>> Martin Blaser: Welcome back.
The rest of today's agenda will be dedicated to discussing the report of recommendations
from the three working groups on incentives.
And I'm going to show a couple of slides to provide an overview about this.
So, the title of the work that we're doing and the report that we will be soon voting
on involves recommendations for incentivizing the development of therapeutics, diagnostics,
and vaccines to combat antibiotic resistance.
Let me provide an overview of our working group activity.
Our overarching task was to address the best way to incentivize the development of therapeutics,
anti-infectives including alternatives to antibiotics, rapid diagnostics, and vaccines
for both humans and animals.
Our approach is that we created three working groups to address incentives in each of these
areas; vaccines, diagnostics, therapeutics and anti-infective.
For a one health approach to the task, the working groups are composed of federal, PACCARB,
and NVAC, the National Vaccine Advisor Center members with subject matter expertise in both
human and animal domains.
The working groups hosted a series of meetings including two public meetings with subject
matter experts on various topics dedicated to this overall topic.
The fundamental approach is shown in this slide.
Working groups developed an analysis framework based on issues and recommendations that were
divided into four broad themes.
First was economics: issues that influence the return on investment to companies or food
animal producers regarding product development or use.
Second theme, research and development: issues related to discovery research and the developmental
process.
Third, regulatory: issues related to the federal regulatory processes that influence the development
or modification of a product ranging from basic research thru studies that meet approval
criteria.
Fourth, behavioral: issue related to the behavior of consumers, providers and companies relative
to product use or development.
We recognize that there is a lot of overlap between these four categories, but this seemed
like a useful division.
I think it's also, let me just, I would like to just thank the working group members who
are listed here in the three groups.
I won't read off everyone's names, but I will tell you that everyone involved put in a lot
of time and effort on this.
This is a process that has been going on for a year with lots of activity over this spring
and summer and we're indebted to everybody who served in this group, which included both
members of our panel, our federal ex-officios, as well as external subject matter experts
who gave important, intellectual contributions to the working group findings.
So, over the next minutes, Kent Kester and Tom Shryock, who have led an important component
of this work will be presenting the working groups top ten recommendations.
Then, the co-chairs of each of the three working groups will present recommendations from their
respective working group.
The council will deliberate on the report that has been circulated to the public as
well as to the council.
We'll consider various recommendations, and then the council will take a public vote on
this question.
So, I think that ends my introduction and now I want to turn over the microphone to
Dr. Kent Kester, who will begin the process.
>> Kent Kester: Thank you.
>> Martin Blaser: And, again, on behalf of Dr. King, he and I, we are very grateful to
all the work that has been done.
>> Kent Kester: Thank you.
Okay, thanks, Marty.
So, just a few opening comments, so the report itself is limited to antibiotic-resistant
bacteria.
It summarized issues with lots of corresponding recommendations that are discussed at length.
We're not going to discuss all the minute details today.
We focused on prevention, primarily around vaccines and alternatives to antibiotics.
The overarching goal through all this is the one health approach.
In fact, when you look at the document and some of slides that will follow, you'll see
alignment of colors and that's intended to sort of show the alignment between animal
health and human health.
There were 46 critical issues that were identified, with 64 recommendations.
And the executive summary, the focus, are the top ten recommendations, and we'll be
highlighting those shortly.
So, first, we'll go through the top recommendations and then we'll focus on more detail on all
the key recommendations generated by each of the work groups; vaccines, diagnostics,
and therapeutics, both human and animal health.
It's important to recognize that no document of this type is ever perfect, especially given
the wide range of participants on the various work groups.
The final product, I think, represents a substantial amount of focused effort, time, thought and
creative energy on the part of many who spent countless hours developing what will hopefully
be a consensus document.
In the end, the recommendations, whether in part or in total, are envisioned as starting
points for the government, HHS, USDA and others to see how best they can implement incentive
strategies.
To all who participated, and especially to our talented National Vaccine Program office
staff, great thanks is due.
So, with that, okay.
So, the inclusion of vaccines is an important aspect of the larger CCARB effort.
Since, normally we focus on really just the need for new antibiotics and better diagnostics.
So, we'll get to more details and the relevance of vaccines shortly.
In the executive summary, we focused on three main areas impacting on vaccines.
Number one is research and development.
And primarily, this revolves around providing additional funding for the development of
new product pipelines for vaccines that prevent viral or bacterial syndromes that drive antibiotic
use.
The second is regulatory.
Here we focus on optimizing the interactions between sponsors, regulatory agencies, such
as the FDA, and use policy committees, such as the ACIP.
And the third is behavioral.
And that focuses on incentivizing the uptake of vaccines by positively influencing behavior
such as reimbursement, insure first cost, first dollar coverage of vaccines.
So, in diagnostics, and you'll see some recurrent themes here, on the research and development
portion, there's emphasis on including the development of concomitant antibiotic susceptibility
testing or devices as part of any new antibiotic funding or funding strategy.
From an economic standpoint, owing to the high costs of development and regulatory approval
required for diagnostics, the idea of providing additional or enhanced financial support for
diagnostic manufacturers is important to help bring new tests to market.
And from a regulatory standpoint, in order to stream line and/or to standardize certain
aspects of antimicrobial susceptibility test development and to reduce the overall regulatory
burden.
The idea of continued funding for clinical trials, networks with common rules for shared
ROBs to reduce duplication of effort and to streamline development was felt to be very
important.
And therapeutics, the major emphasis here is to develop new economic models, so called
pull incentives, for therapies to support the currently available push incentives.
And with that, I'll give it over to Tom.
>> Thomas Shryock: All right, thank you for the relay Kent.
And we'll cover the animal health a little bit differently.
As you'll see on the graphic here, we have a black box around all three of our working
group recommendations because we have proposed, as in this overarching recommendation, two
things to be done.
The first is to develop a national policy on innovation for food-animal disease interventions,
and secondly, to fund an innovation institute housed within the umbrella of the USDA.
So, let me tell you a little more about how we came to this and why all three working
groups, within the animal sector, really feel that this is the way to go and so that's why
it's a little bit different than what our colleagues on the other side of the graphic
here have done.
So, we took, as the animal sector, a holistic approach to putting these incentives for new
product development and application, keeping in mind the objective is to improve antibiotic
stewardship in food animals and minimizing and containing antibiotic resistant bacteria.
So, we found that, as we were talking and implementing some of our initial concepts
via the fact finding or some of the pre-meeting information that we were obtaining, that prevention
of disease was highly valuable.
It was like the initial goal.
But when disease outbreaks occurred, there was a need for rapid and accurate diagnostics,
and affordable diagnostics that could guide a clinician to use the appropriate therapies,
these would be antibiotic therapies primarily, but not exclusively, and then follow that
up with some sort of an after-action review.
So, taking those in mind through the vaccines, through the diagnostics, and through the alternatives
groups was how we choose to come up with the idea that that this is the way to go.
Let's bundle these together, because they are so interlinked.
So, basically what we have decided not to include in this recommendation is the pathways
for new veterinary use antibiotics really didn't require incentives.
There's already sufficient development pathways, as well as regulatory approval pathways in
place for those companies that chose to peruse that as their candidate in future product.
So, basically, what we wanted to do was to put together this USDA-housed innovation institute,
which would be guided by the national policy, so that it could serve as an accelerator,
a springboard, a clearing house, whatever you wish to consider it to be.
So, that we could really emphasize the business of science and connect those early startup
companies, those early researchers, those folks that really need to have speed to get
their candidates into the marketplace, but have technical, as well as logistic and funding
challenges, in terms of finding information, contract research, organizations, and others.
So, we felt that this was a good way to start the process of exhibiting the basic research,
as well as applied research that needs to be done, to bring the various candidates to
the market as quickly as possible.
So, we wanted to propose that the innovation institute could serve as a connector between
existing programs within USDA, FDA, CVM and many, many other agencies who have spoken
today and have a role in product development.
So, by connecting the partners that do the research via this innovation institute can
only serve to really speed the business processes.
So, that was how we wanted to propose the funding of the innovation institute and to
be guided by the national policy.
So, real briefly then, with the idea that we had the three working groups, we have listed
in each one of those boxed here, a separate -- which one is this for?
This one?
>> Kent Kester: The one on the right.
>> Thomas Shryock: My technical consultant here.
There we go.
The three featured recommendations for each of the three working groups.
So, these will be discussed obviously in more detail.
These are just featured highlights that just tease you a little bit as to what's coming
up.
So, for vaccines, not only do we need funding, just like the counterpart on the left-hand
side here on the human side, but one example could be to support basic research in terms
of the immune systems across a species to improve the vaccine take, the immune system
responses.
For the diagnostics, educational programs on how basically veterinarians can most appropriately
use and then make decisions on the interpretations of those diagnostic tests to guide their disease
interventions.
And then, the last one here, which we'll cover later, is on anti-infectives or alternatives,
which we'll talk about later.
And providing resources basically at this point to conduct, evaluate, and create a database
of studies on these, to really firm up the effectiveness and share that information so
that appropriate choices can be made for the users of those products.
So, that's a quick overview from the animal health sector on our overarching recommendations.
And Kent, I think I'll turn it back to you.
>> Kent Kester: Okay.
Thanks Tom.
So, we'll start out with vaccines.
As I mentioned before often times in the public dialogue, vaccines are often not considered
as one of the key elements associated with combating antimicrobial resistance.
But whether one considers a vaccine that prevents infection with an antibiotic resistant or
AMR prone pathogen, or a vaccine that prevents a viral or bacterial syndrome, there's often
associated with inappropriate or overprescribing of antibiotics it's clear that vaccines have
an important role in the larger campaign against antimicrobial resistance.
So, I just -- as Dr. Blaser mentioned at the outset, I do want to acknowledge the participation,
really the subtenant participation of members from the National Vaccine Advisory Committee
on our work group.
Kim Thompson, Tim Cooke, David Fleming, Ann Ginsberg-Sodomor [spelled phonetically], and
Nate Smith.
I think their expertise and perspective was very much appreciated by all and I think added
significantly to our report.
So, for each of the areas, and this was, we read out at the last PACCARB meeting various
key issue statements and I think what we'll do today is summarize those issue statements
and then cut to the chase to the various recommendations.
So, on this one, again, we're on vaccines.
This is economic.
And the first issue statement had to do with federal and nonfederal stakeholders lacking
a common understanding about current potential economic value and societal impact of vaccines
that can reduce AMR.
Clearly, there's value in focusing on modeling and epidemiology efforts to demonstrate the
full range of health and economic benefits of vaccines with respect to AMR.
A comprehensive, multi-sectoral analysis conserved to incentivize further vaccine development.
And so, the recommendation is, logically follows, is analysis on the cost of and societal impacts
associated with new vaccine development, administration and the AMR arena develop via multiagency
process that involves our colleagues from CDC, CMS, treasury and perhaps others in the
interagency sphere, in partnership with industry and public health stakeholders.
The second issue statement on the economic side is for vaccines, is that there's limited
funding for developing infectious disease vaccines, in particular for those targeting
AMR related pathogens.
One of the challenges in vaccine development is the associated high cost and protracted
timelines.
Well, there's no shortage of scientific approaches for novel vaccines.
Smaller companies and research organizations are at a distinct disadvantage to take their
promising vaccine concepts to the full development lifecycle.
This contributes, ultimately, to the erosion in the pipeline for new vaccines that can
help address the AMR challenge.
And so, the recommendation here is an expanded range of incentives to encourage development
of vaccines that could reduce AMR by preventing the syndromes caused by bacteria and viruses
that lead to inappropriate or over-antibiotic use.
On the research and development side, the first issue statement has to do with insufficient
epidemiologic data on antibiotic use for infections caused by pathogens currently or potentially
preventable through vaccination.
Well, we recognize there're many cases of potentially vaccine preventable syndromes
for which antibiotics are inappropriately prescribed.
Our knowledge base for the scope of the problem is incomplete.
Thus, we recommend expanded surveillance by the CDC and CMS to measure antibiotic use
due to infections that could be prevented or reduced by vaccination to assess the impact
or potential impact of prevention through immunization either by existing or to be developed
vaccines.
The second issue statement, the clinical stage pipeline for vaccines targeted specifically
against bacterial pathogens associated with AMR is weak.
Focusing specifically on AMR related pathogens, something that we already heard earlier today,
that's area of interest to our colleagues at the NIH, it is clear that the overall pipeline
related to this is not robust.
And this is likely related to a combination of difficult, hard science and limited funding.
As previously, this lack of funding serves as a disincentive for developers to embark
on a challenging scientific and regulatory pathway associated with these novel vaccines.
This leads to the second recommendation, which are focus financial incentives to encourage
development of vaccines directed at pathogens that have high rates of AMR across the R&D
continuum.
This is from early to advanced development.
From a regulatory perspective, the first issue was that there still is a lack of clarity,
to a degree, about the regulatory pathways for vaccines focused on AMR and this reduces
the willingness of sponsors to develop these vaccines.
While the regulatory process associated with typical population focused vaccines, and that
I would include influenza, various pediatric combination vaccines, is very clear, the regulatory
process associated with the development of vaccines that have an AMR focus -- especially
if these are aimed at much smaller populations -- is less clear.
And to this end, we recommend early interaction between sponsors and the FDA workshops hosted
by CBER, explaining pathways and best practices, which we recognize are developing and undergoing
change as data comes in.
The second issue statement is that potential market for new vaccine, as opposed to other
AMR products, is uncertain.
Because vaccine uptake is heavily influenced by recommendations of the Advisory Committee
on Immunization Practices or ACIP.
And this impacts on funding in many cases.
Unlike drugs, there's a requirement for vaccine use recommendations to pass through the CDC
and the ACIP, following licensure approval by the FDA.
While the process and its independence are very important, early discussion of a novel
vaccine's target product profile or TPP, with both the FDA and ACIP particularly focused
on the role against AMR pathogens is important.
And thus, we recommend early communication between the manufacturer sponsors, the FDA
and CDC, to present and discuss target product profile with particular reference to impact
on AMR pathogens.
And again, this is not preordaining approval or anything like this.
This is to provide more understanding of how vaccines will be view ultimately as they progress
through the developmental and regulatory lifecycle.
From a behavioral standpoint, the first issue statement involves implementation strategies
for optimal vaccine acceptance and utilization are inadequate.
As we discussed yesterday in our session on antimicrobial stewardship, the need for culture
change in the area of, with respect to vaccines and their role in combating AMR is important.
Implementation research is an important aspect of this.
Also, approaches to increased positive reimbursement coverage for all vaccines would similarly
appear to be an important incentive for expanded vaccine uptake.
Thus, programs and interventions based on behavioral insights that aim to increase vaccine
uptake are recommended and continued broadened economic incentives to influence behavior
and increase uptake such as reimbursement to ensure first dollar coverage; that is,
insurance coverage of vaccines without copayments or coinsurance costs for all ages, not just
children.
And finally, the second issue statement, providers lack knowledge about the role of vaccines
in preventing AMR.
As with antibiotic prescribing, a focused educational campaign dealing with vaccines
would also be an important incentive and could be something that testing could assess over
time.
Thus, focused governmental, vaccine-centric, educational policies and approaches, including
vaccination as a means of achieving antibiotic stewardship with involvement of healthcare
facilities, health-related educational institutions such as medical schools and academic health
centers would be similarly important.
And with that, I'll turn it over to Angie.
You want me to or --
>> Angela Caliendo: Okay, thanks.
So, you know, we had considerable discussion on diagnostics yesterday and this morning
and many of the issues that were brought up are going to be addressed in our recommendations.
So, I'm going to start with the economic recommendations first and the first issue statement here for
us is following approval of new antibiotics corresponding ASTs are not immediately available
to insure proper use of the antibiotic.
So, if the laboratory can't test for the antibiotic, there's a disincentive for clinicians to use
it.
And so, our recommendation here is funding for the development of new antibiotics should
always include the development of a concomitant AST device and, you heard Dr. Bitterman talk
about this.
This is a process that's well underway now and at the FDA.
And just for clarification, what we're referring to here are simple devices, maybe an E-test,
maybe a disc.
Not necessarily that every automated system is expected to be up and running at the time
that the antibiotic is approved.
So, issue statement number two, because there's no method to determine really the value of
a diagnostic test, we don't have alignment of reimbursement with that value.
And so, to address this, we recommend a reimbursement plus system, particularly for test of key
public health importance and the example that we use is CRE colonization testing.
And public health agencies such as CMS really need to help us and assist us with these sorts
of decisions.
Just so you understand, what we're trying to encourage is having reimbursement drive
the use of the best diagnostic test.
Not necessarily the cheapest or the one that's reimbursed the best, but in fact the one that's
clinically most appropriate.
Issue statement number three is, there's a lack of outcome studies and we've heard that
several times over the course of this meeting.
And so, our recommendation there is to increase the funding of diagnostic outcome studies
and there's a variety of agencies that could do that, ARC, CDC, PCORI, the NIH, the Department
of Defense.
And really, the goal is we need to assess patient outcomes, length of stay, change in
antibiotic use, rates of antibiotic use in certain populations and the cost of care.
Issue statement number four is the high cost of development of diagnostics is a disincentive
for diagnostic companies.
And so, our recommendation here is to focus on a tax credit for a portion of the qualified
clinical testing expense.
This is where a lot of the expense for the companies lies, is running clinical trials,
and if there was a way to have a tax credit, we thought possibly modeled after the orphan
drug tax credit.
Okay, so let's move to the R&D recommendations.
We have identified several unmet needs in the diagnostic arena.
One of them is a rapid point of care test that could be used in the outpatient setting
to distinguish bacterial from viral infections.
Another is on the inpatient side, is there a better biomarker that we could use to help
us determine when to start antibiotics and maybe more importantly when to stop antibiotics?
And then, third, is tests that detect bacteria directly from the clinical specimen.
So, skipping the entire step of culture and going directly into blood or directly into
a sterile site to identify bacteria and also to have rapid susceptibility results.
And so, the recommendations to address these unmet needs, one is to sustain investment
in funding mechanisms for developing new, cost-effective diagnostic test and updating
existing diagnostic tests through the small business innovation research and small business
technology transfer grants.
These have been very successful mechanisms to date for particularly smaller companies
and we have multiple diagnostics that are on the market now that came through this mechanism
of funding.
The other recommendation is to expand funding of a clinical trials network and the example
here is the NIH supported ARLG and to insure that the networks work though a common IRB.
The cost of the clinical trials, the logistics of the clinical trials are a big challenge
for the diagnostic companies and the purpose of this recommendation is to simplify that
process for the companies.
Issue statement four is collaboration between diagnostic companies and other stakeholders
is limited and inconsistent, and can sometimes lead to the company not having a good understanding
of the best test to develop.
And so, we thought it would be helpful for the federal government agencies to get together,
and you see them all listed here, and create a list of the most critically needed diagnostics
for combating AMR so that when companies are interested in getting involved in this area,
they have an understanding of where the needs are and they can direct their investment accordingly.
Okay, let's move on to regulatory recommendations.
So, the first statement here is the regulatory approval process for clearance of devices
for modifying and improving existing devices is complex and expensive.
So, here we have a test that's already approved and we want to expand to another clinic use,
or what if you have a respiratory test and there's a new influenza virus and you want
to add that to your test?
How can we simplify that process?
And so, we recommend advancing the FDA regulatory efforts that are currently ongoing for improvements
or updates of existing tests that utilize post-marketing study results and real-world
evidence to promote the development of improved tests.
And so, instead of needing to present all of the data to the FDA prior to approval,
some of that data could be collected once it's in clinical use.
And, as I said, this again is something that the FDA is in the process of implementing
and we think it will be very helpful for companies.
Issue statement number two in this area is the same general concept.
Current regulatory process for new tests, so tests that haven't been approved yet, is
time-consuming and costly and poses a disincentive for test developers.
And so, our additional recommendations here, again, are to enhance the clinical trial network
that, and the key really is functioning with a common IRB because that simplifies the logistics
for the company considerably.
And also for the laboratories that may be participating.
Second is to modify the requirements to simplify the process for obtaining CLIA waivers.
CLIA waiver is the status that's necessary so that a test can be performed out of a clinical
lab, by non-laboratory professionals.
So, you can have a nurse or an MA right in the office, right in the emergency room perform
the test.
And so, that regulatory process has gotten a little more complicated over recent years
and is there a way to simplify that?
An additional recommendation again is to utilize post marketing study results in real world
evidence to facilitate the approval of a new diagnostic.
And then, the complementary structuring of the FDA, CDC, Antimicrobial Resistant Isolate
Bank and the ARLG Virtual Biorepository to increase access for diagnostic companies.
And we hear a lot about that this morning, that these repositories are used by companies
quite extensively and is there a way to facilitate that process more effectively.
And finally, the last issue in the regulatory arena is hospitals are currently not required
to update their microbiology lab.
So, if there's new technologies that are out there, there is no requirement that a laboratory
needs to adopt them; particularly, ones that are proven to, you know, improve outcome or
get an answer to the clinician more rapidly.
And so, our recommendation here is that CLIA requirements that update microbiology laboratories
technologies become a part of the accreditation process.
We already have a very well-established accreditation process for laboratories.
We'd just like to add this to it.
And finally, under behavioral recommendations, as we learned a lot yesterday, clinicians
don't always use diagnostic tests, they don't believe the results, they don't act on them
once the results are available, and so we had several recommendations here.
The first is really evidence-based research that's supported by public and private resources
to actually help us develop a better understanding of the behavior that affects these decisions.
Why aren't diagnostics used?
We don't really understand what's behind this and really the goal is to identify drivers
that prevent adoption.
And also, this is something that is ongoing and is the inclusion of experts in clinical
use of diagnostics onto clinical guideline committees.
And so, that they can bring their expertise and perspective on diagnostics into the guidelines.
Third is clinician education on the use and interoperation of diagnostic tests.
And finally, the development of tools and mechanisms that improve a clinician's ability
to make decisions in the ambulatory setting.
And one of the things that we talked about in our working group was, you know, envision
everybody connected into an EMR so that the doc sees the patient, puts in an order, orders
a test, the test result is done, sent to the pharmacy, and the pharmacy doesn't even release
the antibiotic unless the test is appropriate.
It's either positive for flu, they would release an antiviral, if it's not, they would not.
And, you know, with all the EMR efforts out there, can we start integrating them in ways
that actually help clinicians.
So, that was the extent of what we had on the diagnostic side.
I'm going to turn things over to Dr. John Rex, who will talk about incentives for therapeutics.
>> John Rex: Thank you.
Next slide please.
Actually that's me, I did that.
[laughter]
It was happening by magic -- I was watching Angie there, and she said and it happened.
[laughter]
Here we go.
So, again, across the four categories, the first one is the economics, and you'll have
noted that our one topline recommendation out of the therapeutics group is for an economic
attack on the problem.
And the fundamental, underlying issue statement is that the return on investment for developing
new antibiotics is unpredictable because of antibiotic resistance and related restrictions
on use of new agents.
And this is a recurring issue that is actually going to go to all four of them and it's the
reason why the one recommendation of this group focuses on this topic.
There's been a huge amount of work in this area to be leveraged, drive AB, the work of
the Duke-Margolis Group and a way to summarize it is the four bullet points on this slide.
The first is something that Joe Larsen said, loudly, that you need a combination of general
and targeted incentives to introduce a more predictable ORI including push and pull.
You can't just do part of it, it's a balanced ecosystem.
So, on the push side, we need to continue to do what we're doing by providing push incentives
across all phases of discovery and development.
We're doing this.
There's a significant amount of money going into it; could be increased, but there's definitely
money going in.
We must, must, must adopt some form of a de-linkage model as a pull incentive.
There are a number of models for this now floating around and we feel like CMS and the
treasury need to think seriously about this and to think about value metrics for antibiotics
and diagnostics.
The required size of a de-linked market entry ward, options for plausible models including
de-linkage and to do this in consultation with FDA, CEC, public health experts and the
international community.
I'd say this conversation is happening globally, there's a lot to be tapped into here and there's
clearly, the tools exist.
What we know need to do is actually do it.
On R&D, there are a pair of issue statements that work together.
The first is that while it's easy to kill bacteria with steam and fire and bleach, killing
bacteria without also harming the patient is difficult.
And the second is that a paradox about antibiotic development, which is that we'd like to have
studies showing the utility of a new antibiotic against resistive bacteria, but that means
that you've actually got to have people who are infected with the resistant bacteria,
which is not a happy place to be.
So, we're actually quite constrained in the nature of the clinical trials that we can
do routinely, particularly as we invent one or two new drugs, it makes it harder and harder.
And actually it's also good for the patient.
It's good that's it's hard to do this.
To be able to do these studies so, the things that we need to do to bring this together,
shown on this slide.
We need to strengthen the funding for existing mechanisms for innovation R&D picking up from
the previous slide.
FDA needs to continue its excellent work on thinking about refined guidance documents
with a particular emphasis on expanding the guidance on narrow spectrum agents for unmedical
need.
This has been a real focus of the last years' worth of work and I want to complement them
on that.
We just have more to do.
And finally, we need to think about ways to make clinical trials more efficient and less
costly and clinical trial networks based on common master protocols facilitated by BARDA
and NIH could accelerate phase two and phase three programs.
For agents that have adequate spectrum to treat an entire syndrome and that's a topic
that you're going to see appearing over the next year or so.
Regulatory front, there are two issues here, and I've kind of already said them.
Issue statement number one in the document is read out, it's difficult for manufacturers
to develop clear and specific data for any new drug efficiency and infections caused
by highly resistant bacteria.
Let me emphasize again that that's a good thing that it's hard to do that because when
that's easy to do, somebody's dying.
We want that to be hard to do.
The other issue statement is that it's hard to enroll the number of patients needed to
show efficiency of a narrow spectrum antibiotic because of the low rate of infections caused
by specific pathogens.
There are few narrow spectrum cases like staph aureus and gonorrhea where it's not that hard.
But the ones that we really care, the gram negative bacteria, it is quite difficult to
do this.
And again, it's a good thing, but we also want those drugs.
So, the corresponding recommendations are, first is one that has to do with changing
the way we think about this problem.
Via its regular [unintelligible] interactions, the FDA is changing the normative view on
what is an acceptable program.
We've now all clearly stated in public that an acceptable program for a new drug, well
we just saw one get approved, the Vabomere approval, which is a UTI study and an open
label study against some resistant pathogens.
And that's normative.
That's all we're going to get in the future.
We've got to live with that.
And then, CMS treasury under the relevant US government agencies need to look at that
set of data and say, well that's all I'm actually going to have, and that's how I have to think
about this going forward.
And here I point it work by Ramanan, where you're going to see some papers on HTA approaches
beginning to appear in the literature that come out of drive AB.
Talking about all the stuff we can leverage in the universe.
Finally, last slide, behavioral.
The issue statement here is this is not a negative one.
Stewardship activities are appropriately limit the use of current and new antibiotics.
Therefore, novel antibiotics have a low financial ROI from the perspective of the developers.
I'm actually ending where I started.
And the action here is the continued efforts by CMS and treasury, and actually the entire
community to insure that solutions to this problem incorporate incentives and simultaneously
support stewardship.
And I should also say, I left off access on that slide.
So, those are the things that need to be brought together to make the entire ecosystem work.
Thanks.
And next, it's over to Randy Singer.
>> Randall Singer: Okay, great.
We're going to shift now over to the animal health side and I'm just going to start generally
by acknowledging that the ways in which we're using antibiotics in animal agriculture.
It's changing rapidly.
It's changing dramatically.
That's both within the US and globally.
There is a consorted effort, a focus on stewardship, on appropriate antibiotic use in animal agriculture
and this entails then that we emphasize how we're going to replace some of these antibiotic
uses that have been in place for many years with other approaches for maintaining animal
health and how we're going to use the antibiotics that we do have as appropriately and responsibly
as possible.
And as we talk about the shift that we'll seeing and how we maintain animal health,
we need to be cognizant of the fact that the entire cost of these interventions that we'll
be discussing are typically born by the producer.
They're -- this is why we really are talking incentives in a different way than on the
human health side.
How do we get some of these interventions utilized when they represent an actual cost
to the end user?
So, I'll start then, for my section on the incentives for vaccines, and I want to acknowledge
the hard work of Liz Wagstrom, Cyril Gay, and Brian McCluskey, who really did a lot
of the heavy lifting in this section.
In animal health, vaccines have been used for decades, many decades, as a cornerstone
of disease prevention.
As we discuss their relevance with antibiotic use and resistance, it's important to remember
that the challenge we have in animal agriculture is that we're not just trying to control pathogens
that cause disease to animals, but also pathogens that may be transmitted through the food chain
and impact human health.
They may have absolutely no relevance to animal health.
So, we have this duality in the kinds of pathogens we're trying to prevent.
When we talk about the ways in which we use antibiotics, we are trying to either reduce
the bacteria; infections that would result in the use of an antibiotic, but we're also
talking about trying to eliminate the viral infections that might, in animal systems result
in a secondary bacterial infection that then require the antibiotic.
So, it's not just that viral infections are being treated inappropriately, it's that in
animal agriculture many of the viral infections result in secondary bacterial infections.
Again, we're also trying to reduce pathogens.
You can take a salmonella, a campel abactor [spelled phonetically] presence on a farm,
rarely causing any disease in the animal population, but we're trying to reduce those, as well.
So, within the economic piece, we really had one major issue statement, and it comes down
to the notion that for many antibiotics, the cost of purchasing and administering vaccines
can outweigh the cost of purchasing and administering antibiotics.
And so, there is a major incentive here.
There has to be a way to reduce the costs of these vaccines that reduce both bacterial
and viral disease impact on animal populations, so that we can reduce the need for antibiotics.
There has to be a way to make the use of these vaccines cost effective.
When we talk return on investment, we're often talking about how it impacts that producer.
Within research and development, we have three major issue statements.
The first is related to the limited funding that is available for some of the basic research
we still need on the immune systems of some of our key animal species.
Remember, we are dealing with many animal species, not just one, and their immune systems
are highly variable across species.
So, some of the research that is needed to be able to develop next generation vaccines,
adjuvants, and the administration tools is in desperate need of funding.
So, our two recommendations.
First, that we need funding to support the basic research of immune systems across these
species and I know, again, we are asking for money.
We need incentives that is related to funding and I think what we've heard throughout this
meeting and past PACCARB meetings, is that on the animal health side, the agencies are
severely underfunded for this one health issue.
And this aspect of the basics of the immune system is another key aspect of being able
to develop an intervention to reduce the need for antibiotics.
Related to that is sufficient funding for, as Dr. Shryock commented, the innovation institute,
which again would house many of the activities that we're discussing including a way to incorporate
vaccines into an overall health management program.
A second issue statement is related to the vaccine delivery systems for mass vaccination.
Many of these are not optimized for some of the specific animal pathogen production scenarios.
Some of the vaccines that we use injectable and that could be also into the egg, not just
into the animal, but we have many vaccines as well that are aerosolized so a spray vaccine,
they may be water, they use a water system for distribution and the ways in which many
of these pathogen delivery systems are developed aren't necessarily optimized.
We do need research in that area, so we're asking again for funding provided through
this innovation institute that is dedicated to supporting improved vaccine delivery in
animal production.
We are hoping that this would be a shared funding across agencies.
We talk one health, we really need to see the government agencies work together that
includes an emphasis on the animal side given that the end is a benefit to the human health
sector.
A third issue statement relates to something that Dr. Kester already mentioned, which is
the epidemiologic data are currently insufficient about the use of antibiotics for infections
caused by pathogens that are currently or potentially preventable through vaccination.
We desperately need studies that can estimate how much antibiotic use could be eliminated
through the use of vaccines, including the use of viral vaccines.
This includes field studies, it includes models, but it needs to be able to demonstrate the
effectiveness of these vaccines, a benefit to animal health, a return on investment for
the end user, and then, quantify how much antibiotic might we be able to eliminate out
of that production system.
On the regulatory front, there is a single-issue statement and it relates to that the processes,
the regulatory processes prevent a flexible approach and rapid approval of vaccine strain
updates in vaccine development.
For the animal agricultural sector, the vaccines are approved through the USDA's Center for
Veterinary Biologics and there are some hurdles when you want to change out the strains that
are incorporated into the vaccines.
So, we, through our recommendation, want to see a process evaluation by the USDA Center
for Veterinary Biologics to improve the speed of approval of these new strains into the
commercial vaccines.
And finally, the single-issue statement for the behavioral component, this is so critical.
It's really challenging for the producers and for the veterinarians to integrate new
vaccines and new vaccine strategies into their overall health management programs, while
balancing productivity, animal welfare and that return on investment.
So, we need education.
We need training on how do we assess the effectiveness of this disease prevention programs that balance
these various components including welfare through improvements in veterinary and animal
science curricula, continuing education, funding for training programs; again, all about how
do we adopt these vaccines, make it affordable for the end user, the producer, while maintaining
the productivity and welfare of their animal system.
And with that, I'll pass it to Dr. Davies for diagnostics.
>> Peter Davies: Thanks Randy.
And I'd just like to thank all the members of the working group who helped us out on
this issue.
First of all, just generally, a lot of the issues that were, Angie discussed on the human
side reflected pretty much equally or even more so on the animal side.
Just to outline the scope of the activities we had here, certainly we recognize the role
of the companion animal sector with respect to contribution to the AMR picture, but the
scope of the working group here was focused very much on the food animal populations rather
than companion animal populations.
Just to put the diagnostic situation in perspective, on the food animal scenarios, diagnoses overridingly
a population activity.
So, we're looking at outbreaks of diseases in population.
Certainly individual animal diagnosis and treatment is an important part of it, but
particularly in the larger and intensive populations, therapeutic decision making is often based
on both diagnostics conducted on samples of populations and on therapeutic decisions that
might be applied to populations.
So, we have a very different context for applying diagnostics.
Just to move onto our first issue statement, and again, this reflects on the human side
a dearth of clinical outcomes studies, I think in all aspects of therapeutic decision making
and antibiotic treatment.
Sorry.
And particularly, well, including the use of diagnostics.
So, our first recommendation here, well the issue statement [unintelligible], is that
we need show that the use of diagnostic tests can prevent or particularly or quickly protect
the emergence of antibiotic resistant bacteria and it's cost effective.
And the recommendation, as you can see there on side of that, is through the innovation
institute that's being proposed both funding, and perhaps even as importantly potentially
coordination of clinical outcome studies that include a fairly broad spectrum of animal
health and welfare outcomes, resistance emergence, and importantly, impact on cost of production,
because technologies tend to be taken up very quickly in the animal industries with financial
benefits demonstrable.
And it's important that all aspects of the economic impact of proposed approaches is
taken into account.
And I think within each of the food animal industries, obviously there's a need for prioritization
to really be able to decide which of particular disease issues that are, could most beneficially
be addressed by clinical outcome studies.
Because in all species, really, a lot of therapeutic decisions are associated with a relatively
small number of relatively well characterized disease conditions.
The second issue statement we have is, arrived at, that the use of diagnostic testing could
be limited by the expense that is incurred.
I think we should point out here that in the U.S., we have a -- we are very privileged
to have a very high level of veterinary diagnostic infrastructure, largely through our state
veterinary diagnostic laboratories and also the federal laboratories that coordinate and
support them.
The other point on cost of testing is particularly in the context of population testing.
The cost of the individual test is not necessarily that high in relation to the cost of the therapeutic
decision that's being made, which could be involving large costs of animal health negative
outcomes.
So, that balance is a little bit different than at a population level, the individual
test cost is perhaps not as important as in other settings.
So, our recommendation with respect this issue statement is, really, the need to insure ongoing
financial support for the veterinary diagnostic infrastructure that we have in the country
that performs all of the animal diagnostic testing, but also, specifically including
susceptibility testing for animal pathogens.
Okay, moving on to our R&D recommendations, and here I think we, the duality that Randy
spoke of with respect to issues in animal health and issues for potential human health
link to food animal populations and the food supply system is very clear because we couldn't
be focusing diagnostics on priority animal pathogens, but we know that in most cases
the importance on our particularly foodborne pathogens are often occurring in those populations
when they're very health animals with no disease associated with it.
So, we need to look at both sides of the picture there.
Our first issue statement again, reflecting the situation in human medicine is that there's
very few tests that rapidly identify pathogens or provide reputable susceptibility tests
in food animal medicines.
Our recommendation here, again, is investment in research on diagnostics that can rapidly
identify pathogens in food animals and provide rapid susceptibility results directly from
the clinical specimens in the field setting, understanding that in many cases these decisions
are made not in very remote situations.
So, it's not just, really, waiting for diagnostic processing time in a laboratory, but you have
sample transport delays that can be considerable in some areas.
The context of what is rapid then can be very variable for animals where you are making
immediate therapeutic decision in a remote situation to sometimes -- which could be quite
longer in some population settings if the decision is really related to a population
level treatment.
So, what is sufficiently rapid in the veterinary setting is, I think, highly variable depending
on the context that people are facing.
Randy mentioned before the sort of imbalance between the resources available on the human
and animal side, and I think that this is an area where in looking at rapid testing
and new technologies, for diagnostics that we might expect that there'd be more rapid
progress on the human side, and so our recommendation here is to be aware and looking for investment
in translational research that able to adopt new technological platforms and diagnostics
developed for humans into the animal setting because it's likely that they will be highly
transferable and that we're looking at generally bacteria that are closely related, often.
So, there's a lot of potential perhaps for technology transfer from the human to the
animal sector.
The next issue statement relates more specifically to the foodborne disease scenario and the
issue statement here is novel diagnostics are needed to advance process control in the
harvest and post-harvest sectors.
Here, meaning the post-farm sectors of the food supply chain, to reduce exposure risk
to the human population.
So, one of the successes, I think, that we've had regulatory wise over the last 20 years
or so, is that we've had a measurable reduction in the incidents of foodborne diseases for
most of our major bacterial pathogens that are associated at least with terrestrial animals
and a lot of that has been driven by greater focus on carcass hygiene and introduction
of microbiological standards for carcasses.
That happened in 1996 with federal regulation.
We're still using that at a culture-based method, so I think in line with new opportunities
here, we're recommending that there should be support for research to develop culture
independent methods of detecting microbial contamination of carcasses and meats as a
tool for improved process control.
And I think it's keen to point out here, that testing on an individual carcass in animal
disposition approach is probably never going to be economically feasible.
But we could apply the diagnostics to improve processes and under processes at a better
throughout the food supply chain.
The third issue statement we have here is additional information needed on antimicrobial
susceptible testing for key animal pathogens, including validated, clinical breakpoints.
So, we do have a process that's been going on for many years through CLSI to establish
breakpoints for testing of animal pathogens, but it's an incomplete process.
So, we still have, through lack of research investment in many cases, many important animal
pathogens where we either do not have breakpoints that have been established or in other cases
the human breakpoints for the same or related pathogens are just translated into the veterinary
sector.
So, here, we're recommending that research grants for generation and integration of additional
data that's necessary for that process to progress to establish test methods, quality
control range data, all the things they do for a priority animal pathogens for which
there's currently no breakpoints available or for where human breakpoints will do.
So, obviously the value of the antimicrobial susceptibility testing would promote people
to do is dependent on the reliability to translate those breakpoints into a clinical setting.
Moving on to the regulatory recommendations, we can be brief here.
Even though both FDA and USDA have some oversight of animal diagnostic tests, it's largely related
to labeling safety and they're adequately represented.
And the market for veterinary diagnostics is essentially a market-driven one.
As I mentioned before, successful technology tends to be adopted fairly quickly, so the
market is alive there.
So, we don't see any regulatory issues that are probably impacting the development of
diagnostic tests.
The final consideration is the behavioral recommendations, and we had some wonderful
material yesterday related to behavior and therapeutic decision making and prescribing.
I think this is an area again, where we can say that's fairly new on the human medicine
side and it is novel on the animal side.
So, I think our issue statement written is that there's negligible evidence based data
about how veterinarians incorporate diagnostic testing's into making decisions to employ
antibiotic therapy and I think we can extend that further, just to the whole practice of
prescribing.
So, here we're recommending support for research into therapeutic decision-making behavior
in veterinary medicine, including the use of susceptibility testing and potential for
rapid diagnostics.
And secondly, again, and similar to the human recommendations, opportunities for better
educational programs for veterinarians on use and interpretation of diagnostic tests,
stronger curricula and continuing education programs linked to antibiotic stewardship.
Thank you.
And with that, I'll pass back to Tom.
>> Thomas Shryock: All right, we're in the homestretch here.
This is the incentives for alternatives.
You noticed earlier on that we had used the word anti-infectives, now we're changing it
a little bit and calling it alternatives.
And so, I'd like to define, really quickly, what we mean by the word for this particular
presentation.
And here we're talking about non-antibiotic disease interventions.
They're administered to food animals regardless of whether intended for disease prevention
control or treatment.
They're not necessarily interchangeable with or substitutes for antibiotic products.
So, keep that in mind as we go through the next few slides here.
So, our economic considerations in issue one, basically is very similar to what Joe Larsen
was talking about from BARDA.
Funding is lacking to generate a sufficient pool, high quality alternative candidates
in the early and middle stages of R&D.
So, our three recommendations, along the line here to address this would be not only to
fund the innovation institute to get things going, but to basically look at maybe some
user fees to supplement or replace agency funding that might be initially used to get
that off the ground.
The second recommendation here is to use that innovation institute as yet another tool to
encourage CBER funding, which was mentioned by Angie and others, and private sector investment
activities.
Getting the support of that institute for additional, extra funding to advance these
early stage candidates to the point where then in number three recommendation here,
the technology transfer pathways can be facilitated from those early to mid-stage candidates for
acquisition by companies that have a little more breath in interest and ability to carry
them across the regulatory and developmental pipelines and into the marketplace.
Our R&D recommendations, here we have two issue statements.
The first one that we'll talk about here is that small companies, government agencies,
independent investors that don't really have available resources, and mostly in terms of
personnel, to conduct the key activities that are needed to de-risk the alternatives as
they move from the early stages toward the middle stages.
So, things like proof of concept, early safety studies, even some manufacturing studies,
for example.
So, the recommendation here would be that the innovation institute can provide support
services really in the way of connecting the innovators across the sectors to get those
services that they need to advance their candidates in the R&D sector.
And then, aligned with that is that the specific solutions that could be outlined in the national
policies to be developed, really can be used to include what kind of contract research
organizations?
What kind of connectivity might the innovation institute have to blend the resources to the
needs, the needs to the resources to get those early stage candidates moved along?
And then, our second issue statement here has to do a little bit more with the idea
that having information on the effectiveness and the efficacy of these alternative products
could be combined with data that's collected in an actual field production setting so that
you can begin to compare what is actually happening across different farm sectors.
So, to expedite that, the R&D recommendation here would be either outright grants or connectivity
to funding sources to actually get that work done with a caveat that the data generated
would be entered into a larger data pool for larger evaluation, maybe a big data type of
evaluation.
So, the innovation institute could help with advancing RFPs, for which proposals could
be submitted and the funding obtained, or just outright grant funding.
Our regulatory considerations then would be two-fold with issue statements.
The first would be, lots of times the early stage developers, just two, three, four, five
people in a company, don't really know who to turn to, whether it's USDA, it's CVM, it's
somewhere else, perhaps maybe even EPA.
So, how do you get to the right people in the right way in the shortest amount of time?
So, one of the points of contact could be through the innovation institute.
So, thinking of it as a clearing house or a one-stop shop could provide that connectivity.
So, this could supplement, not to replace or be redundant to the existing programs,
the USDA and CVM already have, but just make sure those connections and the communication
are more readily accessible for those who are basically the resource constraint to get
that information.
A second issue here is while there may be standardized guidance with antibiotics in
mind, or other vender and medicinal products, often times with these alternatives there
may be a need for flexibility in how the guidance documents could be interpreted or adapted
so that the developers could actually meet the evidentiary requirements of the regulatory
agencies.
So, the recommendation here is to really provide the resources to the regulatory authorities
to enable them to keep abreast of the latest technologies so that they can be conversant
with and even suggest alternative studies and approaches and data evaluation, such that
the sponsors then can generate the data that meets those requirements for approval in a
more easy fashion rather than relying on a specific guidance that may not be quite appropriate
for the innovation at hand.
And then, our last topic here on behavioral recommendations has to do with a very early
stage of candidates.
And this would be that researchers sometimes lack the business value awareness and the
process of patenting novel technologies.
So, the recommendation here would be that maybe there's a need through the innovation
institute to bring that to light to those developers, researchers and others who maybe
just don't know, or haven't thought through the implications of the timing or other things
like that.
A second possibility would be some sort of patent application fee reimbursement or post-patent
award or something like that to encourage developers or innovators at that very early
stage so the technology is not lost for lack of coverage.
A very important point for those who wish to acquire technology transfer later on.
Our second issue statement here is related to one we talked a little bit about in the
R&D that the effectiveness of alternatives, because they lack trust in their effectiveness
and their safety.
So, having those studies done enables the behavior to be altered such that there's more
trust in the product.
There's more confidence going forward that this would be an appropriate tool to use to
prevent, control or treat a disease.
So, that really wraps up the behavioral aspects.
And it also concludes the working group recommendations in this report.
So, with that I will end and turn it back to our chairs, Marty and Lonnie
>> Martin Blaser: Thank you, co-chairs.
I think we can see that the committee has done very thorough work with much detail and
much depth.
I think it's a really remarkable body of work.
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