TRANSCRIPT, Meeting 9, Session 2

Date

May 17, 2012

Location

Washington, DC

Presenters

Michael R. Anderson, M.D., FAAP
Vice President and Chief Medical Officer, UH Case Medical Center, Associate Professor of Pediatric Critical Care, Case Western Reserve University, Chief Medical Officer, UH Rainbow Babies & Children’s Hospital, Member and Fellow, American Academy of Pediatrics

Nicola P. Klein, M.D., Ph.D.
Research Scientist II, Kaiser Permanente Northern California Division of Research, Co-Director, Kaiser Permanente Vaccine Study Center

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Transcript

SESSION 2: PRACTICAL CHALLENGES POSED BY PEDIATRIC RESEARCH

DR. WAGNER:  And Drs. Anderson and Klein, if you could join us?

Welcome to you both.  This session, as Amy said, focuses on pediatric research and practice, benefits as well as some of the practical challenges that it poses, and we will hear first from Dr. Michael Anderson here on behalf of the American Academy of Pediatrics, Vice President and Chief Medical Officer for University Hospital's Case Medical Center, and Associate Professor of Pediatrics at Case Western Reserve School of Medicine in Cleveland.

He also is Pediatric Critical Care Specialist and Chief Medical Officer at Rainbow Babies & Children's Hospital right there at the same location.

Dr. Anderson was appointed to the National Commission on Children and Disasters in 2008 and also serves as consultant on pediatric disaster issues to the CDC and National Disaster Medical System in the Department of HHS.

In addition to disaster preparedness and response, Dr. Anderson's research and clinical interests include system quality, national physician workforce, pediatric critical care transport, and national health policy issues for children.

It's great to have you here.

DR. ANDERSON:  Good morning.  Thank you all very much.

I'm going to break one of my public speaking rules, which is never to read what you prepared, but I've got such good stuff in here, I've been told there's serious ramifications if I go over 10 minutes.  So I will do a little bit of reading.

Good morning, everyone.  Thank you very much for the kind opportunity to address you.

As was mentioned, I'm representing the American Academy of Pediatrics today, which is 62,000 primary care pediatricians, pediatric medical specialists, and surgical subspecialists, who are dedicated to the health and well‑being of infants, children, adolescents, and young adults.

As was mentioned, I'm proud to be a pediatric intensivist in Cleveland, Ohio.

Many of the laws which led to the formation of the FDA as we know it today came from a result of therapeutic tragedies in children.  At each point in time, new standards for ensuring the safety and efficacy of medical products were then established.

Despite these milestones in public health, most of the therapeutics in children had no clinical data to support their use.  As recently as 1997, nearly 80 percent, 80 percent of drugs used in children were never studied for safety, dosing, or efficacy.

The unapproved use of approved drugs for so‑called off‑label use is extremely prevalent amongst physicians like myself who care for children.

It is of vital importance that children be permitted to serve as participants in clinical research so they may gain from both their personal benefits of participation as well as the benefits that are accrued to children of all ages.

In 1977, the Academy's Committee on Drugs for the first time said it is unethical to adhere to a system which forces physicians to use therapeutic agents in an uncontrolled or experimental fashion.

The Committee also said it is not only ethical but it is imperative that new drugs be used in children should be studied in children under controlled circumstances so that the benefits of therapeutic advances will become available to all children who need them.

Further, it's the combined responsibility of the pediatric community, the pharmaceutical industry, and regulatory agencies to design, approve, and conduct high quality studies in children, and it's the responsibility of the general public to support the necessary research to ensure that all children receive treatment at the most appropriate dose to maximize efficacy and minimize toxicity.

Understanding and protecting the needs of human subjects is particularly critical when research involves vulnerable populations, such as children.  Research that involves children carries with it additional responsibilities for the investigator, the institutional review board, and the product sponsor.

Federal law requires that IRBs review clinical investigations that involve children and only approve those that satisfy one of several specified conditions, some of which Dr. Nelson went over earlier.

All drug study protocols in children must be scrutinized carefully for all potential risks, including those not necessarily concerned in adult studies.  The process of informed consent and pediatric assent are central elements in all clinical research, indispensable for upholding the ethical principle of autonomy, and for assuring the protection of human subjects.

IRBs vary in the criteria that they require for approval and informed consent and pediatric assent procedures, and I hope we'll talk about that as the day rolls on.

Research is needed to further define best practices for both informed consent process, as well as the pediatric assent process.

Since the publication of the 1977 Policy Statement, the Academy has advocated strongly that children deserve the same standards of therapeutic evidence as adults.  The first step forward in public policy solutions to the lack of pediatric drug research came in 1997 when Congress passed the Food and Drug Administration's Modernization Act.  This law contained the first authorization of pediatric exclusivity to incent the study of drugs in children.  This program was reauthorized as BPCA, also known as the Best Pharmaceutical Act for Children, in 2002.

In 2003, the Pediatric Research Equity Act, or PREA, had a requirement for pediatric studies, was passed after the pediatric rule was struck down by the courts, and, finally, recently, in 2007, BPCA and PREA were reauthorized together, creating an integrated system for pediatric research, incentives, and requirements.

Legislation is pending in both the Senate and the House to make pediatric drug testing laws permanent.  BPCA and PREA work together as an effective two‑prong approach to generate pediatric studies.

Through BPCA and PREA, we've gained more useful information on drugs and biologics used in children than we had in 70 years prior to their enactment.  Since 1997, more than 438 drug labels have been updated with pediatric information.  We've really made great progress.

Today, off‑label use of drugs for most pediatric subpopulations has been reduced to about 50 percent.  In the words of Dr. Diane Murphy, the head of the FDA's Office of Pediatric Therapeutics, "We didn't know what we didn't know."

BPCA and PREA studies revealed safety issues, have altered dosing, and helped promote effective formulations, have led to new pediatric indications, and have shown some drugs to lack efficacy in children.

Drug studies under BPCA and since 2007 have involved 167,000 children and have also led to a parallel pediatric program being developed in Europe.  As an intensive care doc, as a pediatrician, and, most importantly, as a parent, I cannot overstate the importance that these laws have had in generating pediatric data and pediatric studies.

Turning to vaccines, unlike in most drugs, pediatrics drives vaccine research and development.  From polio to pertussis to influenza, vaccines save children's lives.  Virtually all vaccines licensed in the U.S. have been approved for pediatric labeling.

A recent Institute of Medicine or IOM Report on Safe and Effective Medicines for Children, that Dr. Nelson also referenced, found that of 55 vaccines listed by the FDA Center for Biologic and Evaluation, only three (or five percent) were not licensed for use in kids.  For most vaccines and drugs, adult safety and immunogenicity data is needed before products can be studied in children.  In some cases, products are monitored for any safety signals that might appear in adults once the product is used in a broad population, obviously before we start to study these in children.

For chemical, biologic, radiologic, nuclear, or explosive or CBRNE threats, children have unique vulnerabilities that are outlined in this slide.  These vulnerabilities must be accounted for in pediatric medical countermeasure research and development, and in my written testimony, we have many more of the details.

The SNS or Strategic National Stockpile, which is the nation's repository of MCMs includes medications, vaccines, and medical equipment.  As was mentioned, in 2008, I had the honor of being appointed by President George W. Bush to the National Commission on Children and Disasters, which I served as vice chair on until 2011.

The Commission, as well as the National Bioscience Board, the American Academy of Pediatrics, and other experts have found the SNS is not only understocked with formulations of medical countermeasures for children but that information on pediatric for dosing for MCMs is sorely lacking.

Products purchased for SNS in advance of emergency can usually only be labeled and only be used for their labeled indication, limiting their research in the pediatric world.

Congress gave the HHS Secretary authority to approve or request what's called an EUA or an Emergency Use Authorization.  Once an emergency has been declared, which may allow an approved product to be used for unapproved uses or may allow an unapproved product to be used under certain circumstances, including, when available, information on the product safety and efficacy, will allow the Secretary to determine what benefits of use are likely to outweigh the potential risks.

EUAs have been used in the past.  For example, in the pandemic flu, multiple EUAs were issued, including Oseltamivir for children under one.

Proposals are pending in Congress that would expand the ability of the Secretary to use EUAs prior to the declaration of emergency, but as we've heard, the FDA has said, based upon existing data, the agency would not issue an EUA for the use of anthrax vaccine in children.  Rather, AVA would be subject to an IND application which requires informed consent and IRB approval.

It would be incorrect not to begin to collect data pre‑event to support the approval of an EUA for pediatric use at AVA should one become necessary.  Any such research must comply with obviously appropriate federal law that we've heard about.  The collection of data pre‑event may be best initiated in a tiered approach, one that begins with older pediatric age groups first.  However, as we'll talk about later, there will be significant challenges in this approach.

Parents may be very unwilling to enroll their child in a research trial looking at anthrax vaccine.  They may see little or no benefit to participating in such a research trial if they feel their child or any child is not likely to be harmed by anthrax in a bioterrorism event.

For MCMs, like AVA, measuring benefits and risks also involves a consideration of national security, as we talked about, and threat assessments, and while detailed information may be classified, parents and potential enrollees in a research study must be given enough information about the risk of anthrax to assess for themselves the benefits and risks in participating in such a study and hopefully we'll talk about that more as the morning goes on.

Pediatric subject matter experts should be consulted in the design of a pre‑event study as well as post‑event care, follow‑up, and MCM distribution.

I'd like to thank the Commission for inviting the American Academy of Pediatrics to participate.  We look forward to providing additional insight as the Commission continues its work.

Thank you very much.

DR. WAGNER:  Thank you very much.

DR. ANDERSON:  Thank you.

DR. WAGNER:  But next we'll hear and then, as we did before, we'll field questions once we've heard from you both, Dr. Nicola Klein.

Thank you for being here.  Dr. Klein is Co‑Director of Kaiser Permanente Vaccine Study Center and a Research Scientist with Kaiser, the Northern California Division of Research.

Her research interests include vaccine safety and efficacy, genetic influences on vaccine responses, and vaccine responses in safety among special populations.

She is the Principal Investigator of numerous vaccine safety and efficacy studies and has published on vaccine safety and efficacy in children and infants.

Welcome.  The floor is yours.

DR. KLEIN:  Thank you for the opportunity.  I'm really going to change focus just a little bit and talk about some of the practical considerations.  When we think about ethical considerations in pediatric research, I'll really do it on an age‑based fact basis, and hopefully try and bring in some case examples.

So to begin, though, I would like to discuss some general considerations when we think about doing pediatric research, and I think, as we've heard today, very, very important is the first step is to do a careful review of proposed protocols for scientific benefit, including subject benefit and ethical designs, and taking them into consideration, as we've heard about IRBs, thinking about how would this be viewed by an IRB, as well as by the investigators and the families, and I think along with that has to be a realistic assessment regarding how feasible is a study in a population because I think you need to have a study that you think is feasible both in terms of number of staff you have, in terms of the training and your background in terms of approaching a study in an ethical manner.

Now following that, you need to have well‑trained investigators and staff and along with very well‑documented standard operating procedures and these are really critical steps to ensuring an ethically conducted study.

So one of the things I'm going to discuss here is I say here ethical considerations vary by age of the child and it's not that the ethics change based on the age of a child. The ethics of doing a study are the ethics, but in terms of how you approach, those considerations do change based on the age of the child, and along with that has to be an understanding that when you ‑‑ every study that you involve with a study in a child involves the entire family and must be pondered with the family and that's an essential component of conducting a study in children.

And, finally, recognizing that ethical issues in pediatric studies are very much entwined with conducting a study and really do affect the entire study and how you conduct the study.

So going first to ethical considerations, when we think about a newborn to one‑year‑old.  So in vaccine studies, vaccines are, as we heard, are often predominantly given to children and including starting at two months of age.  So we do do studies in two‑month‑old children and in that case, when we enroll a child, we have to be very, very careful because in parents of a two‑month‑old are very much overwhelmed.  They're sleep‑deprived.  They may come in with a lot of misinformation from a variety of sources.  We all remember this, right.  And, you know, in this step, education is absolutely crucial to the parents.

We have to take really a complex decision making ability in terms of whether these families are actually understanding what it is that we're talking about.  Are they understanding the study?  Are they understanding the implications of the study?  We do studies that last one to two years.  So do they understand that this is a long‑term commitment and that we have to appropriate adequate time for the staff to be able to do that.

So following that, we have to have well‑trained staff and these staff have to be able to clearly communicate expectations to the parents and they need to be proficient at obtaining required blood draws.

Now when you move to the toddler years, the one to two year‑olds, of course, education becomes critical.  The parents are a little bit more comfortable but still ongoing communication and partner with the parents and education is critical because, as I said, a lot of these studies often were enrolled when the babies were two month‑old and are now 12, 14, 15‑months old.

Going along with that is we need to keep in mind that very often, and nowadays in most vaccine studies, there is the informed consent document was signed by the families when the babies were two month‑olds and there's not typically a requirement for a reconsenting during the toddler years.  So we have to make sure that the parents are continually educated and are continually still partnered and still have a good understanding of what is going on with the study.

So in terms of bringing up specific challenges, there was a recent study that we did over the last few years in which we did enroll infants in a vaccine study for a four‑dose series and by the time that the infants had become toddlers, there had been 17 modifications to the protocol and four informed consent changes, including changes to the treatment or vaccine schedule.  So I think these are certain challenges that I think they do pose ethical challenges because when you have to go back to the families over and over again and changing consents and changing vaccine schedule, I think that does pose some trust issues in fact with the families.

Now when you go into the two to six year‑old population, we all know children this age can protest very loudly that they don't like the needles, they don't like the shots, and they know what's happening, particularly the older ones in this group, but the two and three year‑olds do their best, as well.

So what really you need to approach this is those children need to be a part of the process.  They have to be on the team and they have to in the system and, as you can see, you're probably wondering what I brought here.  Some of these are tools that we use to actually make these children be the assistant.  We have them blow the whistle while they're getting the blood drawn and they make them invested in the study, and the reason this really is an ethical issue is because in that first visit when they come and whatever you're doing to them, whether it's drawing blood or giving them the first dose of a vaccine or a placebo or whatever study intervention they are getting, if that visit doesn't go well, there's a very high likelihood that family is not returning for subsequent visits and I think that's really an ethical issue.

If they don't return, we don't want to be enrolling children and doing subject activities to children that may have a high probability of not returning for the next visit.

So when you start to get to the seven to 12 year‑olds, as we heard earlier today, this is the age in which children need to give assent as well as parental consent.  So clearly the children need to stay involved and agree to be a participant in that capacity.

Specifically--One specific consideration that has recently been more ‑‑ it's happening more currently is that many vaccine studies are now requiring that children as young as 10 years of age or girls as young as 10 years of age have to have a pregnanancy test before enrollment.

So, of course, that's require a young age for many families and many girls and so it does bring up a lot of sensitive issues.  So you must have staff that's trained in how to sensitively approach and discuss this issue.  Of course, you have to have privacy for the subject and those girls, as well.

And going along with that is not just that you have to do that upfront but you have to ‑‑ it's absolutely critical that there's an already‑developed contingency plan in place should you have a positive pregnancy test in these young girls and that includes thinking up various scenarios of who are the next five people that need to be contacted should you have a positive pregnancy test because now you no longer have a research subject and what you have is a patient, a young girl who needs to be taken care of, and so that has to really be in place and thought of ahead of time.

Now when you get to the 13 to 18 year‑olds, at this point you've had to do this all along, but this is when it becomes you have 100 percent have to recruit those teenagers and they have to be 100 percent committed as well as the parents do, the parents, and there's a lot of ethical issues in teenagers.

Pregnancy, of course, remains a very important issue and it's more common in this age but they also have children ‑‑ teenagers, of course, are a little bit older than the younger children I was referring to earlier, but you also have noncompliance now with teenagers.  So that's why you really have to have children--teenagers who are 100 percent committed to being in the study and the reason this has actually become very much of an ethical issue is that for many studies now, teenagers are the ones who collect all the safety data.

We're currently doing a study in which teenagers input the safety data into a handheld electronic device and the parents are not allowed to do that.  So if you don't have a teenager who's 100 percent committed, you are putting them at risk for not capturing their safety data, as well as not capturing the data for the entire study.

And then, finally, I think one of the really critical issues that does need to be just mentioned and discussed openly in terms of teenagers is that teenagers can be incentivized to participate.  They will respond to incentives.

So anybody who's recruiting teenagers must be very careful to walk that fine line between what is considered a reasonable reimbursement and, well, some sort of a coercion or a bribe, really.

For example, we did a study looking at long‑term varicella vaccine immune responses over 15 years and the oldest children in that study were 10‑12 years old when they were enrolled and it went on.  By the time they finished the study, they were in their 20s and we still had those young adults calling us up every year saying when am I coming in for my yearly blood draws so I can get my $25 and I don't think $25 would be considered a coercive amount but you can see how that can really, if it was taken to extreme, that teenagers can be incentivized.

So just some considerations at the end.  We talked about some of the ethical considerations, and how you approach the considerations for the ethics, do vary by age.  I hope you understand the appropriate investigator and staff training are absolutely essential to do pediatric studies, and that recognizing and addressing ethical issues in pediatric studies actually is what will help ensure the successful study in pediatrics.

DR. WAGNER:  Thank you.  Thanks to both of you.  Very good.

We actually have a good deal of time for ‑‑ we said that last time and we ran out.  We have time for questions and conversation.

Nelson?

DR. MICHAEL:  Let me just reiterate.  Those are two fabulous presentations and I think if I ever was to do pediatric and infectious disease research, I'm going to be calling Dr. Klein.

So my question really is oriented a bit more toward Dr. Anderson, but I wanted to carry your argument a little bit further and maybe using a framework that may be a little extreme or provocative.

If we're going to inform decisions for low‑probability but very high‑impact scenarios, as it may relate to disaster preparedness, and especially informing studies that might change what currently is in the National Stockpile, then it seems to me that it's inevitable we're going to have to ask a small number of individuals to take that risk to, frankly, for the greater good, right?

So you're going to have to ‑‑ in some fashion, you're going to have to ask a small number of people to be involved in research that is inherently going to be greater than minimal risk because the outcome of that research has such a fantastic ability to inform what the risks would be if in fact now we are in an emergency situation and the decision‑makers are faced with the impact of rolling out biologics or therapeutics that in fact have not had much experience in testing in children.  So to be able to assess that risk‑benefit, you're going to need those sort of data.

In that sense, we struggled recently post‑Guatemala with relooking at ethical principles across the board and one area we talked about a lot was the selection of a site where we would actually execute certain studies.

Would you think, and this is all finally getting to my question, would you think therefore that it would be reasonable to look at areas in our country where there might in fact be such a low probability of a high‑impact event?  Would it make more sense to ask for volunteers from those communities to take that risk?

In other words, I'm talking about recruiting from Washington, D.C., or New York or Los Angeles instead of recruiting from perhaps a small town outside of Akron, Ohio.

DR. ANDERSON:  I think those are the important ethical questions that we have to ask and answer, and I'd also follow up with what Dr. Garza said earlier.  This is sort of a paradigm shift in how we think about a threat and the risk versus benefit and I think that the entire point of my presentation was these are the right questions.

In the past children had been underrepresented, and in off‑label use, etcetera, etcetera, and I think reaching out to those populations that would have more potential interest in this is a very important question, but this is the right process, transparent, upfront, public.

I mean, this is the exact right thing that kids deserve and I think that's the shift that we have to engage in.  So my answer is yes.

DR. WAGNER:  Please, Amy.

DR. GUTMANN:  So I have a follow‑up on that to your yes.

Given that children consent is imperfect because they're not as autonomous as adults, is there also a reason, if we're going to test something with these kinds of uncertain probabilities, to make sure that we don't test it on particularly vulnerable populations?

In other words, not low‑income children from low‑income families but, rather, if this is going to be in the public good and there are risks involved that it be in communities that are most likely to actually be affected but more, I think perhaps more importantly, and I'm asking a question, make sure that the families and the children are not from low‑income vulnerable populations because if you can't get consent from parents who don't need this extra care that might come from being part of an experiment, that raises the question of whether you should be doing it at all.

DR. ANDERSON:  Sure.  It's a great question.  Obviously as a pediatrician, vulnerable populations is what kids are and, first and foremost, they need to be equally represented.

You raise a great point.  We have to be equal across the board in how we enroll kids and not incent those that would be at unfair disadvantage, if you will, to be in that trial.  I think that's a very important point.

DR. GUTMANN:  I would want Nicola to answer this because $25 means a lot less to people whose income is higher than to people whose income is lower.

DR. KLEIN:  Right.  So I think that this is a very complicated question and I think it's a very important question.

When I think about who is allowed to enroll, we have to be very careful to make sure that we offer, for example, studies to all of our patients because we want to make sure that everyone has equal chance to participate in terms of the families being involved.

But you do have to be careful not to incentivize those who are from lower‑income populations.  Absolutely.  Whether in this particular case, when the ‑‑ one could argue the risk of anthrax, for example, disease is really very, very low in a lot of populations.  I do think that's a very important comment.

DR. GUTMANN:  Mind you, I think it's important for the record that it flips.  In the case of testing that could actually directly benefit the people, then there isn't this ‑‑ the barrier is at least minimal.  In fact, it might even ‑‑ you don't want that barrier because you may have high‑income families flocking to this.

This is a case where there is really in the strict sense no direct benefit.

DR. KLEIN:  Right.

DR. WAGNER:  Christine?

DR. GRADY:  Thank you both for good comments.  I wanted to maybe be a little provocative here.

We've been focusing on the vaccine for anthrax and I agree with everything you said, Dr. Anderson, about the need to test things in children so we know how to treat children, etcetera, but when I look at this situation, I think what are we actually going to learn from doing anthrax studies of the vaccine in children and wouldn't we be better situated to be studying new antibiotics or alternatives to Ciprofloxacin or something like that in kids if we're really worried about helping the kids down the road and then to add to that, I think you said start with the oldest kids and work your way backwards.

So again sort of thinking a little bit provocatively, I think it makes sense to me that maybe immunologically teenagers are closer to adults than five‑year‑olds.  So maybe we should skip the teenagers and go right away, if we're worried about dosing and immunogenicity, go right away to five‑year‑olds or younger.

So what do you think about those two ideas?

DR. ANDERSON:  I think I like provocative questions.  I mean, they're both excellent.

The first, to say there's a limited pool of resources and how we can divvy up those resources to do the greatest amount of good for children and it's an important and appropriate question.

I think the specific thing that I am here as a disaster planner, a disaster advocate for kids is, as I think someone pointed out earlier, if anthrax, indeed, is released and we now are pushing out the SNS, we have zero data in kids, and I think that's what we're trying to tackle in that limited amount of resources that we could spend.  So personally, as a disaster researcher/advocate, I think that limited pool of resources is important.

Your next question about adolescents versus school‑aged versus younger kids, I think that's what bright people at the FDA and the pediatric community have to sit down and answer together.  What's the best immunogenicity data that we can then say to our colleagues in the Federal Government we have some data to now start pushing these out?

So I think that they're both important questions.

DR. GRADY:  Can I just add one thing to that ‑‑

DR. ANDERSON:  Of course.

DR. GRADY:  ‑‑ and maybe Dr. Klein has a response too?

I think sometimes the ethics might get in the way in the sense of we say we want to protect kids and therefore we start with the older kids who are a little less vulnerable than the five‑year‑olds, but is that logical in this kind of setting?

DR. KLEIN:  I think you could make the argument that starting in teenagers is not an unreasonable way to go. I absolutely think that, for example, a vaccine would need to be tested in five‑year‑olds and in younger children because we know immunologically they are not the same.  They are not responsive.

A good example is the flu vaccine.  Children respond differently, young children than do older adults and teenagers.  So whether we jump straight into five‑year‑olds or teenagers, I don't know that answer, but we absolutely would need to test in younger children if we do it that way.

DR. FARAHANY:  Thank you.  These are both incredibly helpful and provocative.

I'm struggling a little bit with a question that Alex asked in the last session and building on what Christine is saying about antibiotics, which is the first question is, is testing appropriate in children, period, right, and in this case, in particular, we say, well, this is a low‑probability/high‑magnitude kind of risk, and I think that with the low‑probability/high‑magnitude kind of risk, that may lead you in a different direction of analyzing what's appropriate than a high probability kind of risk.

And the second question I would ask is, well, if we think that it's appropriate when it's low probability/high magnitude, then what are the alternatives and what are the possibilities that are on the table and one of the alternatives that's on the table potentially would be antibiotics and antibiotics, it seems to me, doesn't present the same problem of anthrax, of do we test it just on children in Washington, D.C., and New York and other places because the benefits that are potentially available are much broader than just anthrax and accrue both directly to the children who are involved and broadly across the class of children at each of the different agent groups, as well.

And so why is that not, I guess, the right way to think about it, even in disaster planning, when you actually could get much bigger bang for your buck if antibiotics were effective?

DR. ANDERSON:  It's a great question.  If I'll start, it's a great question because I think, once again, limited resources, a study in antibiotics in kids could have a broader implication just outside of anthrax.

I know that General Parker is going to speak later. I think the one thing the NBSB has looked at is, God forbid, in an attack vaccine saves lives because people are not going to take 46 days of antibiotics or antibacterials.

So this vaccine is not only important in the prevention but in a post‑exposure world, it does save lives. So I think that they're not to me mutually exclusive goals.  Study antibiotics may be a broader impact on that, but as I understand it, and I'm not an infectious disease doc by any means, but that this vaccine, because of problems with compliance in antibacterials, can really save thousands of people's lives potentially.  So I think that's why to me they're not mutually exclusive foci, if that's answering your question.

DR. GUTMANN:  Although you're saying they're not mutually ‑‑ they're certainly logically not mutually exclusive but if there's limited resources ‑‑

DR. ANDERSON:  Right.  There's a trade‑off.  Exactly.

DR. GUTMANN:  ‑‑ there's a trade‑off.

DR. FARAHANY:  If you were thinking about staging… testing… right, so if you were thinking what's the first thing you would do, potentially something broader, like antibiotics, might be something you would do first, and you might explore alternatives to Christine's point.  If the problem is you have to take it for long periods of time, 45 days, are there alternatives?  Are there more effective antibiotics that you could take for shorter periods of time which would overcome the compliance issues and then you have a broader benefit.

Next step, if that doesn't work, given that we're still talking about low probability/high magnitude, it could be something like investigating anthrax, but, I mean, that's just ‑‑ I'm wondering if there's some reason not to think about it that way, other than this one, which is important, which is we know it'll save lives.

DR. ANDERSON:  I guess I'm coming back to my original answer, that I don't see them as mutually exclusive. Maybe I'm waving a magic wand and giving us all the resources in the world to study both.  Unfortunately, I don't have that wand but I still think, because of the immunogenicity and the potential re-sporation, once again idea words that I'm not qualified to use, I still think studying the vaccine will be potentially life‑saving.  That's sort of my understanding.

DR. WAGNER:  Let me go to John, but I have just a quick technical question.

The 45 days, I thought that was the time that it would take for an administered vaccine to kick in.

DR. ANDERSON:  I also believe it's the post‑exposure prophylaxis potential.  It may be longer than that. I don't want to go outside my boundaries of knowledge.

DR. WAGNER:  But they certainly have the option, even if they choose not to do it, as you say, they may not be compliant, but they do have the option.

DR. ANDERSON:  Correct.

DR. WAGNER:  Okay.  And it does have an end‑of‑course, ‑‑

DR. ANDERSON:  Correct.

DR. WAGNER:  ‑‑ even with the ‑‑

DR. ANDERSON:  Post‑exposure.

DR. WAGNER:  Okay.  Thank you.  John?

DR. ARRAS:  Let me add my thanks to the terrific presentations.

So, Dr. Anderson, you're representing the American Academy of Pediatrics here, and I fully understand and endorse your concern that drugs that are given to children be tested so that we know what we're giving them.  So I think that's really extremely important and certainly no argument from me there.

I'm wondering if ‑‑ but that, of course, gets us only halfway on this particular issue, right?  So I'm wondering has the Academy dealt forthrightly upfront with this particular question and I'm really interested in the reasoning behind that.

I mean, again, it's a given that we need to test these drugs on children.  That is a huge social obligation, right, but how does the Academy deal with the problem that this most likely falls into a category of research that is going to be kicked up to a panel of this sort.

In other words, you've got no direct benefit. You've got more than minimal risk most likely.  So in terms of your role as the protectors of children's interests, where does the Academy come out on that?

DR. ANDERSON:  Great question.  I think one of the joys of sitting here is representing those 62,000 pediatricians who you say, first and foremost, want to protect children, and I think what the Academy brings to the table is a very long commitment to that through our Committee on Ethics, our Committee on Drugs.

As I pointed out in my presentation, really being advocates for decades about studying these in kids, but you're right, that only gets us halfway.

I think what the Academy is saying is these are the right questions.  We need to be at the table with our expertise to help answer them, but, once again, if there is a threat and it's always back to what is that threat, and I think there's national security questions as to what we can and cannot know.  That's always that sort of gorilla in the room that is very difficult to address.

I think we're here saying if we think there's a threat, if our data in either animal models or in adults say that this could potentially save lives, then we need to consider studying it.

So I think what the Academy brings is a lot of people that want to look at this question, a lot of people, a lot of pediatricians and medical specialists that want to protect kids, and also great folks, like yourself, that are asking and answering the right ethical questions.

DR. WAGNER:  Alex, why don't you give us the last question, the penultimate question before we go to break?  Alex?

DR. GARZA:  Thank you.  So thank you both for your presentations.  Those were both terrific.

So I wanted to ‑‑ and actually, it's more to clarify some of the, I think, questions that were brought up here, as well.  I don't think we need to look at this as a singular action item or a singular event.

So most of our discussion has been around response to an attack, right?  Do we need anthrax vaccine to decrease morbidity and mortality in pediatric populations and what would that look like?  Then there's been debate on the appropriate dosing of antibiotics and whether other antibiotics are available, things like that, but if you take the totality of it.

So, first of all, there's not great data on countermeasures, even for adults, in the event of an anthracis attack.  So that's one thing to consider.  There are, as I think we all understand, there are side effects to medications, as well, and so if you're asking people to take medications for 60 days, which is, I believe, still the current regiment, after exposure to anthracis, there is risk for taking antibiotics for 60 days and the goal of a vaccine would be to decrease the amount of antibiotics that you would use.

But the second and third order effects also of an event, were it to happen in the United States, I think are uncalculable and so, for instance, if there was a singular incident within Washington, D.C., New York, pick your high‑risk city, you can almost assure yourself that other cities are going to be saying who's next?

This happened during the anthrax attacks of 2001. This happens during flu every year when we don't say we have vaccine.  Everybody lines up to get vaccine as soon as it's available because of the risk, right, and so the information that you would get from a post‑exposure trial would also be beneficial in a pre‑exposure trial.  So it would be of some benefit.

So there's little data on the effectiveness of antibiotics and so, although I agree with Nita that you would probably get more bang for your buck looking at antibiotic effectiveness across multiple different scenarios is beneficial, however, I think it would be still somewhat limited in the issues that we're talking about today.

DR. WAGNER:  Very, very quickly so we can move on. We do have one from Toby Sibelman in the audience there, Principal Consultant.

The question is around whether or not ‑‑ actually, it's a follow‑up to a question Amy had raised ‑‑ whether or not geography is an important consideration and specifically in this case, though, they're asking are there sufficient number of cases where there is naturally occurring anthrax that that would be a logical place to take this risk?

And the second question is, if so, could we extrapolate those data to weaponized anthrax?

Those are the two parts to the question.  Alex, you may know the answer to that.

DR. GARZA:  So the disease state that we worry about is pulmonary anthrax, although there's three different forms--GI, dermatologic, and pulmonary--and the dermatological one we don't worry about so much but the GI and the pulmonary, especially the pulmonary, are the three that you worry about.

Anthrax is ubiquitous in the environment.  So there's anthrax spores in the United States.  It's throughout the world.  It's in Afghanistan.  If you remember correctly from the U.K. a couple of years ago, there was anthrax‑laced heroin and so we saw a big increase in heroin users getting anthrax and so it's very rare, though, when you have naturally occurring pulmonary cases of anthracis, very rare.

We had one last year from a gentleman who was digging for rocks in South Dakota‑Minnesota who apparently dug up some dirt that had anthrax spores in it.  Cattle die from anthrax in the United States right now, but most of the cases that you see in humans are usually in the Far East, Asian countries, and it's usually GI or the skin condition, and so there isn't a big population.  There's not a big population of pulmonary anthrax.

DR. WAGNER:  It doesn't offer us a solution in this case.

I think with that, we should attempt to get back on schedule, take a break and convene as soon as we can at 11 o'clock.  Quick break.

(Applause.)

DR. WAGNER:  Thank you, both.  I'm sorry.  We should have done that first.

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