions, we feel. One of the things that's quantified in this thing with a number, which drives people up the wall but I think is a good idea, is burden of disease. I can tell you that if you have a child with a condition and you're treating them and so forth, the burden might be — is, as a matter of fact, quite different than what someone else perceives. Someone who is taking care of a child with a very complex diet, like low phenylalanine or something, that burden is a lot more than someone might think when you have to monitor everything.
So again, there's a considerable amount of weight that's been placed on the families which the group working felt was very important and I still think is very important.
Derek?
MR. ROBERTSON: Well, actually, my comment was following on what Greg said and you just said, because I think sometimes we look at all these conditions and probably tend to forget the babies and the parents and the people who are behind those conditions which are just listed, and some names that I can't pronounce but certainly are there. I was involved in the process, and sometimes I went home and I said to my wife, you know, I sit on this committee and I'm the parent representative, and I feel that that's such a tremendous burden, to say, well, okay, you are the parent representative of all these different conditions over there, to try to get a sense of what's out there and how people are affected by it daily.
I think, as Greg was saying, for me one of the important things about the report was the emphasis on follow-up and the emphasis on training and getting the providers to understand the diseases and to get the parents to understand the diseases. There can't ever be, I don't think, a perfect list of diseases, because something is always going to be left off for whatever the criteria. But I think the committee did the best it could do to come up with a list and as objective a criteria as possible.
I think the important thing is to get to a point where it doesn't matter where your child is born that will determine whether or not you're going to live or die. I think that's the critical thing that we're trying to get here, this uniform panel, that each state will recognize that they have to be testing for these disorders and they have to have as expansive a list as possible, because is one baby's death enough to just look over because it's too rare. I think we always want to maintain that focus.
DR. HOWELL: Dr. Howse has a comment.
DR. HOWSE: I think this has been a wonderfully rich set of exchanges, and I just wanted to thank Steve for putting the question on the table of the weight of the report and whether the scientific evidence in the report was justified, the committee's support in moving it forward. I think what I've heard, and it certainly reflects the opinion of our organization, is that the report represents the best available information, that it represents the weight of expert opinion, that it represents a very rigorous and lengthy review across families and consumers and experts and practitioners and clinicians and state lab directors, et cetera, and that the uniform panel recommendations, which we're still a very long way from having in place in states across the country, that the uniform panel represents on that list of principles conditions for which there's an accurate test, for which early detection is essential, and for which there's efficacious treatment.
That seems, at least to me, both a sufficient and appropriate basis for the report to continue to be supported by this group, and with the emphasis also in the recommendations for follow-along and tracking and report-backs, et cetera, I think it's a very strong basis to proceed.
The other aspect of what Coleen brought up, I think we might spend a bit more time, and that's up to you all really, and that is this question of the process and criteria by which we would recommend additional tests be added to the uniform panel. I know there's a section in the report that deals with that, but I'm not sure we've had quite the full discussion about how to add tests from our standpoint to the uniform panel.
DR. HOWELL: That's a good takeoff point. It's time for a break, and after the break perhaps we can have some — we have additional time before lunch. We'll take a 15-minute break and we'll be back quite promptly. Thank you very much.
(Recess.)
DR. HOWELL: We've had a very fruitful discussion, and I think that we want to move now to discuss the criteria for adding conditions, and maybe we can ask Jennifer to restate her question, because I think that's a very good starting point for this period of discussion.
DR. HOWSE: Well, thank you, Mr. Chairman. I thought that Coleen Boyle raised two sets of appropriate questions and concerns, the first of which has to do with addressing some of the issues about the formulation of the report, which we had quite a fulsome discussion about. Then the second question, which I thought perhaps we should discuss a bit more, was the question about criteria and the process for adding new tests to the uniform panel. I thought, since we had Dr. Watson here and all of us are kind of keen on the subject, that this might be an appropriate opportunity.
DR. HOWELL: As we move ahead to discuss that particular thing, I'd like to go back, as we think about adding things, to point out the issue of a change in criteria that seems rather small and subtle, but it's not. That is that the emphasis that the importance of some of these conditions might have much broader implications to benefits to the family and so forth than has historically been the case, and maybe Dr. Alexander would like to comment about that. I know that certain of the conditions that his institute is interested in are exploring the benefits of early diagnosis and treatment of such conditions, such as Fragile X.
DR. ALEXANDER: Thanks, Rod. You had earlier raised this as an issue and nobody picked up on it. But I would like to address that for a minute because I think it's so important in our deliberations overall to consider what is included in the concept of benefit.
In the history of newborn screening programs, the consistent belief and practice and dogma has been that there has to be benefit to the child in terms of an effective treatment before you screen for anything, and that has been the effective treatment for the disease/disorder itself. That has been the only benefit that has been entered into the calculation.
Many people today are starting to think that there is a broader definition of benefit, a broader category of benefits to the child and to the family than just an effective treatment for the disorder, that even if we don't have an effective treatment that's completely effective for helping avoid the consequences of the disorder or disease, that there are still benefits to be accrued from an earlier diagnosis for this child, that this child is eventually going to get diagnosed with that condition at some point in their life anyway, and the question is whether early diagnosis is beneficial to that child's life and to the family in ways above and beyond just the treatment for the disease.
The arguments include things such as having the diagnosis early is beneficial to the child and to the family because, in part, it avoids the search for a diagnosis that often starts later in life after the symptoms develop, when it's often too late to intervene effectively if you did have a more effective treatment, and that that search for a diagnosis is not only traumatic for the family but also for the child, that you go from one medical center to another oftentimes because the first place you go for the diagnosis doesn't make it, and then the evaluation starts over again and sometimes it's two, three, four places where you go before you finally get that diagnosis. Each workup involves more stickings and prickings and exposures to radiation and other kinds of diagnostic procedures that the child goes through, many of which are uncomfortable; whereas making that diagnosis initially in infancy and in the newborn period avoids this prolonged search, often with the diagnosis coming too late for potential benefit if there were an effective treatment that could be applied earlier.
It's also advantageous for the family, not so much for the child, it's hard to argue, but for the family for family planning reasons. Many families would like to avail themselves of other techniques for having children, whether it's adoption, prenatal diagnosis, preimplantation genetic diagnosis, whatever other alternatives there might be, in order to avoid another child affected; or at least if there is a chance, know about it before they make a decision about having another child. So family planning is another benefit to the family from having this diagnosis made early.
Avoiding the diagnostic search I've talked about, and also the fact that there are other interventions that are beneficial to the child even if you don't have a direct therapy for the disorder that can be more helpful if they are started early. Earlier involvement with programs to foster healthy development, foster development of motor skills, foster development of other functions can often be helpful to the family and to the child in managing the disorder, again if the diagnosis is known ahead of time.
If you talk to parents about whether they would rather have this diagnosis made early in the newborn period or late, you get various thoughts, but generally the experience that I've had is that the parents often say even though it would have been hard if I'd known about it in the newborn period, I would rather, looking back, have known about it then rather than after we went through all this diagnostic search and everything else. That's not uniform, but that's certainly the prevalent response that I've heard from the parents that I've discussed it with.
I would ask the committee that as we hear parents testifying here and talking to us, if we would ask them that question about the timing of the diagnosis and what their preference would be about knowing it earlier versus later.
I think the committee also needs to take this into account in both our comments on this report itself and in our deliberations as we get into more detail. Two things. First, avoiding harm in the process of initiating treatments so that we make that diagnosis as early and as accurately and precisely as possible, looking at variance in the disease that is associated with different genetic variance and trying to tailor the treatment or intervention as much as possible with existing knowledge so that harm is not done to this child in the course of providing treatment.
The other issue is, in our recommendations, pointing out these other benefits that may accrue to the child and to the family as a consequence of having the diagnosis made earlier, even if it's not 100 percent effective treatment for the disorder. Also, having the concept that I addressed earlier incorporated in our recommendations at some point in time, probably initially with regard to this report but as we go on with our deliberations later, and that is this issue of having available a population for study of interventions so that our knowledge base grows and we get to the point of having evidence-based practice rather than opinion leader or best judgment-based practice.
If you look at the example that's been mentioned here of the children's oncology groups that have been operating over the last 30-plus years or so, most children in the United States who were diagnosed with cancer, 85-plus percent, are entered into treatment protocols in a research context, and this practice that's developed over the last 30 years is really responsible for the marked improvements in treatment and even cures for children's cancers.
We have an even better opportunity with newborn screening for enrolling children, because they all get diagnosed at the same time and through the same process, in treatment protocols when they do exist for disorders and gaining information with every child who enters a protocol who has this diagnosis that will help not only that child but help us gain the information to build this database of information.
So I would hope that the committee would consider emphasizing that aspect of the report. It's there, but we need to emphasize that as a way to move from opinion, best expert advice, to where we have the solid database coming from clinical trials, so that we have the opportunity to offer clinical trials from a registry system and a knowledge base based on clinicaltrials.gov, which is the registry of clinical trials, and the opportunity to offer parents the participation of their child in a clinical trial that exists at that time, and if a trial does not exist at that time, an indication of the parents' willingness to be contacted should a trial develop for this particular disorder at a later point in time, not a commitment to enroll but a commitment to be contacted to consider the possibility of enrolling a child in that particular study.
Only if we do this can we get the knowledge base that we're lacking at the present time and why we have this dilemma of having to rely on expert opinion rather than on a knowledge base.
Thanks.
(Applause.)
DR. HOWELL: Thank you very much. You brought your own cheering section back here. That's always very helpful, a very familiar cheering section back here.
We want to go ahead with the discussion of criteria for adding, but I think that, particularly after Duane's very elegant remarks, Denise has had a very specific idea bearing on your comment that I think would be very important to hear about at the current time. I think it's a very interesting suggestion that she had.
I assume that's what you're going to talk about.
DR. DOUGHERTY: Yes, yes. I mean, it does seem like it's time to move forward on the criteria and what we do about the next diseases and tests that become available, and I guess rather than just sitting here and people throwing out criteria, even though many of them are well considered, such as Duane's, I would suggest that we step back a little bit and have a paper produced for us by an expert in evidence-based decision-making, because this conversation is really happening in many, many rooms all over the country and all over Washington about what is the role of the evidence base and expert opinion in making policy decisions and clinical decisions, and there's been a lot written about that, a lot of very thoughtful people, and most everybody says that the evidence base alone is not the determining factor in making a decision. There are many other factors.
So what I would propose is to have a paper done by someone very thoughtful and experienced who would address what is the current thinking about doing an evidence base for screening, diagnosis, and so forth, and then what are the other factors to consider in a systematic look at whether a procedure should be endorsed and paid for and so forth. Values come in, cost may come in. It's not just whether there's an evidence base. I think where this previous report kind of tried to mix a lot of those kinds of things into one judgment, there are systematic ways to kind of lay out how to do a systematic expert consensus, how to do a systematic evidence review, and how those things can come together to make a decision.
So I would propose that a paper be done like that and that it be presented to the committee for their comments and for their recommendations, which we're gathering today, on if you're doing an evidence review or an expert consensus, what benefits do you want to look at, and what possible harms do you want to avoid, and how you get that information more systematically into a decision-making process.
DR. HOWELL: Mike has a comment, and then Derek.
DR. WATSON: I completely agree, but I would actually add another piece to that, which is I would step back. I don't know if you'll find the same person to do both, but I would look very hard at the nature of genetic diseases and the difficulties that one has in genetic diseases with an evidence base. As we move to the molecular side of diseases like cystic fibrosis, we start binning things increasingly smaller. We have a disease where you have a wide range of outcomes based on the mutations there. We know there's over 1,000 in the CFTR gene. Some of them are private to families. The only evidence base you'll ever have on a mutation that is only in one family in the world is going to be one data point.
So I think that, in addition to thinking about the nature of evidence-based medicine, think a lot about the nature of genetics and how those two things are going to fit together.
DR. DOUGHERTY: Yes, and just let me respond to that. I'm not suggesting that there be a paper that's done in the abstract but something that's done in the context of what this committee is looking at. If we can't find a single expert who knows all of this, which is probably the case, then perhaps a writer plus an advisory committee who can help understand some of the issues with genetic diseases might be a way to go.
DR. HOWELL: Derek had a comment.
MR. ROBERTSON: Yes, kind of just following on Dr. Alexander, I think if there is going to be more of an emphasis on trying to enroll people into studies and that part, which will obviously be very important, I think there has to be a huge emphasis on educating the parents, because a lot of times, having worked with physicians, it seems almost sometimes that it's obvious, why wouldn't you sign up and join this cause that obviously is going to benefit you and benefit others.
I think sometimes when you're weighing basically the risk between this new medicine, new treatment versus what exists, that's a very, very difficult decision. I commend all the parents who have enrolled their children in studies. I was listening to NPR about the anniversary of the polio vaccine and just wondering, when they were enrolling their kids in that polio vaccine, and I wondered if I would have done that with my child. I don't know, because I struggle with that today with my own children in terms of studies.
I think one of the things with oncology is that sometimes the reality is the alternative to not enrolling in a study is extremely grave. For some other diseases there may be other options which are already there. I think the education of the parents to not just assume that there's a protocol, there's a study, so you'll sign up. Probably the best way to do that would be to get other parents you have enrolled their children, the decision-making process that went into that, and the courage it took to do that and why they also should be encouraging, to get a group of parents who would be encouraging other parents, physicians who would be educating parents to the benefits and the reason why you have to do this.
DR. HOWELL: Piero, you had a comment?
DR. RINALDO: Yes. I actually like the idea of proposing the next steps. So I would like to propose another one. In the beginning of that old project, we were looking at a very large number of conditions, and I think it's a reasonable statement to say that many of the conditions that were included in the initial group but weren't included later in the uniform panel I think are making some solid progress.
So perhaps we could define a process where proponents for extension of the panel could actually come here and present to this committee and make the argument, using as a starting point what we did in the survey, and perhaps point out to us that we didn't have sufficient participation. That was very obvious with infectious diseases. But just imagine severe combined immunodeficiency, we know that there is very, very active effort toward screening.
So at some point the proponent for such screening could make their case, and I think this committee perhaps is a good place to start. I don't know how that would work from an organizational perspective, but maybe every meeting we should have a session on the agenda devoted to a presentation by a group or whoever is the proponent — the experts, the parent support groups — to come here and make the argument for inclusion of additional conditions. In this way I think we could start spinning this wheel, because we all talk about this not being a static thing but something that is meant to evolve. But I think it's probably one responsibility for us to facilitate this evolution. Just an idea.
DR. HOWELL: That's an interesting thought, to have someone come, an expert in the area, and present and discuss the criteria by which they would recommend the addition of this condition based really on the stuff that's in this report is what you're suggesting. What are the thoughts about that?
DR. BROWER: I agree with Piero, and I think it's part of the charge of the Laboratory Subcommittee to look at new tests and the adoption of new tests. I think the best thing that we can do as a committee is to communicate to the public and to experts about what level do they need to meet before we'll consider that a disorder or a test has been validated, what level do we need to have as evidence to implement a test for SCID. So I think that if we can work in the Laboratory Subcommittee and with the committee as a whole to come up with some of those guidelines based on the report, then I think that would be helpful.
DR. HOWELL: So you're suggesting that a person or persons or whatever would meet with a given committee, like the Laboratory Committee, that would look about the data and so forth, and then come at it from that point.
DR. BROWER: Well, I think it's the job of the Laboratory Committee to start looking at all the disorders and figuring out what's next.
DR. HOWELL: Any thoughts about that around the table?
Joseph?
DR. TELFAIR: Actually, I would agree with Amy in the direction that she's going. I brought up the question earlier about utility and actual use of the information. I mean, a lot of work has gone into this, and I think we all have come to some level of agreement on that part. It seems to make a lot of sense that maybe the next steps, as Piero was just pointing out, would be for us to be thinking about how can we begin to take those recommendations and put them into something that is usable, some structure, something that is tangible and useable by those who are in the positions to influence what happens next from the national, state, local and community level, including parents and including others who are decision-makers.
So it would seem to me that that would be something maybe the committees in their current structure, or maybe even this committee as a whole, can take on responsibility-wise, even bringing in other people and talking with them and that sort of thing. It's along the same line but it's focusing on the other aspects of that.
DR. HOWELL: Dr. Alexander?
DR. ALEXANDER: Obviously, there's going to be a need for this type of function to exist as the tests evolve and the number of disorders you can screen for expands, and the number of treatments that hopefully we have treatments for expands. This is a role for some type of an organization, and I think this committee has a valuable role to play in suggesting what kind of a group might take this on and what kind of criteria they might use in making the decisions about what gets added.
Doing this by this committee for a few disorders I think might give us some useful information on which to base such suggestions. But for this committee to take it on as a formal charge I don't think is probably within our capabilities or our charge or our time.
Let me suggest something that could be considered as a model and we might talk about as we come up with a recommendation on this particular topic, guided I would hope by trying to deal with the issues condition by condition, as has been suggested, and that would be a parallel to what we have for immunization, with an Advisory Committee on Immunization Practices that is convened by the CDC that has expertise on it from the practicing medical profession, has other scientists on it, public representatives, public health people on it, and so forth.
You could establish a parallel committee with the CDC operating it for an advisory committee on newborn screening practices or genetic screening practices, something like that, that would meet on a periodic basis to review potential new additions to the screening regimens that are used in the states. These do not have the force of law. They are a guidance to the practicing community, but they are widely regarded because of the database that is utilized in putting them together that they become pretty much the standards of practice for immunization, both for adults and for children.
So I would think that this is a parallel situation in many ways. As we have candidates for new additions to screening panel, just like we have candidates for new vaccines, and that a parallel committee arrangement, like the Advisory Committee on Immunization Practices, could be set up as an advisory committee on newborn screening practices.
DR. RINALDO: I think this point is well taken.
I have a question for Michele and Peter, because the uniform panel, I think the ownership of this panel now is, I believe, HRSA. So I think it's really the job of whoever controls and owns this product to decide or to find a solution how to modify it and expand it, as needed. I don't know if you can comment on that.
DR. VAN DYCK: Well, I think I'd only comment that I'd agree with Duane generally that I would not want to take this role on as a committee because I don't think it's the role of the committee and I don't think there's time, and I'm not sure the mix in the committee is the appropriate mix to do this kind of thing. I also think that that's a consideration that could be in the final output of whatever the Department recommends eventually. I would assume that part of that recommendation would include the best way to suggest to states to add new conditions, but I think the Secretary would be interested in what this panel would say about that and how to go about it.
DR. HOWELL: It would seem to me that this group should certainly have an opportunity to look at and comment about any changes in the recommendations, because I think that is in the purview of the committee. But one of the questions I guess that's been posed is the mechanism by which those decisions would be handled. Amy had suggested a subcommittee, Duane had suggested a parallel committee, and I gather that everybody's thinking that there would be some other type of structure that would review things and so forth, make recommendations that would come to this committee, and then to the Secretary.
DR. DOUGHERTY: Could I just go back to how we started and just not lose the fact that I think we still need to step back and reexamine whether the current fact sheets and that approach is the best mechanism and hear about some alternatives that may be helpful to whoever comes forth, whether it's a parent group who will need some guidance from us, or a committee.
DR. HOWELL: Bill, you had a comment?
DR. BECKER: Yes, I want to add to Denise's comment because I agree, and it actually correlates nicely with what Peter said. This committee, in my opinion, seems to be about establishing the process by which the panel could be added to or subtracted from or in some way modified, and certainly Duane's suggestion seems like a reasonable one. But we ought to be more focused on the process and providing guidance to how those decisions are made.
One of the fundamental considerations that we just spent an hour or so talking about is this issue of the expert opinion versus evidence base spectrum that we have in existence right now. Regardless of whatever subcommittee or advisory committee or whatever process we devise, we're still going to have that fundamental question to resolve and provide guidance to that process. While I don't know that maybe a paper is the right forum, I think Denise is exactly right that we still are going to have to answer that central question each and every time it comes up until we provide the guidance, or at least the conventional wisdom from this committee.
So I think this committee needs to be about the process as to how will we decide it, maybe not to the particulars, but we're going to continue to have to use the evidence base/expert opinion commentary as sort of a central tenet to whatever we decide to do.
DR. HOWELL: Piero?
DR. RINALDO: Maybe I misspoke. My intention wasn't to say, okay, this is the ultimate stop where decisions are made. My point was let's try to define the process, because newborn screening has evolved, and I think the best definition is by spontaneous combustion. Eventually, somebody decided to do something, no matter what. I think that there should be, again, a defined checklist or something, and it's a process. I think Amy is right, it certainly sounds like a job for the Laboratory Subcommittee to come up with a first attempt to define what the process ought to be and present it to the entire committee and then see how that can be improved.
My concern is more how we make sure that this process becomes available and people become aware that this is one way, endorsed by this committee if that's the case, to seek extension of a panel. I completely agree with Jennifer. This has been progress, but I think it would be a disservice to the public if we now sit on it for the next 10 years and nothing changes. It must be an evolving process. So in a sense, although I understand the point that was made that this is not the job of either HRSA or this committee, I really think we have a moral responsibility to make sure that the children affected with other diseases are never considered less important. We really have a duty to serve all of them affected with whatever diseases where there is a test and early intervention can be beneficial.
DR. HOWELL: Comment about Denise's recommendation of a paper being written and a presentation on the mechanisms and so forth.
DR. DOUGHERTY: And this is just to be background, just to get the big picture of how this is done currently, and for people to then weigh in on it.
DR. RINA