ORAQ IND Workshop – June 13, 2017

Alright, I think we’re going to go ahead
and get started. I want to welcome you all to the investigational new drug or
IND workshop. This is the first of our two-part series on the best practices
for the preparation submission and maintenance of sponsor investigator INDs
and IDEs the second part of our workshop series will be presented
tomorrow morning and that will focus on devices and the IDE these workshops are
being presented by the office of regulatory affairs and quality here at
Duke or also known as ORAQ or ORAQ we were formerly known as DTMI regulatory
affairs and it’s also being presented in collaboration with regard so I’ll
mention more about regard in a few slides but just briefly this is a
collaboration that we have with our regulatory staff here at Duke with the
regulatory folks over at UNC RTI and Wake Forest so we have some participants
calling in from those institutions today as well they’re attending via WebEx so
we want to welcome you all so my name is Kristen Foss I am a regulatory affairs
scientist with the Duke office of regulatory affairs and quality and I’ll
be presenting on part 1 of today’s workshop where we’ll talk about IND
exemptions and determining whether or not you need an IND for your study and
then at the end of part 1 we’re going to talk briefly about pre-ind meetings and
how you can meet with the FDA prior to actually submitting an IND and talk
about when you might want to consider having a pre-ind meeting then we’ll take
a quick break between parts 1 and part 2 and Dr. Stephanie Pierce will be
presenting part 2 where she’ll tell you about best practices for preparing and
maintaining an IND so a few pieces of housekeeping information before we get
started this session is being recorded and will be available on our website
following the addition of closed captioning and for those of you
specifically that are calling in via WebEx we ask that you please keep
yourself on mute throughout the talk and if you would like to ask questions we
encourage you to use the chat box feature of WebEx
and send the questions to the host of the meeting which will show up as
Kristen Foss hope so don’t send them to the presenter send them to Kristen
Foss host we had someone from our team manning that chat box and they’ll share
those questions as they come in and for those of you here on site we if you need
to leave at any point during the during the workshops today please use the doors
in the rear of this room if you’re not familiar with this building in the
restroom locations they’re back over in this corner so if you exit out of the
back take a left and another quick left walk all the way to the back and the
restrooms will be there on your left we do encourage you to ask questions
throughout the workshop today we would just ask that you would use the
microphones because we are recording the session and also have folks listening in
remotely so we have a microphone on a stand here that you can use we do also
have a couple people that are carrying handheld mics and if you raise your hand
they’ll bring a mic to you so you can ask your questions if you’re attending
today to fulfill your sponsor investigator training requirements
please make sure that you let Audrey or Susan know at the sign-in table to make
sure that you receive credit for this so here at Duke all sponsor investigators
of INDs and IDEs require they’re required to have training on their
responsibilities so one way that you can fulfill this training is by attending
this workshop here so if you need this training or if you think in the future
that you may potentially hold an IND then let them know and they can they can
mark you down for that I also just wanted to note that we hope you all got
a chance to sign in before you came in today and hopefully we’re able to pick
up an evaluation form so please we would really appreciate it at the end of the
workshop if you could take a few minutes and fill that out and give us some
feedback on the workshops today and then at the end after part two of the
workshop we’re actually going to have a speaker’s here from dr. who’s going to
talk to you all about an exciting new system that’s being developed that will
assist investigators here with submitting single patient IND’s
specifically for duke investigator so those of you calling on via WebEx
that part of the talk won’t be as applicable to you if you’re at another
institution so feel free to sign off at that time if you’d like okay so these
are all of the friendly faces that make up the Duke office of regulatory affairs
and quality many members of our team are here today including our director Dr.
Amanda Parrish a director of regulatory affairs and quality we are a free
resource for the Duke research community so we’re here to help you any study
teams that may need FDA oversight for their studies were we’re here to help
relevant to today’s topic we can assist you in determining whether or not your
study requires an IND and we also help with preparing IDs submitting them to
FDA and also maintaining those IND applications as you’ll learn more about
in part two of the workshop today we can be involved in your study to many
different capacities or with your IND we can simply be a resource for you to come
to and ask questions when they arise or we can actually help you with as I said
preparing and submitting that IND application and then maintaining it as
well so we are as I said the office of regulatory affairs and quality so this
is a newer part of our group and we’re working now on building up this quality
side of the office we currently have just one person that’s devoted 100% to
quality which is Dan Ozaki not pictured here but where as I said working on
building out this part of the office so we encourage you to contact us anytime
you have questions reach out to us you can find us you can find our website
through the School of Medicine so it’s medschool.duke.edu/ORAQ on our
website you’ll find regulatory templates such as for inds
and instructions for filling out those templates we also have information on
educational seminars and events such as the workshop that you’re all attending
today and also information on our training program which we offer
quarterly and this training program covers a lot of the same information
that we’ll be talking about during the workshops
over the next couple days and then we do have a general office e-mail so Oh Rach
at vmz edu so you can use this email address if you have any general
regulatory questions please direct them to this email address so I mentioned
regard briefly back on the first slide but I wanted to introduce regard to you
all if you are not familiar with it it stands for regulatory guidance for
academic research of drugs and devices and this is a collaboration between the
regulatory affairs specialist at fee for North Carolina institutions that receive
CTSA funding that’s the NIH clinical and translational science award so that is
unc RTI Wake Forest and Duke and the mission of this group is to provide
researchers with the tools and resources that are necessary to find a successful
pathway from discovery all the way through to clinical implementation of
new and innovative drugs biologics and medical devices so this group also has a
website with useful information for regulatory or just clinical researchers
and so you can check that out if you’d like regard org it is still a work in
process and there will be a new and updated version coming very soon so for
those of you who are attending remotely from UNC RTI or Wake Forest these are
the regulatory context that you can reach out to if you have questions about
inds or ID es so at unc your first point of contact is going to be amanda wood
and then at Wake Forest dr. Heather Hatcher will be the point of contact for
you all for regulatory questions okay so let’s jump in now to part one
where we’re going to be talking about IND exemption studies and pre-ind
meetings so a good place to start is always going over a few key definitions
so we’ll touch on some important definitions in the beginning and then
we’re going to jump into when you need an IND for a clinical study and
hang out when when you could be what we say IMD exemption when you don’t need an
IND so we’ll talk about the difference between conducting studies that are
using products that are not lawfully marketed as drugs versus lawfully
marketed drugs and then we’ll talk about the difference between on label and
off-label use and how that could affect the need for an IND
we’ll look at IMD exemptions and some guidance that FDA has issued on IND
exemptions and the exemptions will then look at the FDA review process so if you
decide you want to go to FDA to get them to weigh in on whether or not your study
is is exempt then we’ll talk about a few specific issues or special cases where
the applicability of the IND regulations might not be as obvious and lastly well
second for the end we’ll look at some case scenarios where we’ll test some of
the knowledge that we’ve talked about in the first part and then the last thing
we’ll do is touch on pre-ind meetings and when you might want to consider
having a pre-ind meeting and the process for that okay so some definitions so
first off what is a drug well a drug is anything that meets the definition of a
drug / the FD&C Act so there are two parts to the drug definition the first
is that drugs are articles intended for use in the diagnosis cure mitigation
treatment or prevention of disease in man or other animals and then the second
part is that drugs are substances other than food intended to affect the
structure or any function of the body so it’s really important to keep in mind
the second piece of the definition and remember that drugs are not just
products that are intended for therapeutic purposes so this second part
of the definition also includes compounds that are administered to blunt
or provoke a physiological response or to study the mechanism of action or
metabolism of a drug so for instance if an investigator was going to do a study
just administering histamine to healthy subjects purely to study that
physiological response that they want to go back and research in their lab
histamine in that scenario would be considered as a drug even if
it’s not not obvious that you’re not using that to treat that patient or the
subject so what is an investigational drug investigational drug is defined in
the Code of Federal Regulations so in 21 CFR part 312 which is where you’ll find
all of the IND regulations and it says that an investigational drug is a new
drug or biological drug that is used in a clinical investigation and there are
really two types of investigational drugs so the first is an article that is
not lawfully marketed in the US as a drug and then the second is an article
that in fluffily marketed in the US as a drug but it’s not being used according
to the approved label so when a drug gets approved it gets approved to be
used in a very specific way and if you are using this drug off-label in a
clinical study it’s been an investigational drug it’s important to
note that the practice of medicine does allow a physician to use any lawfully
marketed drug without prior regulatory approval whether it’s on label or
off-label which we’ll talk more about what that means later on but as soon as
they want to use that that drug off-label in a clinical study that’s
where it would become now an investigational drug so what is a
clinical investigation this is also defined in 21 CFR 312 and it’s defined
as an experiment in which a drug is administered or dispensed to or used
involving one or more human subjects and specifically for the purposes of the IND
regulations they say that it’s an experiment or an experiment is used
experiment using any drug whether approved or unapproved except for the
use of a marketed drug in the course of medical practice so as we said
physicians are allowed to use any marketed drug as their treating patients
to however that they see fit okay so now that we’ve gone over a few key
definitions we’re going to jump into how to determine if a clinical investigation
requires an IND and the first thing that you want to consider
whether or not your study is using a product that is lawfully marketed as a
drug so what do we mean when we say that it’s a lawfully marketed drug
well lawfully marketed drugs these are articles that are commercially available
and they are also legally marketed in the US as drug so important to note that
not all commercially available drugs are legally marketed there are products out
there that are marketed as drugs that are commercially available but they may
not be legally marketed and that they haven’t undergone the proper review
process before they have been made available we also want to note that this
when we refer to lawfully marketed drugs we’re talking about drugs that are
lawfully marketed in the US as opposed to being marketed lawfully in the EU or
in Canada or other countries and they must also be currently marketed as a
drug so there are some products that have been lawfully marketed in the past
but were withdrawn from the market for one reason or another and those would
then obviously no longer be lawfully marketed and typically when we think
about lawfully marketed drugs this is usually going to be synonymous with FDA
approved drug products but it is important to note that there are some
drug products or active ingredients that are considered legally marketed but are
not formally approved by FDA and there could be a few reasons for this
over-the-counter medicines are one example that aren’t approved by the FDA
but are legally marketed if they follow the correct requirements for that so if
you are unsure about the marketing status of the product that you’re
studying you can always contact our office if you’re here at do for your
respective regulatory office if you’re at another institution so you can get we
can help you get that final clarification on the marketing status of
your product and we also want to note here as I mentioned briefly before that
approval of a drug is for marketing a drug in a very specific manner as
defined by the drug labeling we’re going to talk more about that later on but
this is this drug label and the information that goes in there is going to
based on the clinical study data that’s submitted by the sponsor of the IND
application to FDA to support that approval okay so if you’re conducting a
clinical investigation that uses a product that is not lawfully marketed in
the US as a drug that study will require an investigational new drug application
or an IND and an IND is a request to the FDA for
authorization to administer an investigational drug or biologic to
humans so the term drug when we use that today is generally going to refer to
both drugs and biologics the IND is applicable for both drugs drugs and
biologics and also authorization must be secured prior to interstate shipment of
any new drug or biologics that is not lawfully marketed in the US as a drug so
this is V is what gives you what allows you to ship the product across state
lines it gives you an exemption to the current federal law that actually
requires a drug to be the subject of an approved marketing application before it
can be transported or distributed across state lines all right so this flowchart
is going to walk us through the decision-making process for determining
whether or not your study requires an IND so here on the left side we have the
first question that you’re going to ask yourself is if you’re testing a study
that’s using a test article is that test article legally marketed in the US as a
drug and if the answer is yes then we we know that that is an investigational
drug that will require an IND so that’s kind of the more simple straightforward
side of the flowchart if you are using a legal product that is legally marketed
in the US as a drug it’s what we would say it’s a lawfully marketed drug and
you may need an IND or you may not need an IND and that really depends on how
the drug is being used in the clinical investigation whether you meet the
exemption criteria that we’ll talk about in a later so we’re next going to look at on label
use versus off-label use and how this can affect whether or not you need an
IND before we get into that let’s first just talk about what is drug labeling
and drug labeling refers to basically anything that goes along with with the
drugs so refers to all the printed material
that accompanies the drug so that’s going to be the label that’s on the
product any wrapping or packaging material that comes with it if that has
information on it and also then the package insert which is what we
typically think of as the label we’re going to look at an example of one of
those on the next few slides this package insert is going to include
all the instructions for how that product should be used
um in order for it to be used safely and effectively for how FDA has approved it
so it’s going to include the indications and usage dosage judgment and
administration contraindications and many other things as well there are two
websites that you can go to if you’re looking for package inserts for products
these are searchable databases that you can find online so the first is through
FDA’s website the Center for Drug Evaluation and Research has a searchable
database that will have all of the drugs and biologics that are regulated by
cedar the dailymed site which is the second link here is going to contain
label information for drugs and biologics and nice thing about this
dailymed site is it also includes marketing the marketing status so that
can be helpful if you’re trying to determine whether or not your product is
lawfully marketed so we’re going to take a look at what this first access data
that FDA gov site looks like or drugs at FDA so if you’re trying to search for a
label you would just go to the site type in the drug that you’re looking for
so in this case we’re looking for Pember lism ad and then it’ll bring up any
products that fit that name and you can see the bottom link there is for label
so if you click on that it’ll take you to the package insert and so this is an
example of the first part of what the package insert looks like this is just
the highlights of prescribing information the full package insert is
going to be much longer but you can see here it has the the indications and
usage dosage and administration dosage forms and strengths contraindications
warnings and precautions a lot of information here that can be found in
the package insert so it’s going to be really important to keep in mind how the
product that you’re studying is approved to be used by FDA so what is included in
this package insert so when we refer to on label use that means that you are
using that product in the exact same manner as what’s described in that
package insert so the same indication dose route of administration patient
population drug formulation everything is the same so if you are using a drug
on label in a clinical study you do not require an IND that’s not considered
investigational because you’re using it in the same way that it was approved and
there is just one caveat to that and that is as long as the data from your
study will not be used in a marketing application or to change the advertising
which typically in an academic institution that’s usually not the case
so then off-label use is going to be essentially just any difference from
what is approved in the label and importantly this includes drug
combinations so even if you have two approved drugs that you’re planning to
combine together in a clinical study and if that combination is not listed in the
label for those two drugs that combination is off-label and would be
seen as investigational an off-label use as you probably know is very common and
is allowed as we said before in the practice of medicine it’s often even the
standard of care as we said that the FDA doesn’t regulate the practice of
medicine so it’s only once those drugs begun begin to be used
off-label in a clinical investigation that FDA oversight would would apply
okay so coming back to our flowchart here and on the right side of this
flowchart where we’re looking at lawfully marketed drugs so we said if
you are studying that drug on label then an IND would not be required again just
assuming that no marketing application or change in advertising is planned and
if you are using that product off-label so anything that is different from the
product or the package insert then as we like to say well it depends and it
depends on if your study meets the exemption criteria that we’re going to
cover in the next part of the talk all right so IND
exemptions we’re going to take a look at the IND exemption regulations next and
some guidance from FDA on how to determine if your study requires an IND so as I mentioned earlier the IND
regulations are in 21 CFR part 312 and specifically in part 312
2 B is where you’ll find the IND exemption criteria so we’ll talk about
FDA has two really excellent guidance documents that can be quite helpful in
trying to determine whether or not your study needs an IND the first is focused
more specifically on products view for the treatment of cancer but this
guidance document can be really helpful even if you’re not studying cancer
especially if you’re studying other serious or life-threatening conditions
but even if that’s not the case it can be really helpful just to get an idea
about how FDA thinks about these types of situations and it also gives a lot of
examples as well so that can be quite helpful all right so when is an IND not
needed for clinical investigations involving drugs as we mentioned before
there are some studies that use lawfully marketed drugs for instance if you’re
using a lawfully marketed drug on label you would not need anion
or if you’re using it we’ll talk more about if you’re using an off-label as
well but the second bullet point there is for some studies using in vitro
diagnostic biological products so if you’re using blood grouping serum
reagent red blood cells or anti-human globulin in an in vitro diagnostic sort
of situation you would not require an IND also studies that use drugs only in
vitro or in laboratory animals don’t require IMD’s there are some studies
that are using radioactive or cold isotopes that would not require an IND
we’re not going to talk about that too much today but the the second guidance
that was listed on the previous slide has more details about what types of
studies would not require an IND for radioactive or cold isotopes and then
lastly certain bioavailability or bio equivalent studies can be conducted
without an IND alright so if you’re trying to determine whether or not your
study can be considered for an IND exemption what we say is the first
hurdle for determining whether or not you are eligible for an IND exemption is
whether or not you are conducting an investigation of a drug product that is
lawfully marketed in the United States so if your your product is currently
lawfully marketed in the US then that study is eligible for an IND exemption
or in other words that study can be considered for an IND exemption so you
want to keep this in mind when we get to the case scenarios near the end keep in
mind that this is really that first hurdle to cross when you’re considering
whether or not your study can be I can be eligible for an IND exemption so if
you are studying a product that is lawfully marketed in the US as a drug
you can be exempt if you meet five criteria that we’re going to go over
next and you have to meet all five of these criteria so the first is if the
study is not designed to support approval of a new indication or a change
in label and the second is the study is not intended to support a significant
change in the advertising for the product
so as we said before this is typically not the case in an academic setting so
usually we don’t have any trouble meeting those first two criteria now the
third criteria here is the the most important one we found for investigators
to focus on in assessing whether or not your study can be IND exempt and this
one says that the study does not involve a route of administration dosage level
or patient population that significantly increases the risk or decreases the
acceptability of the risks associated with the use of the product we’re going
to spend several slides going over what sorts of things you would need to
consider in assessing the risks associated with changes in say the route
of administration or the patient population so we’ll focus on that one
more in the next coming slides but this is really the only exemption criteria
that’s really dependent on the protocol itself so the fourth criteria is that
the study is conducted in compliance with the IRB and informed consent
regulations which you all I’m sure are doing regardless of whether or not you
have an IND so that one shouldn’t be a problem
and then the fifth exemption criteria is that the study is conducted in
compliance with regulations regarding promotion for investigational drugs so
this means that you’re not going to be promoting your drug is being safe and
effective for an indication that it hasn’t been shown to be to be so okay so
we’re going to focus now on this criteria number three next as we move on
and how do you evaluate the risks associated with these changes so as we
said you’re going to be looking at risks associated and changes in the patient
population the route of administration dose drug combinations and also drug
modifications so if you’re going to be modifying that drug in any way so on the
next few slides we’re going to take a closer look at each one of these label
components and look at what the FDA guidance documents say about what to
consider when assessing the risks associated with any changes all right so
saying you want to conduct a study in a different patient population from what
that product was approved to be used for SBA says that the acceptability of known
and unknown risks can vary across different treatment population the
population chosen for study could be at increased risk compared to the approved
youth population for a variety of reasons such as increased age different
disease or stage of disease concomitant illness decreased renal or hepatic
function or concomitant therapy so there’s a number of reasons why a
different patient population could be at an increased risk so for example if you
are studying a cancer drug and if you look in the cancer drug guidance that we
referenced previously they say that typically for a lot of cancer drugs
trying them from in a different indication from what they were approved
is oftentimes not going to significantly increase the risk unless you’re talking
about moving it to a patient population that may be Ari has an effective therapy
and you would be withholding that therapy from them then that would
clearly be increasing the risk or if you’re talking about a cancer patient
population that potentially has a much better prognosis or longer survival as
compared to the product indication the patient population that that product was
initially approved for so a lot of potential changes in the risk there with
different patient population so in thinking about the route of
administration FDA gives an example that there could be significant increase in
risk if the marketed drug for oral administration is going to be converted
to a dosage form that is to be administered by injection or intravenous
intrathecal or inhalation route so if you’re making any route of
administration changes you want to assess whether or not there are any
additional risk to the subjects so for instance you would need to consider
things like how are you going to ensure that the product is sterile if you’re
going from an oral form to a an intravenous injection whether or not the
differences in PK are going to create safety issues for the patients and
things like that so dose when you think about dose I think it makes sense that
if you’re going to be increased the dose from the approved level that’s
approved in that package insert there could clearly be some increased risk to
the patient but it’s also possible that decreasing the dose could cause an
increase in the risk the FDA guidance document gives an example of
administering a low dose of a pure polysaccharide vaccine to study subjects
that this can induce a hypo immuno genic or an on or immunologic response in
those subjects and this could potentially induce tolerance to the
vaccine and put those subjects at risk for the infectious disease that the
vaccine is intended to prevent so you want to assess risk associated with any
change in the dose whether you’re increasing or decreasing the dose and
drug combinations are another area where you want to consider risk so as we
mentioned before if you’re combining two even two approved drugs but they’re not
approved to be used together that would be seen as investigational and the FDA
does say that unless adequately described in the literature initial
studies involving new drug combinations likely will need an IND and they say
should be performed under an IND and that’s because they’re concerned about
the possible occurrence of synergistic toxicity so keep that in mind if you’re
using two new drugs that have not been used together before there’s no reports
of it in the literature then you’re likely not going to be exempt and will
require an IND all right so say you want to make some drug modification so you’re
wanting to actually alter the drug product itself this is is okay to do and
FDA even does say that they the exemption provision was not intended to
require use of only the marketed product so the sponsor investigator is allowed
to make some low-risk modifications to the product if it’s a lawfully marketed
drug so this could be things like over encapsulation or changing the color or
scoring or size of the product for the purpose of say blinding the
investigation those are are generally could be okay but we would recommend
that you would just want to consult with FDA just to make sure
that they they don’t have concerns about that they may if you’re doing a lot of
changes it’s potentially they could potentially want you to submit an IND so
you would want to provide them with detailed manufacturing information so
that they can make a determination as to whether or not they feel that that study
should be run under an I&D and so we’ll talk about the mechanism for how you
would contact FDA in a few slides as well so when it comes to the use of a
placebo as long as you meet those other five exemption criteria then the use of
a placebo is going to be fine and you can still get an IND exemption so if the
investigation does not otherwise require the submission of an IND than a clinical
investigation involving the use of a placebo is exempt okay so now that we’ve
discussed these five exemption criteria for how to determine whether or not a
study requires an IND or not we wanted to well now we just want to find out
from you all do you think that you need to go to the FDA to get an IND exemption
what do you think yes or no you just may be ya know so the answer is actually no
you do not need to go to the FDA to get an IND exemption and FDA actually says
in there both of their guidance documents that because the assessment of
risk is involved in the therapeutic procedure are involved in a prosthetic
procedure is an everyday part of the practice of medicine the individual
investigators should usually be able to determine the applicability of the
exemption so the the investigator should make that initial risk determination as
to whether or not they feel that the risks to the subjects are significantly
increased or the acceptability of the risk is decreased so if the investigator
you know they make that initial assessment of risk and they think that
their study does not require see they would then submit that
rationale to their institutional review board or the IRB and this may be in a
checklist we would also recommend that you submit a narrative statement as well
especially addressing that third criteria addressing the risks for any
changes in the label but you would want to just check with your local IRB
policies for those of you calling in from other institutions on how they
would like that to be presented for them and then if the IRB agrees with you and
they say that yes this is not a significant increase in risk then you
can proceed with your study with just IRB oversight but if the IRB does not
agree then you would need to go to the FDA to get the FDA to weigh in there are
some other reasons why you would want to go to the FDA and you can actually go to
the FDA initially you don’t have to go to the IRB first in some reasons that
you may want to seek FDA input aside from just the IRB requesting that you
receive FDA input would be if you have some time constraints on when your study
is going to begin or when it needs to begin so if you go to the IRB first
thinking that you won’t need an IND and then they tell you that well we want you
to actually go to the FDA and see what they think then that could delay the
start of your study if you’re doing an investigation with an industry partner
that industry partner may request FDA input before they will donate the drug
or release the funding potentially or if you have a situation that’s just really
unclear from the start you really feel unsure about whether or not there’s a
significant increase in the risk then that would be another instance where you
might just want to go to FDA and get their opinion potentially you want
documentation for a grant application some grant applications may even require
this documentation to show that your study doesn’t need an IND and
potentially your local policy might even require FDA input so that’s not the case
here at Duke with their IRB you don’t necessarily have to have FDA input on
whether or not your study is IND exempt but some local policies may may require
that okay so we’re going to move on now to
the FDA review process so if you do submit your studies to the FDA for them
to make that exemption determination we’re going to go over what that review
process looks like does anybody have any questions now we’ve been moving right
along but feel free if you do have any questions raise your hand or come to the
mic just feel free at any point okay so if FDA is evaluating your study for an
IND exemption determination they’re going to be assessing the risk by
focusing on the same essentially five criteria that we just went over and
they’re going to now be making their determination as to whether or not the
changes that you’re making in these areas are significantly increasing the
risk or decreasing the acceptability of the risk to the subjects in the study there are two different processes that
can be used to get an IND exemption determination from FDA so there’s the
formal process in the informal process the formal process is basically just
submitting an IND application to FDA just because you submit an IND
application doesn’t necessarily mean that you’re going to have one FDA will
always do an independent assessment of whether or not that study really does
need to have an IND or not so you can always just submit an IND this will put
FDA then on a 30-day review clock so you’ll hear back within 30 days as to
whether or not your study requires an IND
and if you’re not exempt then the benefit is you already have an active
IND now there’s not going to be any additional work as far as submitting the
initial inb now the informal process simply involves contacting the FDA
review division that would be reviewing your IND should you submit the IND and
we’ll talk about how you determine which review division is appropriate this
route is going to be less work upfront most likely and you might get a faster
response as well if you go this route but not all review divisions are
necessarily going to do this informal so so you would want to check with your
review division and first and make sure ask if they would be willing to do this
informal request or informal process so if you want to go this formal route and
just submit an IND what is that submission going to look like well it’s
going to include a cover letter which we’ll talk more about on the next slide
and then you’ll have your inv which is going to consist of the IND document
which is important in case you’re not exempt it also includes all of the other
components that you would be submitting in your IND that Stephanie we’ll be
talking about in the second part of the talk today so your protocol your consent
there’s a few different forms that get submitted a letter of authorization
potentially if that’s applicable to you and also reprints from the literature so
if there has been other similar types of studies that have been performed before
and published you can actually include reprints of those in your IND
application two to three references would be acceptable and so then if FCA
determines that the study is exempt you will receive an official letter of IND
exemption that could be provided to the IRB or potentially your industry sponsor
or anybody who is interested in that the the cover letter for going this formal
route and submitting your your request for IND exemption is going to include in
the first paragraph just a statement that you believe this study may be
exempt and then you want to restate in the body of that cover letter each of
those five exemption criteria and explain how or why you meet them
especially focusing on the exemption criteria number three and focusing on
safety because that’s what FDA is going to be focused on so explain to FDA why
you don’t think your changes from that approved label are increased
significantly increasing the risk to the subjects so if you decide to go the
informal process for obtaining an exemption you’re going to first just
contact the appropriate FDA review division and explain the situation
tell them basically what you’re planning to do
that you want to request an IND exemption or see a fill they’ll review
that study for you so as I said not all review divisions will necessarily do
this you want to ask them if they would do that for you
and if they say yes then you would send in your protocol synopsis and/or the
full protocol for review they may request other forms or information from
you as well and that’s going to be review divisions specific so you could
you would need to submit that as well and typically we’ve seen that you’ll
receive a decision from the FDA usually within around two weeks or so so it
could be faster potentially than submitting an actual IND but the
response that you get back from FDA it might only be a verbal response then
telling you no we don’t think your study needs an IND
on the phone they might not want to put it in writing or it could be an email
potentially or it could be a formal letter so if it’s important that you do
have it in writing you would want to ask them about that up front and then
potentially you could decide if the formal route might be more appropriate
for you so how do you determine the appropriate FDA review division for your
IND or your request for an exemption well if you’re studying a drug you’re
going to be going through the Center for Drug Evaluation and Research or seeder
if you have a biologic that will be the Center for biologics Evaluation and
Research and we have up here the websites for each of those centers with
a list of the different review divisions that they have four-seater the review
divisions are broken down by the therapeutic area that you’re studying
and we’ll look at an example on the next slide of what you would see when you go
to that website and click on review division for the therapeutic area that
you’re studying and then perceiver their offices are divided more based on the
type of product that you’re studying so they have the office of blood research
and review office of vaccines research and review and the office of tissues and
advanced therapies and then review divisions within each of those offices
so if you are studying a drug and looking for where it would go to which
review division it would go to as I said you click on the link from that previous
slide it’ll bring up a list of all the review divisions and say you’re studying
a product that might be overseen by the division of cardiovascular and renal
products if you click on that division it will take you to this slide here and
you can see that they include a pretty extensive list of the types of
indications or therapeutic areas that this review division would be reviewing
so this will give you a good idea as to whether or not this is the appropriate
division for the submission of your IND or your request for an IND exemption we
point out on this slide the it lists the director of the division this is who you
would address your cover letter to it also lists the chiefs of the project
management staff as well this is going to be the person that you would contact
if you want to go through the informal process for obtaining an exemption so
seeder also has a very convenient chart on their website for all of the pre-ind
consultation contacts for their various different review divisions so this chart
lays out all of the review divisions with the contact information for the
person that you would contact if you want to go that informal route of
getting an IND exemption or just have other questions for them as well prior
to submitting an IND so any questions on the FBA review process or anything we’ve
covered so far okay we’re going to move on then to look at a few specific issues
or special cases that we find oftentimes raise questions for investigators when
it comes to determining if the inv regulations apply so these include
studies using endogenous compounds live organisms dietary supplements tobacco
products as well and then we’re going to talk briefly just at the end about
research with non-commercial intent so the regulatory landscape for some of
these articles is changing and so if you are planning
a study that touches on these many of these issues we would encourage you just
to reach out to our office so we can discuss the study with you and any
regulatory implications so endogenous compounds are those that are naturally
found in the body and these compounds are often used in studies that are used
to evoke physiological response characterize the disease or establish
mechanism of action and importantly these studies do require an IND
if they’re not conducted with lawfully marketed drug than they would require an
I and B because again remember that even though there’s no intent here to treat
or mitigate disease there is intent to affect the structure or function of the
body and if we go back and look at the definition of a drug here you remember
that that second part is a substance intended to affect the structure or
function of the body so if an endogenous compound is being used in this way then
it would meet that definition of a drug and would require an IND so live
organisms are often used in challenge studies as well they may be administered
to study pathogenesis or host response to the virus bacteria or fungi that
you’re studying and no studies also will require IMD’s as long as that you know
virus bacteria or fungi that you’re studying is not a lawfully marketed drug
product because it is being used to affect the structure function of the
body so it would also meet that definition of a drug
so dietary supplements are kind of their their own interesting category and they
fall somewhere between a drug and a food and so FDA kind of regulates them in
that way so dietary supplements they’re defined as products that are taken by
mouth that are intended to supplement the diet and contain a dietary
ingredient some examples include vitamins minerals herbs and botanicals
amino acids metabolites or also extracts or any combinations of these things it
also includes things like probiotics as well so anything again taken by mouth
intended to supplement the diet and containing a dietary ingredient dietary
supplements are interesting and that the need for an IND is determined by the
intent of your study so if you’re conducting a structure-function study
then no IND is required so for example if you’re studying the effects of
calcium on bone mass or if you’re studying the effect of fiber on bowel
regularity those are both seen as structure function studies and an IND
would not be required however if you are now doing a study that is therapeutic
study so intended to treat diagnosed cure mitigate disease that study would
now require an IND so if we tweak the objectives of that
study a little bit so that now we’re studying the effect of calcium on
osteoporosis prevention or we’re studying the effect of fiber to treat
diarrhea those are now going to be regulated as drugs and they would
require an IND so even though the dietary supplement may be legally
marketed as a dietary supplement because it’s not legally marketed as a drug it
cannot be exempt so that’s why it would need an IND all right and then we’re going to talk
about tobacco products here as well so what is this tobacco product it’s any
product that’s made or derived from tobacco that is intended for human
consumption including an a component part or accessory of a tobacco product
so this includes more recently under FDA’s purview is electronic nicotine
delivery systems or a cigarette so you might be wondering canna tobacco
products study require an IND and they can so if that tobacco product is being
used as as a drug it will be regulated as a drug under two circumstances so the
first is that the tobacco product is intended for use in the diagnosis of
disease or other conditions or in the cure mitigation treatment or prevention
of disease and so some examples of this would be
using a tobacco product to in the cure treatment of nicotine addiction for
example smoking cessation or relapse prevention or release release of
nicotine withdrawal symptoms so in those cases the tobacco product is being used
as a drug and so it would potentially need an IND
most likely so the second circumstance is that the tobacco product is intended
to affect the structure or any function of the body in any way that is different
from effects related to nicotine that were commonly and legally claimed in the
marketing of cigarettes and smokeless tobacco products prior to March 21st
2000 so this might seem like kind of a
confusing circumstance but essentially there was some court case that was
decided March 21st of two thousand that we’re not going to get into but some
some examples of structure function claims that are commonly and legally
claimed from March 21st 2000 include things like satisfaction including of
addiction pleasure enjoyment and refreshment if you’re doing a study to
see whether or not to tobacco products comparing to tobacco products and how
you know pleasurable they are then that would not be regulated as a as a drug
the product there would not be regulated as a drug so essentially if the tobacco
product is being used as a drug then it would be subject to the drug regulations
including the IND regulations in 21 CFR 312 so for tobacco product studies that
did not require an IND you may submit an investigational tobacco product
application or an IPP and these applications are reviewed by FDA Center
for tobacco products ICPs are currently voluntary but we do
encourage study teams to submit them they will likely become mandatory at
some point so if you are doing a study using an investigational tobacco product
we would encourage you to come talk to our office about whether or not you
might want to submit an IPP we do have a handful of IT peas held by
sponsor investigators here at Duke so again we would encourage you to come
come talk to us an example of a study that might be conducted under an ITP
would be if you’re assessing smoker preference for cigarettes of varying
nicotine levels so if you want to see whether or not smokers would use
cigarettes that have lower nicotine levels and prefer them just as much as a
cigarette with higher nicotine levels that might be a study that you would
want to run under an ITT so any questions about that well okay we’ll
move on to research with non-commercial intent so the inv regulations apply to
investigations regardless of if the intent of the study is commercial or
non-commercial so some investigators may think that because they are because
they’re not conducting a they’re not planning some market this drug they’re
just doing research that they might not need an IND but that’s not the case the
IND exemptions they they apply to studies of commercial and non-commercial
intent Kristin we have a question from about webbing it okay so someone saying
why would an IND not be required in the examples given regarding bone mass and
bowel function and how they are affected by dietary supplements wouldn’t these
studies fall under the drug definition and that they affect the structure and
or function of the body yes so that’s so that’s a good question so they are
affecting the structure and or function of the body but as we said dietary
supplements are kind of this special category so because they are I guess
kind of similar to a food and that they’re supplementing the diet FDA
allows structure function studies to be conducted without needing an IND
so it’s kind of a a bit of a gray line I guess in terms of you know studying the
effect of calcium on bone mass as compared to osteoporosis prevention but
they’re just basically because of the way dietary supplements are regulated if
you’re studying them for just purely looking at structure
function you would not require an IND so hope that answers your question any
other questions before we move on to a few case scenarios we’ll test out the
knowledge that we’ve learned so far in determining whether or not a and B is
required for these studies so we have four case scenarios that we’re going to
walk through so in this first scenario we have an investigator who plans to
study an anti flu drug to treat flu symptoms and children this drug called
in saloon this is the drug that the investigator is planning to use and then
who it is currently approved in the u.s. in the pediatric setting and it’s given
as an intramuscular injection so in this proposed study the in fluid ministered
via intranasal drops and the investigator is going to work with a
compounding pharmacy who will receive the influenza and create the nasal drops
for use in this study so I hope you all picked up on the key piece of
information in there regarding to whether or not this study can be
considered for an IND exemption or in other words what we’re really asking
here is is this study using a lawfully marketed drug product so who says yes
any hands yes is any nose okay the answer is
actually yes so I’ll go back head test your memory a little bit there as well
but this drug is currently approved in the US so because it is currently
approved we would say that this study can be considered for IND exemption so
that’s that first hurdle that has to be crossed before you can even you know
consider if your study can be IND exempt it’s not necessarily going to be IND
exempt but we can start thinking about those exemption criteria at this at this
stage so we would next consider what is off-label in this case so in this case
we had a change in the route of administration so it was going from and
intramuscular injection 2 being delivered through a intranasal drops so
we have that change potentially there could be changes to the formulation or
the dosage as well so the investigator would want to assess the risks
associated with these changes from from how it was approved to be used and they
would then if they think that those changes you know are low-risk they would
want to submit some documentation to the IRB or FDA to support their their
assessment so what kind of documentation would they want to provide we would say
you know if there is any previously published data available if anybody else
has used this drug is in an intranasal drop form that would certainly be very
helpful to provide also manufacturing information on how the compounding
pharmacy is going to be changing it from an oral injection to to a intranasal
spray because there may be concerns about contamination or consistency of
the drug amounts you would want to explain what controls are in place to
make sure that that those concerns are adequately addressed so moving on to
case scenario number two here we have an investigator that plans to conduct a
trial to assess the effectiveness of folic acid for the treatment of
depression and so folic acid is actually in this case manufactured by two
different companies the first is company X and this company
legally is marketing folic acid legally as a drug to treat osteoporosis the
second company company Y is legally marketing folic acid as a dietary
supplement so this investigator is planning to use folic acid capsules from
company Y for this study so the question is can this study be considered for an
IND exemption and planning to you who says yes who says no all right looks
like we had most people saying no that that’s correct
so because the study is using a source of folic acid that is not legally
marketed as a drug he’s planning to use the dietary supplements version of folic
acid then and also so as we said in the case of dietary supplements the need for
an IND is determined by intent so if he was planning to do only a structure
function study he wouldn’t need an IND but because he’s trying to treat
osteoporosis and he would require an IND so if this investigator were to use the
folic acid from company X that was marketed as a drug then he may not need
an ID or we would say that it could be considered for exemption and they would
want to just then assess assess the risk associated with the off-label use so
good job scenario number three we have an
investigator that plans to study the effectiveness of a combination of three
fda-approved drugs drugs a B and C in colon cancer patients so drug a and drug
B are currently approved to be given in combination for the treatment of pollen
cancer and drug C is FDA approved for breast cancer
now this investigator is planning the study based on previously published
study that he saw that was assessing the risks of this therapeutic cocktail of
drugs a B and C in breast cancer patients so can the study be considered
for an IND exemption because yes he says no okay so yes it can because all three
of these drug products are approved we would say that it can be considered for
exemption so that’s essentially just what we’re what we’re asking with this
first question can you even consider whether or not the study could be ing
exempt so what is off-label in this example we have so this new combination
right of drugs a and B which are approved to be given in combination but
now we’re adding in this third that while it’s approved to be given on
its own it’s not approved for this combination so that’s off-label and then
we also have drug see that’s not approved for this indication it was
approved for use in breast cancer but not in colon cancer so I think a lot of
you are we’re guessing that this study would probably not be exempt because I
mentioned to you before that if you’re testing new combinations of drugs then
it’s likely not going to be exempt unless there’s some data in the
literature which in this case the there was that previously published data that
the investigator had seen that was using this combination of drugs in the breast
cancer patients so you would want to support provide that to the IRB and/or
the FDA in support of your IND exemption and if they feel that that is supportive
then potentially you might not need an IND
and then also if you have any data on the use of drugs see in this indication
that would be provided as well okay so our last case scenario is we have an
investigator that’s planning to conduct a trial to study structural and
functional changes that occur in the eye after exposure to ragweed extract in the
ragweed extract that the investigator is planning to use is an fda-approved drug
and essentially approved for use in the skin prick test to diagnose allergies so
first question can the study be considered for an IND exemption yes yes
and he knows all right very good yes it can be considered for an IND exemption
because the ragweed extract is legally marketed as a drug and what is off-label
in this case well we have a change in the route of administration and again
potentially this could mean that there are changes to the formulation or
changes to the dose addition as well so as far as what kind of documentation you
would want to provide to the IRB and/or the FDA again if there is any previously
published data out they’re on the use of this reg weed
extract in the eye that would definitely want to be provided to the IRB or FDA to
support if you think this study should be exempt that the risks are low in
other words okay so that wraps up the part of our first talk here on IND
exemptions we’re next going to move on to pre-ind meetings do we have any
questions so on ID exemptions before we move on anything that we covered in the
first part of the top okay we will move right on then to pre-ind meetings kind
of switching gears now and talking about pre-ind meeting so these are an
opportunity to meet formally with the FDA to get their advice on your specific
study prior to submitting your IND and we found that these can be really
helpful opportunities for investigators to take advantage of in certain
situations so coming back to this flowchart that we’ve gone through on the
first part of the talk and so far we’ve mostly been focused on you know the
right side of this flow chart here in determining whether or not you will need
an IV for your clinical study but if you’re conducting a study that falls
more on the left side of the flow chart so using a product that’s not legally
marketed in the US as a drug in those instances you’re more likely to want to
consider having a pre-ind meeting especially if you yourself are
controlling the manufacturing or having you know CMO do that manufacturing for
you so there are them so you may want to
have a pre-ind meeting if you are using a product that’s not legally marketed in
the US as a drug but there are instances when you may want to have a pre-ind
meeting even if you are using a lawfully marketed drug if you for example are
using a product in a study that you’re was approved for one population and now
you’re wanting to move it into a more vulnerable population where you may have
some clinical questions associated with the use of that product in the study you
can go to FDA via the pre-ind meeting process and request their feedback on
any questions that you might have so pre-ind meetings are a method to
receive feedback from FDA on your manufacturing plan preclinical studies
or your clinical study whichever is applicable to you you can seek their
their feedback on in any of these areas these meetings can be really helpful to
prevent issues during the review of your initial IND so this is a chance for you
to meet with FDA and get a sense for what they would be expecting to see in
your IND application before you actually submit it so that way you can you know
preemptively prepare everything that you know FDA is going to want to see when
you submit your inv then hopefully you won’t have any issues or problems there
as I said these types of meetings we found our most helpful when using a non
fda-approved drug where you control the manufacturing just because there’s going
to be more variables there are more things that you control and you need to
get FDA input on but they can be useful in other situations before as we said it
is best to have these pre-ind meetings before making any major manufacturing or
pre clinical decisions and that’s just because you know if you go too far down
one path you’ve completed all your preclinical studies and then you go to
FDA as your pre-ind meeting and ask like do you agree with these preclinical
studies they may they may not agree and they may tell you that you need to do
different studies so definitely goes to try to have your pre-ind meeting as
early as you can and but also keep in mind that you do only get one pre-ind
meeting per application so you want to try to time it right so you can get the
most information as you can from FDA so both in terms of manufacturing
preclinical and clinical questions so that’s important to keep in mind so here
is just an overview of that pre-ind meeting request process so it starts out
by the investigators submitting their meeting requests to the appropriate FDA
review division FDA will then determine whether or not they will grant the
meeting if they if they deny it they’ll provide you with the reason why
sometimes SBA feels that the questions that you’ve provided can be adequately
addressed in just written response so you may just receive written
responses and not an actual meeting if FDA determines that to be adequate but
if they do grant the meeting they’ll next provide you with the date and time
the location of the meeting if it’s going to be an in-person meeting the
lists of the FDA participants as well that will be all provided to the sponsor
and the next step the sponsor is going to submit a pre-meeting briefing package
to FDA this needs to be submitted at least one month before the meeting and
this is going to contain your final list of questions for the FDA and also all of
the the background information that FDA is going to require in order to address
your questions and answer those questions and then shortly before the
meeting is held usually just one or two days before the FDA will send
preliminary written responses to the questions that the sponsor provided and
then after that the meeting will be held and the minutes will be distributed
after the meeting so the meeting is typically held within 60 days from when
FDA receives your request so the whole process takes roughly 60 days from when
the request is submitted till when the meeting is held so what to
do before making a meeting request if you think you would like to request a
pre-ind meeting the first thing you want to do is identify specific well phrased
questions these are really going to be the key to having a successful meeting
coming up with these good questions so you don’t want to ask FDA just
open-ended questions such as you know what types of preclinical studies should
I do which is my clinical study design look like what you would do is propose
to FDA what you ideally would like to do your best case scenario and then
FDA would tell you whether or not they agree and expand on that as well as if
they disagree so the next thing you would do you you have the opportunity to
either have a face-to-face meeting or a teleconference or just request written
responses from FDA so you would decide what method of feedback you would like
to have and then you also want to start
preparing that meeting briefing package so as we said that will be submitted at
least one month before the meeting and because the meeting request is submitted
typically about 60 days ahead of when the actual meeting is held that only
gives you about 30 days in between submitting the meeting requests and
submitting the briefing package so we typically say you want to have that
meeting briefing package pretty well complete even by the time you submit
that meeting request and then lastly you want to identify the appropriate FDA
review division and we talked earlier in the talk about how you would go about
doing that okay so for the meeting request letter you’re going to include
product information in the proposed indication for your study the specific
objectives for the meeting and I’ll see your expected outcomes of the meeting
you would include a proposed agenda which can be very brief just something
like introductions discussion of questions and then wrap up our
conclusions at the end importantly this meeting request will contain your draft
list of questions for FDA this doesn’t need to be your absolute final list but
it should be fairly close because these draft questions are going to influence
who from the FDA will be attending your meeting you’re going to provide them
with the attendees from your side that will be attending the meeting and then
if you have any SBA staff that you would like to attend the meeting you can
request you can request to their presence at the meeting in that meeting
request letter you would tell them an approximate date for when you’re
planning to submit the briefing package and then also suggested meeting dates
and times to assist FDA with actually scheduling that that meeting if you are
interested in having a pre-ind meeting definitely reach out to our office we
can assist you with this whole process and we can also attend the meetings with
you if you would like and we do have templates available on our website for
this meeting request and also the briefing package as well so you can
check those out so the briefing package is going to contain you know some of the
same information as what was in the request but now you’re going to provide
FDA with a final list of questions that you want
to answer for you you’re also going to provide all of the relevant information
for those questions and the discussion topics to allow them to be able to
answer your questions so that could be manufacturing information preclinical
information or your clinical protocol so whatever you’re asking questions about
you want to be sure to give FDA all the information that they’re going to need
in order to be able to answer that question for you
so as we said FDA will provide you with preliminary written responses after they
have had an internal meeting at FDA amongst the reviewers they will come up
with answers to your to your questions and they will submit those to you
typically just one or two days in advance of the meeting so then the
sponsor needs to review those responses very carefully and identify whether or
not they have any questions or any issues with those responses that they
want to discuss at the meeting so the sponsor then at that point makes a
decision as to whether or not they want to proceed with the meeting or if all of
FDA’s responses have adequately addressed their questions then they
would cancel the meeting if if those responses are acceptable as
we said so then on the actual day of the meeting what is this meeting going to
look like whether it’s in person or over the phone it will start out by having
just brief introductions everybody will go around the room or introduce
themselves on the phone and then the sponsor can give a short introduction we
would say keep it very short two minutes at the most you don’t want to give along
like 30 minute PowerPoint presentation to the FDA reviewers telling them about
how wonderful your product is and how it’s going to cure cancer
they have already read your briefing package they know I’ll just background
on your product so you don’t need to give them a lengthy introduction and you
want to spend most of your time on the questions and answers with FDA keep in
mind that the meetings are typically only 60 minutes long so it’s not a lot
of time so you want to optimize this time as much as you can to get
as much out of out of the meeting as possible and remember that it is your
meeting so you’re going to be expected to be driving this meeting
SVA is there to help you and answer your questions so just bring up the questions
that you still have you want to prioritize your questions you don’t need
to run through all of the questions that you submitted in your briefing package
because remember they have already given you preliminary written responses so for
any of those questions that they’ve adequately addressed there’s no need to
bring them up during the meeting just focus on those areas that you still have
questions on and don’t hide concerns you want to be open with them so that you
can have a productive dialogue about how to you know move your product forward or
move your study forward also don’t present data that was not included in
the briefing package make sure that you get all of the relevant information in
the briefing package to submit to FDA ahead of time because they’re not going
to be able to you know analyze that data during the meeting and come to a
decision that also makes sure that you prevent presents everything in that
briefing package during the meeting everybody should be taking notes for
debriefing afterwards and ideally you would have you know one or two people
specifically designated for taking notes who don’t need to participate in the
meeting to make sure that everything gets captured and then at the end of the
meeting you would summarize any major decisions that were made and the action
items moving forward so after the meeting you would be briefed thoroughly
with your team document any of those decisions or action items that were made
and then also draft minutes as soon as you can you’re not required to submit
your minutes to FDA for pre-ind meetings but we often typically would offer them
to the FDA project manager in case they may want to see them to draft their
minutes usually they’re appreciative of that so FDA is actually responsible for
providing the official minutes and they will do that within 30 days from when
the meeting was held so you’ll get those official minutes back from FDA we’re
next going to look at just a couple quick questions on pre-ind meetings but
do we any questions up to this point yes come
to the microphone hmm thank you it seems like the pre-ind debriefing package is
just like submitting an IND how does it differ
well it could be very similar actually that’s a good point a lot of the
information that you would be submitting in there would be very similar to what
you would submit in an IND so the difference now is now you’re you’re not
submitting that IND applications FBA you’re just submitting the information
to them to ask like if they agree or not and you’re going to get more more
feedback as well so as we said it’s good to do early on in the process say if you
if you know you’re going to need to do preclinical studies for your IND this is
a chance for you to run the design and your plans for those preclinical studies
by FDA before you go ahead and you know spend a lot of time and money on those
studies only to find out when you actually submit your IND that they tell
you you you shouldn’t have done that so it is a very similar package okay any
other questions okay so just a couple quick questions here now about pre and
E’s so in which of these situations can you request a pre-ind meeting with FDA
so answer a is you want to know if your proposed manufacturing plan and release
specifications for your products are acceptable to FDA you want to know if
your proposed non clinical studies will be adequate to support your plans
clinical study or you want to know if the dosing schedule in your proposed
clinical protocol is acceptable to FDA or V all of the above the good job yes
you can ask FDA about any of you situations in a pre-ind meeting so
manufacturing questions preclinical questions questions on your clinical
protocol these can all be addressed in in a pre-ind meeting very good
okay now our second question is when is the best time to request a pre-ind
meeting so a after you have conducted your preclinical safety studies B before
you have made any major manufacturing or pre clinical decisions C before you have
made any manufacturing or preclinical decisions and you have a clinical
protocol or protocol synopsis then D one month before your grant application is
due what do you guys think good I heard a lot of C’s out there that’s great
so yes you want to request a pre-ind meeting as we said before you’ve made
any major manufacturing or pre clinical decisions but you also want to have at
least a protocol synopsis that you can for your clinical protocol that you can
submit in your briefing package as well because fda is going to be evaluating
whether or not your preclinical studies are adequate to support that clinical
investigation so it’s important for them to know what you’re planning to do in
your clinical study and then also if you want to write your grant application to
say that you have had a pre-ind meeting with the fda you’re going to need to
request that more than one month in advance of when your application is due
because the process takes at least 60 days so not Z so any questions on
pre-ind meetings or anything from part one if not we’re going to give you a
quick break and we will meet back here let’s see a little after 2:20 do we want
to say 2:30 that’s in good okay so we’ll try to start back up on part 2 at 2:30 hey everybody I know some people are
still in line to the bathroom but we’re going to go through a couple of the
opening slides real quick so I’m Stephanie Pierce I’m regulatory affairs
scientist for the office of regulatory affairs and quality and I’m going to be
presenting the second part of the workshop today so now that you’ve gone
through with suit or a Kristin about whether or not your need an ID if you
found out you do yeah I’m going to help you go through the process on how you
would prepare that document and then also how you would maintain it so before
we get started just to go through again this is being recorded and this will be
available on our website once we’ve added closed captioning and
for a remote participant via WebEx please do not unmute yourself submit a
question at any time in the chat box to Kristin Foss parentheses host do not
send it to the presenter I may not see your question and for our participants
on site please use the doors in the back restrooms are down here on the left and
if you could ask questions at the microphone and if it’s not accessible
just raise your hand and we’ll have somebody come bring you a mic and if
you’re here to fulfill your sponsor investigator training requirements
please see Audrey or Susan at the sign-in table to make sure you receive
credit and even if you’re just thinking about holding an I&D someday go ahead
and sign up to receive that credit if you like and you should have received a
evaluation form when you signed in so please take a few minutes at the end of
the top to fill that in and when I start wrapping up my talk please don’t get up
and leave we have Jen Hamill here from docker and she’ll be presenting
information on a new system for submitting single patient IMD’s for Duke
investigators and it should only take about 10 minutes so first I’m going to
go through a couple of – definitions so a sponsor is an individual
company academic institution or other organization that takes responsibility
for and initiates a clinical trial or a clinical investigation and so a
regulatory sponsor in the context of an IND is different from a financial
sponsor so for example just because they’re companies providing the funding
for the study it doesn’t necessarily mean that they are the sponsor of the
IND so an investigator is an individual who conducts a clinical trial and under
whose immediate direction a drug is administered or dispensed and at many
academic institutions there is a sponsor investigator and this individual both
initiates and conducts investigation and under whose immediate direction a drug
is administered or dispensed so there’s two different types of ieds that we’re
going to talk about there’s the commercial IND and the ultimate goal is
to obtain marketing approval and then there’s the sponsor investigator I&D
or as it’s sometimes called the investigator initiated IND and this is
primarily what we see at academic institutions and this is research driven
and the goal is usually publication so we’re going to go through the IND format
and content so for best practice you should follow this format and content
which is based on FDA guidance and regulations this left of 12 sections
looks a bit cumbersome but we have some very helpful IND templates and
instructions on our website that you’re always welcome to utilize and so for
section one as your form FDA 1571 this is going to go in with every submission
that you have to your IND and this basically tells the FDA who you are
what kind of submission this is what kind of information is provided in your
submission and Cyril you’re going to include the serial number so your first
one is going to be 0 0 0 0 and then 0 0 1 so on and so forth
and also in box through teen of this form it does contain these 12 sections
and so this is the contents of your application so we didn’t just pull these
twelve sections out of nowhere and so section to Table of Contents I think
that’s pretty self-explanatory and then for section three your introductory
statement that introduces the FDA to your product and this information is
usually derived from your clinical protocol section three your general
investigational plan this lists the indication to be studied objectives of
your study the rationale and the general approach for how the study will be
conducted and your clinical protocol will provide more detailed information
on this approach so the next section is the investigators brochure or as we
abbreviate as ID so this isn’t required for a single state site study only for
multi-site studies it’s basically a summary of all the relevant information
needed for an investigator to conduct the study according to the IND and
includes lots of different info the chemical toxicology tox toxicological
pharmacogenetic aspects of an investigational drug and any information
on safety and efficacy prior clinical trials basically everything an
investigator is going to need to know to conduct the study and we do have
templates available on our website to fill out this brochure and so the next
couple section is going to go into much more detail throughout the workshop but
I will say that section 11 the biosimilar user fee cover sheet I’m
not going to go over because it’s really applicable to academic institutions this
sheet would you would fill out if you were developing a generic form of a
biologic so this is usually not something that you would do here in an
academic institution does anybody have any questions before we move on okay so why should you follow the script
and fill in all these headings that we had just went through well the FDA
receives a lot of submissions that must be reviewed within a short window so if
your IND application does not contain sufficient information needed to assess
the risk to the subject or it’s difficult to find that information the
FDA will not allow your study to proceed and it can hold up your investigation
you can see from this chart from cedar and I would assume similar numbers would
be obtained from Sieber but the commercial IMD’s that were received by
them are in blue and the number of research I and DS are in red and the
total number is in green good they are actually that color so this is how many
they receive each year and so you can tell since 2012 that that number has
been increasing so it’s becoming even more important that your IND is
formatted in a way that’s easy for the FDA to review it as quickly and
accurately as possible so that your study doesn’t get held up so is there a
drug label or a letter of authorization to support your IND so if you’re using
an fda-approved drug off-label you can reference that drug label in support of
your IND and the two different links that Kristin talked about earlier you
can look at the FDA it drugs at FDA com I don’t think it’s FDA comm but it was
written out and Susan’s slide for the drug label and also you can look at
dailymed which is through the NIH or if you’re using an unapproved drug from a
company you can reference a letter of authorization and support of your IND
and we’ll go into what a letter of authorization is or if you’re using an
unapproved drug that you’re manufacturing the sponsors is
responsible for providing all the information for those 12 sections so
what is a letter of authorization this is a letter from a sponsor or company
stating that confidential information from their submission which can be a
nine and IDE which is an investigational
device exemption which Sara and Kelly are going to talk about in much greater
detail tomorrow at the workshop or can be a DMF which stands for a drug master
file and these can be used in support of your submission how many people know
what a DMF is so quite a few people but just in case you don’t know a drug
master file is something a company submits the FDA that contains
confidential detailed information for any number of things it can be a drug
substance it could be a packaging material a flavoring or even a
manufacturing process and the company may give you a letter of authorization
to reference that confidential information your I and D so as an
example we had a study team that wanted to use a special raspberry extract in a
cough syrup that they were doing an investigation with and so since this
companies that developed the extract wouldn’t want to provide proprietary
information to everybody using this extract they created a drug master file
for that information and then sent a letter of authorization for any study
teams that wanted to use that for their investigation
thus the FDA has permission to reference the name materials in support of your
IND and you want to make sure and get a copy of that letter to include in your
submission so next if you’re doing a study that can be supported by a drug
label or a letter of authorization you can reference those documents to cover a
number of sections so sometimes this can cover section 5 section 7 section 8 and
section 9 so that you don’t need to fill in as much information for those four
sections so we’re going to go through a couple questions to see if you
understand when a letter of authorization is needed so for you some
investigational not lawfully marketed drug from an outside source would you
need a letter of authorization for this study raise your hand if yes how many
think No probably unless the company doesn’t have
an IND perhaps if you were studying a dietary supplement otherwise yes so what
if you were using a lawfully marketed product would you need a letter of
authorization yes or no yes no probably not unless the drug company has
additional information maybe there’d have an ING for a different indication
which would include previous human experience or something that you would
like to reference possibly to provide you a letter of authorization to
reference that IND or if you’re using an investigational lot that you would need
a letter of authorization for so if there’s a case scenario drug TCG’s
approved for use in rheumatoid arthritis an investigator at UNC would like to
conduct a trial with type 1 diabetes the drug manufacturer be providing the
product from their commercial supply and the FDA is required an IND
will a letter of authorization required required how many say yes and how many
say no probably not since this is from their commercial
supply you should be able to refer to the approved label so now we’re going to
change it up a little bit so using the same drug at Duke University studying
the same indication and the drug manufacturer will be providing this
product from their investigational lot and again an IND is required in this
instance for a letter of authorization be required
how many yes how many no so in this case yes since you are using an
investigational supply you will need a letter of authorization so is there any
questions before we move on so next we’re going to move on to Section six
this is the protocol section so the protocol section contains a couple
different components it can contain multiple protocols as long as the same
drug and same indication your informed consent documents as well as your
investigator and facilities data so the slide basically says the same thing but
a little bit more detail so one thing that would be different from what I
described before and the slide as so as part of your investigator information
you need to provide the Seavey’s and your form FDA 1572 in this section and
that form is an agreement between the investigator and the sponsor and I want
to point out that even if you are the investigator and the sponsor you still
need to have an agreement with yourself so please don’t skip this form so next
we’re going to move on to going over the chemistry manufacturing and control data
in section 7 and then pharmacology and toxicology data section if you’re using
a lawfully marketed product these section can usually covered by referring
to the drug label drug label or if the drug is provided by a company you can
reference a letter of authorization to cover these two sections if you’re
manufacturing the drug yourself then you need to provide all the information for
these sections we have an expanded IND template on our website that provides
more detail for these sections so I recommend that you look at that template
to help fill out your IND and also you can always contact your regulatory
person to help you with that so the CMC section is divided into drug substance
which is your active pharmaceutical ingredients in raw materials and a drug
product which is the final product that gets administered to the patient in this
section you’ll need to list all manufacturers and raw materials that go
into the drug and describe all the steps used to manufacture the drug you also
need to include information how the drug is tested throughout the process and
also at release and you’ll need to provide a certificate of analysis
describing your spa vacations and show that your drug has
met those specifications throughout the manufacturing process you’ll also need
to include stability testing of your drug product to demonstrate the shelf
life and often the FDA will accept a stability plan if that test is still in
process so if you’re going to if you’re anticipating the shelf life is going to
be a couple years they wouldn’t necessarily expect you to have that
testing complete yet but if you have a well-thought-out plan this may be
sufficient to allow your IND to proceed so you’ll also need to provide the
details of your container closure system to show that it’s adequate to keep your
drug safe and pure and also I need to provide an example of the labeling of
your drug product which needs to include a statement that basically says caution
this is for investigational use and I also wanted to point out if you’re
working with a cell therapy product this can present additional manufacturing
challenges and also make the CMC section more variable and complex as compared to
a small molecule but there’s an FDA guidance for CMC information for human
somatic cell therapy IDs that you can use to help prepare this section or you
can always reach out to us or your regulatory contact wherever you’re at
for assistance if you’re working with a atypical or complex drug so section 8 is
your pharmacology and toxicology section so adequate farm tox information
involving animals or in vitro studies to demonstrate is reasonably safe to
conduct the proposed clinical trial and a full panel of animal studies are
required for a marketing application but for an IND you will need to perform
enabling toxicity studies or GLP safety studies so for an IND submission you
perform enough preclinical studies to show that the use of your drug is safe
in humans and the studies need to be done using GLP or good laboratory
practice which are regulations that govern the
conduct of how these studies are done in order to support an application for
research or marketing applications so if the product has already been used in
humans before a farm talk studies may not be necessary cases where the drug is
Venu pretty frequently in humans people should come talk to us or your
regulatory context to help strategize a way to leverage existing clinical data
to help move your study forward so those two sections are pretty complicated does
anybody have any questions I could answer okay next we’re going to move on
to section 9 this is your previous human experience you may not there may not be
any previous human experience of your drug if it’s completely new the previous
human experience is kind of like a literature review of all the clinical
data that there is to support the safety in humans and this can include
information from published journals or even unpublished data but that data will
need to be available to the FDA you have to show them graphs and charts you can’t
just say I heard it from some guy at a conference if this is the first in man
study you can provide supporting evidence with drugs that are similar for
example a drug that has the same mode of action of yours and so if you’re looking
at the published literature it can be a drug that has the same indication or
maybe even a different indication or a different route of administration and
remember for this section if you’re using an approved drug that you can
refer to the label or a letter of authorization that’s applicable so next
we’re going to go through the different forms that you’ll need to include with
your IND there’s your 1571 that’s your cover sheet that’s an agreement between
the FDA and the sponsor and this will be included with all of your IND
submissions the 1572 that goes in sections 6 with
protocol this is an agreement between the investigator and sponsor so even if
su you still have to submit this document and the 30 674 which goes in
section 12 this is a certification of registration at clinical Dredd clinical
trials.gov and you want to make sure you have the
right version of these forms they do have an expiration date on them so if
you check the link down below it’ll have the most up-to-date form and so we’re
going to go over the most confusing parts of these sections the screen
turned off is everything okay okay okay so first we’re going to go over the key
components of form FDA 1571 and so this is just a screenshot of what that form
looks like but again this is a contractual agreement between the
sponsor and the FDA and you would include the name of the person
responsible for monitoring the conduct and the progress of the study the name
of the person responsible for the review and evaluation of the safety information
on the drug so a lot of times that can be the same person but as a sponsor you
don’t have to hold any kind of certain degree but the person that’s monitoring
the safety should have an MD so it’s possible that could be two different
people and also you as part of this form the sponsor agrees to conduct an
investigation in accordance with all applicable regulatory requirements and
it must be submitted with each of your submissions to your IND so next we’re
going to go over the key components of the form FDA 1572 so here’s a screenshot
of that form so this is a contractual agreement between investigator and the
sponsor need to include the name of the person responsible for conducting the
investigation and their convential you’ll need to list all the facilities
and labs or participating in the investigation you’ll list the IRB
responsible for reviewing and approving the study list
the additional sub investigators and this forum is the investor that this
forum says that the investigator agrees to conduct investigation in accordance
with all applicable regulatory requirements and this is this form you
don’t need to submit with every IND submission well every submission to your
IND but it should be kept up to date so if you have a new investigator or
there’s some sort of change in information then you’ll want to update
that and you must submit a 1572 for each site if your study is a multi-site study
and I also want to point out that there’s an instructional guidance
document from the FDA and also a QA document on the 1572 that can be very
useful if some part of this form is not clear so next we’re going to go over the
key components of the form FDA 36 74 and here’s a screenshot of that form so most
of this form is basic info but the box that trips the most teams up is box nine
letter A basically says that this requirement doesn’t apply out so 36 74
in case you don’t remember is the part that certifies that you’ve registered at
clinical trials.gov so letter A basically says that the requirement
doesn’t apply because this isn’t a clinical trial but it’s pretty likely if
you’re submitting an IND that you are doing a clinical trial so a is probably
not applicable letter B says the requirement doesn’t apply because this
clinical trial it’s not necessary so we’ll go over which clinical trials it
would be necessary to register and letter C so that the requirement does
apply to your clinical trial and so if you select C you’ll need to add the NCP
number of your trial in box 10 and if you haven’t registered yet this
shouldn’t hold up your submission we often select C and then write in
pending for box 10
and so you’re probably either B or C do you have a question yes I just had a
quick question about the expiration dates okay
so come March 1st 2019 do you have to resubmit a new new sets of documents to
the FDA or is it just if you need to update it to make sure at that time
you’re using the Carn form I think it’s just if you need to update is that
correct yeah and it’s also possible that when one of those documents expired or
those forms expired the FDA might not put out the new one
right away and so you’ll have to keep using that expired one until that’s
available but you want to make sure in check that you have the most up-to-date
one so which trials must be registered to meet that requirement on that form
436 74 so those trials that need to register our applicable clinical trial
for a CTS and in order to be an ACP you have to meet these four requirements so
if it’s an interventional study so if you’re using a drug biologic or device
of Phase two through four so phase one trials do not need to register if you’re
under US FDA jurisdiction so that’s going to be most trials that would be
submitting an IND and studies that are initiated after September 27th 2000 or 7
or still ongoing as of December 26 2007 so let’s starting to get a long ways
away so it’s probably going to be most trials so what are some of the other
reasons that you might register at CT gov besides trying to meet your FDA
requirement so another reason would be to protect your right to publish so the
International Committee of medical journal editors and also a lot of other
medical journals have followed suit as it being a requirement that you register
your trial at CQ gov if you want to publish in their journals so you want to
make sure and check on that or if your clinical trial is funded in whole or in
part by NIH so in order to ensure compliance
with the NIH policy of dissemination of NIH funded clinical trial information
Mehta make sure that you register your clinical trial and so there’s probably
some other reasons you might want to register at CQ gov CT gov so make sure
and check your institutional policies as well so this is a table of the deadlines
for registering your trial and so before I go over this table I want to point out
that these answers are accurate per the regulations for these requirements but
your institutional policy could be different and in the case of Duke there
are definitely some differences and I’ll try to point those out I very strongly
recommend that you find out what your institutional policies are for
registering to trial so if you’re registering to meet the requirement for
an ACP or for NIH funding the deadlines are the same so the registration
timeline is no later than 21 days after enrolling the first patient but Purdue
policy the registration timeline is prior to institutional approval and you
have to update that every 12 months and that’s at least every 12 months there
are certain fields that you need to update within 30 days of a change so
make sure that you do that and it is required to report your results and
those need to be submitted within 12 months of the primary completion date of
your study and so in order to publish you need to register prior to enrollment
that needs to be updated at least every six months and you’re not required to
report your results but you’re very strongly encouraged and if you’re here
at Duke a doctor can help your study tu navigate to hkey gov the registration
and reporting requirements so I have that email down below if you ever need
any help and you can also reach out to us as well so I’m just going to go over
the different parts that we already talked about so the forms that I just
spoke about your form 1571 goes in with every submission and that’s in Section
one your form 15 seven two goes in section six with your
protocol and your form 36 74 goes at the very end and section 3 and section 4 you
can mainly take from your clinical protocol remember section 6 is not only
your clinical protocol but also your informed consent documents as well as
your investigator and facility’s data and your form 15 some of you q and if
you have a letter of authorization or you’re using an approved product you can
refer to the product label for section seven eight nine and probably ten so
does anybody have any questions because we’re going to move on to the next part so next we’re going to go through how to
follow your ing and then the FDA review process so with each of your submissions
you’re also going to include a cover letter and so we’ll go through that a
little bit more detail on the next slide and when you send this the FDA you want
to include an original with wet signatures and two additional copies if
you send less than three copies this could result in delays of your in the
review of your IND and your original copy should be put in a great echo like
report cover and the other two copies just need to be in a different color
report cover we like to use blue and red at our office but it doesn’t have to be
those colors and your IND should be paginate adduce throughout that doesn’t
mean it needs to be numbered sequentially one through 100 but the FDA
needs to know when you refer to page three of your clinical protocol what
page you’re talking about so next we’re going to go over the cover letter since
you do have to submit this with all of your FDA submissions we find it to be
best practice to include the actual dates that you submitted some sciences
take a little planning if you have to find your investigator to sign it you
want to address it correctly to either cedar or Sieber and you also want to
choose the appropriate division you want to make sure that you
send all of your submissions to the central document room they’re not going
to be very happy if you try to send it to someone’s office for initial IND
submissions you’re going to want to address those to the division director
and then for your subsequent submissions you can address those to your point of
contact once the FDA has assigned you one next
you want to include in the subject line the type of submission you’re sending
and the serial number so for this one it’s your initial investigation Allu
drug application and some it’s your first submission it’s serial zero zero
zero zero so then for your next one it’s be zero zero one so on and so forth then
in the body of the letter summarize the content of your submission and include
what exactly you’re submitting how many copies who the sponsor is and the title
of your submission also the body of the cover letter is the appropriate place to
include any questions or requesting comments back from the FDA and it’s also
very important to include an alternate contact in the case that the sponsor
can’t be reached oops and once your inds compiles you’re
going to send that original with the wet signatures along with two copies to the
appropriate center and division and you want to make sure that you have the
correct address for that and so I think Sieber had recently moved a few years
ago so that address has been updated so make sure and check on that or contact
your regulatory person to make sure you have the right address so what happens
after you submit the sponsor should receive an acknowledgement letter from
the FDA this letter is very important because it contains information such as
a sign review division you did select one in your cover letter but it’s
possible that you get assigned to a different one so make sure and check
that this letter will also include your int number and also when I mentioned
that you can request a pre signed IND number before you submit
and sometimes this will be required if you’re getting an L of a or something
like that so if you just go to the FDA website you can request that pre assign
number so the acknowledgement letter will also contain your assigned division
contact and that’s the person that you’re going to address for future
submissions and who you can send your questions to and also your official FDA
date of receipt for your submission so once the FDA has your IND a
multidisciplinary review team is assigned to review your submission which
includes clinical reviewers chemists toxicologists clinical pharmacologist
project managers statisticians and microbiologist and during the review the
FDA’s primary objective is to help protect the rights and safety of
subjects so what happens after you submit an IND will go into effect 30
days after the FDA receives your IND so that that date that was in your letter
it says when they received it so that starts this 30-day clock so if the FDA
doesn’t notify the sponsors that the IND is subject to clinical hold then you can
begin your study or on earlier notification by the FDA that the
clinical investigation may begin so the FDA does not reach a routine Lea send a
letter stating that the ing is in effect so you want to make sure in check the
30th day after receipt is your effective date so you can legally begin your study
once you have IRB approval if that 30 days is passed but we strongly meka
recommend that you confirm with the FDA that no issues were identified so what
if there are issues identified in your IND so if there are concerns the FDA
review team will contact the sponsor and or the alternative contact with requests
for information commitments of writing will often preclude a clinical hold and
these would be submitted as an amendment to the I and D so for example
the FDA requested certain testing to be done of the drug product that could take
a long time it’s possible that committing to perform those tests and
writing may be sufficient for the FDA to not put your study on clinical hold
again this is why an alternate context stating the cover letter is so important
so that that person could quickly respond is sponsor happens to be
unavailable and also we’re going to talk about so if they do request information
you can send a quick email to the FDA division contact to meet that
requirement and then it’s possible after the review period that you can formally
submit that information to your I and D as an amendment and we’re going to talk
about amendments in a few slides so if there are if the concerns cannot
be resolved within that 30-day period the FDA will place your study and
clinical hold and clinical hold is put in place when subjects would be exposed
to unreasonable or significant risk of illness or injury and or if the IND
application does not contain sufficient information needed to assess the risk to
subjects so hopefully if you follow those twelve sections that we already
went through it would hopefully contain sufficient information for the review or
it’s possible that they couldn’t find that information if you didn’t follow
that format but hopefully if you did follow that format this wouldn’t happen so if a clinical hold would be imposed
by telephone or other means of rapid communication most of our investigators
have received a phone call and then I will receive an official letter that
will outline the basis for that clinical hold and they should get that within 30
days the sponsor is expected to address the clinical hold comments in writing
and submit a complete response to the I and D so there’s no timeline for how
long the sponsor has to submit that complete response it’s up to them but
once we’ve completed it and son at the FDA it starts a new 30-day review period
and the investigation may resume after you
he is notified the applicant that the I and D mu Percy they may not notify you
so keep an eye on that 30-day clock and contact your project manager and once
the hold is lifted you want to make sure and verify your I and D effective date
so that you know when to submit your annual report so here’s a little
flowchart to go over what we just talked about so the sponsor investigators
submits their IND to FDA it goes through a 30 day review period so is your study
safe to proceed if the answer is yes and you have IRB approval you can ship your
drug and you can start your trial but if during that review period it’s decided
that it’s not safe to proceed the sponsor may not start their trial the
FDA will notify them usually by telephone to tell them around clinical
hold and then within 30 days the sponsor investigator will receive a letter they
will outline the basis for their hold and then the sponsor investigator can
submit a complete response the FDA is concerned and then that will start a
whole new 30 day review period and the process will start all over again
hopefully at this point your answer is risk efficient and your study would be
allowed to proceed there are any questions about the review process I had a question about when the FDA has
concerns but doesn’t issue a clinical hold so if you submitted your protocol
to the FDA and the IRB at the same time and the protocol that’s approved by the
IRB doesn’t include the changes that you committed to make are you authorized to
start that study or can you not start the study until you’ve made those
changes in your approved protocol at the institution it depends on if those
affect the safety of the subject so if it does I would definitely submit that
the FDA first before you proceed I mean I would probably do that no matter what
that would definitely be best practice I agree I would just add that I think like
you said sometimes you get like anything this clinical hold needs to be addressed
before the study could start at the institution there may be other comments
like you said that you get where the essays like recommending that you make
certain changes and we would typically encourage teams to do that like up front
even before the study starts but legally they’re not necessarily required to do
that but we always try to help them make sure that like whatever especially if
they’re doing things in parallel but whatever got approved of the IRB gets
back to the FDA and then whatever the FDA like agreed to gets back to the IRB
so that before the study starts like everything is aligned and at the same
page and that we would encourage like that is kind of what we’re requiring
teams to do because or the regulations require teams to do that because you
have to have the protocol that’s approved at the FDA or at your IND also
approved by the IRB does that make sense yeah you want to make sure that your
protocol with the IRB and the FDA stays consistent and we’ll talk about protocol
amendments later on in the talk so next we’re going to talk about CTD and
electronic submissions of IND so the FDA has a electronic submission pathway and
it has to be submitted in ECT D format this is called the common technical
document the common format was developed by the International Conference on
harmonization to eliminate the need for reformatting of applications different
countries so now if you submit this to the FDA you can easily send it to Europe
or Japan and commercial inds must submit electronically by May 28 keen this is
not required of research I DS so this format isn’t something I would submit
just for fun it requires expensive software and
specific training to use you’ll also need a secure login to submit through
the FDA electronic gateway we have the capability to do this kind of submission
here at Duke but if you happen to leave once you’ve submitted electronically you
cannot go back to paper however if you do submit a paper submission you can
always switch to electronic later if you decide that your clinical study is
proceeding in a marketing direction and so the content and format of CJD
contains all the twelve sections that we talked about before they’re just in
different places and so for CPG format there’s five modules module one is going
to be administration administrative information so this is things that are
country specific and this will include things like your cover letter and your
form 1571 things like that module two is going to be a summary of module three
four and five module three is quality this is going to be your chemistry
manufacturing and control data module four is going to be safety information
it’s going to include your farm and tox data and module five is going to be
efficacy that’s going to contain all your clinical information and clinical
data and so does anybody have any questions about this it’s a more
complicated process so there’s hold classes on how to do
this format okay next we’re going to move on to a
and D maintenance so now that you’ve compiled your I and D you’ve made it
through a review period you do have to care for and feed your ing and so we’re
going to go through the different ways that you can maintain that IND so here’s
a screenshot of your form FDA 1571 which you’re going to include with all of your
submissions and in box 11 and includes all those different kinds of submissions
so these are the ones that we’re going to go through today protocol amendments
information amendments safety reports and annual reports and so first we’re
going to talk about protocol amendments there’s four different kinds there’s new
protocols a change in protocol new investigator and there’s also a
marketing protocol which isn’t applicable to most academic institution
so we’re actually not going to go through number four so for a protocol
amendment you can submit a new protocol so a study that is not covered by a
protocol already contain your IND as long as the same drug in indication you
can submit that as a protocol amendment or if you have a change in your protocol
so per 21 CFR 3 12.30 report changes that so the FDA is mostly concerned
during phase one about changes that sniffily significantly affect the safety
of the subjects and then during phase two or three they’re concerned not only
about safety but as well as the scope of the investigation and the scientific
quality of the study and we find it best practice to submit all changes the FDA
you want to make sure that your IRB protocol states can submit consistent
with your FDA protocol and so unless it’s some sort of change that’s
extremely minor like maybe fixing the typo we recommend you submit all of
those changes as a protocol amendment and so in order to submit a protocol
amendment you’ll include your cover letter and your 1571 and if it’s a new
protocol you want to include a brief description of that new protocol if it’s
a change in protocol you’ll include a brief summary of the differences between
the new or revised protocol and that previous protocol we have a lot of
investigators that like to send a track changes version and then a clean version
of the protocol and with both new protocols and changes in protocols
there’s no 30-day review period for FDA submission but you must have IRB
approval before beginning and we strongly encourage that you check with
your FDA project managers that you can proceed especially if it’s going to
significantly impact the safety of your subjects you can submit the FDA an IRB
in any order but we do recommend that you send those IRB approval letters to
the FDA and I believe Sieber requires that I just wanted to mention that there
is an exception to a change in protocol if that change is intended to eliminate
an apparent immediate hazard to the subjects this
can be implemented immediately but you do need to provide notification to the
FDA and IRB as soon as possible and also included in protocol amendments is new
investigators so if you have a multicenter study the FDA must be
notified of the new principal investigator or a site opening within 30
days of the investigator being added and the sponsor sponsor must collect and
submit the 1572 and the CB cv of each investigator for each site to
the FDA and the sponsor must collect IRB approval letters from each site prior to
shipping the drug and they should submit that to the FDA the letters not the drug
does anybody have any questions about protocol amendments okay next we’re going to move on to
information amendments there’s five different kinds and you’ll select the
review discipline to which that submission applies and there’s five
different kinds there’s a changes or updates in your chemistry and
manufacturing data of farm talks data clinical data statistics and clinical
pharmacology and those would be submitted as information amendment so
information amendments generally comprised of any new technical
information and you’ll want to include a statement identifying the nature and
purpose of this amendment and I want to note that this continuation of the
clinical study can be submitted as an information amendment under clinical and
you can submit this information as much as needed but if possible not more than
every 30 days so next we’re going to talk about IND
safety reports there’s two different kinds there’s your initial written
report and then there’s a follow-up to that written report if you get
additional information so the FDA wants to know about any serious unexpected
adverse events associated with use of the drug and these must be reported
quickly and we’ll talk about what the f day means by quickly further any
findings from animal studies that suggest the significant risk for human
subjects must also be reported quickly and so I want to point out so the
sponsor is responsible for keeping up to date with any information available
that’s related to their studies but even includes information in the literature
so in the case of results that are found in animals or in vitro studies if it
suggests a significant rest of their patients it must be reported the FDA in
a safety report if it’s not a significant risk of their patients but
it’s still relevant you want to submit those as an information amendment or
include it in your annual report the sponsor investigator must notify the FDA
and all participating investigators of any safety reports so what does the FDA
mean I serious so serious is any adverse drug
experience occurring at any dose that results in the following outcomes death
life-threatening adverse drug experience inpatient hospitalization or
prolongation of existing hospitalization a persistent or significant disability
or incapacity or a congenital anomaly or a birth defect so what is the FDA mean
by unexpected so this is any event in which the specificity or severity which
is not consistent with the current investigator brochure or package insert
or if you don’t have an IV or it’s not required or it’s not an approved drug
the specificity or severity which is not consistent with risk information
described in your I and D or elsewhere in your application and here’s a chart
of that timeline by what the FDA means by quickly if the event is unexpected
fatal or right life-threatening and in relation to your drug so after you want
to know within seven calendar days if it meets the other criteria for serious and
patient hospitalization persistent or significant disability or congenital
anomaly and it’s unexpected the FDA wants to know within 15 days if it’s a
new animal finding that suggests significant risk the FDA wants to know
within 15 calendar days and if you get additional relevant information after
the fact that needs to be submitted in the follow-up report no later than 15
calendar days after the sponsor receives that info so you want to make sure you
have the correct form when you submit a safety report you want to use form FDA
3,500 a this is a mandatory MedWatch form that’s for IND reporters make sure
you don’t confuse it with the voluntary MedWatch form has a very similar name
FDA 3500 this is for healthcare professionals consumers and patients so
when you’re submitting your safety report you want to include a cover
letter and your 15 somebody one and your form FDA 3,500 a or in
narrative format if it has to do with an animal study and if it’s in a foreign
event you can use the Council for international organizations of medical
sciences form and in the report you also want to identify all safety reports
previously filed PID for a similar adverse experience and analyze the
significance of that experience in light of previous similar reports so we’re
going to go through a couple of case studies but does anybody have any
questions about safety reports what is the sponsor investigator responsibility
when they’re relying on the inds from manufacturers of the drugs that they’re
using is it the same you know you a I will submit the things under sponsor
then yes they’re still responsible for okay safety of their subjects so we
submit our IND safety reports to the manufacturers we should also submit to
the FDA under our IND yes right we hold the IND
drug use drug that you hold the idea but it’s for a drug that another company
owns yes yeah so if there’s a safety report you’re still responsible for
submitting it to your IND as the sponsor of that IND okay and we can help you
with that well though the real-time ones though
are only the ones that meet the requirements that Stephanie just
outlined though the rest could go in your annual report so case scenario one
a study coordinator reported that a 38 year old female patient developed
vestibular toxicity manifested Mya stigmas nausea and vomiting as well as
myasthenia and memory loss following an overdose of an investigational product
called no pain while enrolled in a phase three study the overdose was estimated
at a hundred times the prescribed dose to be
saved in a 24 hour time frame the patient received supportive care and did
not require hospitalization the investigators did characterize the event
as life-threatening but evaluated the event as possibly related to the
overdose the patient recovered from the events and withdrew from the study so
according to the investigator brochure for no pain as the product is a new type
of calcium channel blocker which is considered by the sponsor to be a
revolutionary way to treat neurological pain the no pain investigator brochure
describes the reported events of vestibular toxicity myasthenia and
memory loss is being possibly related to the use of no pain at high doses the
sponsor is in the process of compiling information for an NDA submission phase
three type phase three trials are ongoing in one country in the EU and the
u.s. so what do you guys think because this case considered serious by the FDA
show of hands yes show of hands now so in this case it does not seem to meet
the criteria for serious so there was an a death the investigator decided it
wasn’t life-threatening the patient wasn’t hospitalized etc so would this be
considered expected or unexpected raise your hand have expected unexpected so
yes it’s expected those symptoms the patient had were described in the
investigator brochure so is this event study related raise your hand yes no
good yes it is study related the investigator determined that how and
when should you report this event to the FDA annual report so since it doesn’t
meet the require you for serious and it was expected this would be included in
your annual report so for scenario two a female patient was really tired and
adjusted 40 milligrams of sleep more to try and get more rest she was admitted
to the ICU with severe bradycardia and a prolonged QT interval the patient was
treated with atropine and the bradycardia resolved the QT interval
normalized two weeks later and the reporting physician assessed that the
event was life-threatening and possibly related to sleep more according to the
IV for sleep more it states that conduction abnormalities
have been reported including bradycardia and a prolonged QT interval which have
resolved quickly upon discontinuation of the product the case was not submitted
as an IND safety report however in your monthly review questions arose as to
whether this was a grade of severity than what was described in the IV so
what do you guys think does the FDA consider this serious raise your hand
yes raise your hand no good yes the patient was hospitalized so that is
considered to be serious by the FDA is this event expected or unexpected
expected unexpected okay in this case it was unexpected although that symptom was
described in the IV it also states that the QT interval should resolve quickly
and in this example the prolongation resolved two weeks later
therefore this event would be more severe than what was listed in the IV
yes um it doesn’t matter what dose they use
they still have to report any adverse drug experiences sorry what she might
have but if she had a symptom that was unexpected you’d still need to report
that so is this does the study event-related raise your hand yes raise
your hand no I think most people said yes so yes this is so related the
investigator had decided that it was so how and when would you report this event
to the FDA as soon as possible so in the case of this scenario they actually
didn’t submit it right away but typically you would want to submit this
the FDA within seven calendar days because it is serious unexpected and it
is related to the drug so any questions about safety reports okay next we’re
going to move on to annual reports and reports are due within 60 days the
anniversary of your ing effective date that’s why it’s really important to
confirm with your division contact whether or not yes go ahead
sure I want to bring you in microphone all right can you just clarify for me
why that one was qualified for seven-day reporting rather than 15 because I know
it was a serious adverse event and she was hospitalized and everything but I
thought it would fall into the 15 calendar days so it’s a serious event
that is life-threatening that needs to be reported within seven calendar days
and so the investigator had decided that it was life-threatening let me go back
to that yes so one small detail in there that
you have to try to remember but yeah so it was life-threatening and that needs
to be reported in seven days rather than 15 okay so in reports need to be
submitted within 16 calendar or 60 days of your anniversary effective date and
we do have templates available on our website so in your IND and report you
want to include individual study information such as enrollment and
results if you have any summary information such as your most frequent
and serious adverse events a summary of all your IND safety reports a summary of
subjects who dropped out during an adverse event any new information
regarding the drugs action non clinical studies or CMC changes that you didn’t
already submit as an information amendment any updates to your general
investigational plan any changes to your investigator brochure on any changes to
your protocol not any protocol modifications that you didn’t already
submit as a protocol amendment any foreign marketing development and any
outstanding business that you have with the FDA so there are any questions about
annual reports so we’re going to talk a little bit about multicenter studies
most of these points I’ve covered throughout the talk but we want to make
sure and summarize them all together so if your sponsor and you’re in charge of
a mall tour of multicenter study you must obtain the 1572 and CV of each
investigator from each site and you must submit those to the FDA within 30 days
of that sites first enrollment and they must also obtain the IRB approval
letters from each site and also submit those to the FDA and as a sponsor must
monitor your study at each of these sites whether it’s in person by mail or
electronically and as a sponsor you must send any ind safety reports to all
of your sites in addition to the FDA and each investigator must also submit those
safety reports to their IRB and they should request information early for
their annual reporting requirements investigators get very busy so your life
will be made a lot easier if you make sure and request that information early
and always remember as the sponsor you have ultimate responsibility of your
centers so next we’re going to talk a little bit about financial disclosure
forms so 21 CFR part 50 for applicants who submit a marketing application are
required to submit information concerning the compensation to and
financial interests and arrangements of any clinical investigator conducting
clinical studies covered by the regulation and so this applies only to
studies that are being used in support of a marketing application like a new
drug application or a budget biologic licensing application or any study in
which a single investigator makes the significant contribution to the
demonstration of safety and so if you only want to publish this doesn’t apply
to your study and only applies to covered clinical trials but if your
study might head in a marketing direction you want to make sure that you
keep track of any financial disclosure information and there is a link down
here at the bottom that has a guidance from the FDA about financial disclosure
if you’d like more information so in general phase one studies are not
applicable unless they are critical for demonstrating efficacy for a marketing
application and sponsor investigator studies are usually not applicable but
if you do want to keep track of financial information of form FDA 34:54
can be used to provide certification that none of the financial interests or
arrangements of your investigators that are described in 21 CFR 54.4 a 3x
or you can use form sua 34:55 which can be used to disclose the nature of any
financial interest or arrangements and the steps that have been taken to
minimize bias so in any case these are never submitted to your IND only for
your marketing application but you don’t want to wait until it’s too late you
want to make sure and start collecting those financial disclosure forms right
away if you start heading in a marketing direction are there any questions about
that so next we’re going to move on to the end of the night of an IND not the
end of the talk so don’t get up so if evidence a sponsor you can
withdraw your study and so you want to make sure that when you’ve completed
your study that you’re completely done because once you withdrawal you can’t
undo that and if you start going through your data and realize you want to enroll
a few more patients you have to submit a whole new I&D
and if you withdraw for any safety reason you must notify your IRB and
there’s an inactive status this can be initiated by the FDA or the sponsor the
FDA mint may inactivate your ing if no subjects are entered into a clinical
study in two years or if an investigation remains on clinical holds
for greater than a year so if you remember going through the the clinical
hold steps there wasn’t a timeline when you needed to submit a response to their
basis for clinical hold but if you don’t respond to them within a year as
possible they can inactivate your IND and a sponsor can also request to
inactivate their I and D and a benefit of this is that the sponsor is not
required to submit annual reports and an inactive IND can easily be reactivated
via a protocol amendment although an IND that’s been inactive for more than five
years could be terminated by the FDA and an ing could also be terminated this is
initiated by the FDA this is usually based on safety issues
deficiencies in Ind or the conduct of the investigation and sponsors usually
have a chance to respond to this any questions about the end of an IND next
we’re going to go through expanded access so expanded access IDs are a
mechanism that can be used to gain access to investigational drugs for
treatment use under investigational new drug application these are often called
treatment treatment use or compassionate use and ease they may also be used for
access to an approved drug when availability has been limited by a risk
evaluation and mitigation strategy and the primary goal of expanded access inds
is to treat rather than research so expanded access has three different
kinds there is individual patient which also includes emergencies so this is one
person and I want to point out that unlike other inds when you withdraw an
individual patient IND you need to provide a summary of that expanded
access use and so if you’re doing an intermediate sized patient population
that’s anywhere between two people to a few hundred and this would also you
would also choose this kind of expanded access ing if the drug is not being
developed for marketing and large patient population expanded access would
be if you have several hundred or more patients for a widespread use of the
drug through a treatment IND or a treatment protocol and the drug is also
being developed for marketing this kind of expanded access IND often bridges the
gap between when a clinical development of the drug has been completed but the
marketing is still in the development process and a treatment protocol can be
submitted as a protocol amendment to an already existing IND and treatment IND
is a new IND mission so a treatment IND is used when
there is no IND effect or when the sponsor of an existing IND declines to
be the sponsor of the expanded access use so expanded access regulations 21
CFR 312 points 305 requirements for all expanded use our patients must have a
serious or immediately life-threatening disease or condition and no comparable
or satisfactory alternative therapy immediate life-threatening means that
there’s no reasonable likelihood or there is a reasonable likelihood that
death will occur within a matter of months or that premature death is likely
without treatment serious disease or condition means a disease or condition
associated with morbidity that has substantial impact on day-to-day
functioning and the potential benefit has to justify potential risk and
potential risks must not be unreasonable in the context of the disease or
condition that you’re treating and access will not interfere with clinical
investigations to support marketing approval of the expanded access use so
here’s a new form the FDA point out last year in 2016 to help streamline the
process for individual patient expanded access use and Jen Hamels here today
from doctors it’s going to present for a few minutes at the end of the day about
a new system at Duke for submitting single patient inds
for investigators so don’t leave at the end of the talk so the individual
patient expanded access form 36 26 or 30 926 so for in 1571 was seen as an overly
complicated and poor fit for submissions submitting an individual expanded access
new I&D since the 1571 was designed for
commercial applications they decided to streamline and create form 39 26 to
simplify that form and reduce attachments and time burden
and this can also be used for emergency use and you will need a letter of
authorization in order to use an investigational product from another
company so here’s the screenshot of that form 3926 so if you’re not going to use
form 3926 for a single patient i and d you will need to submit a paper copy
that includes a cover letter and cover sheet patient history proposed treatment
plan CMC and farm tox information which will hopefully be covered by a letter of
authorization you need to include informed consent documents as well as
investigator qualifications and info such as 1572 and cv and all of that
information I just went through would be covered in a 39:26
and you can also submit an emergency individual patient IND and in order to
check if your treatment meets the criteria for emergency there’s a link
here and a checklist and eligibility tool if your if the FDA would consider
this to be an emergency so this is usually a patient that needs to be
treated within hours or very few days and if you’re submitting an intermediate
size population IND or a treatment IND you would follow those 12 sections that
we went through before so that’s the end of my section but don’t get up yet Jen
Hamel is going to be here to talk about a new system for submitting single
patient IMD’s but i’m happy to take any questions right now
and if you have additional questions in the future you can look at our website
and also contact us via email at over at dot o Rock at DM zdu and please remember
to fill out those evaluations is there any questions there’s a table outside
the door where you signed in if you’ll just place your evaluations there as you
lay that would be great thank you okay if we don’t have any questions Jen
are you ready should just build a quick so I’m going to talk with you about
submitting individual patients and emergency IMG’s on the hospital side I
work with the Department of Clinical Research and I’m the research practice
manager in the heart center so I am primarily on the research side but
doctors Chet Patel and Barbara Alexander came to us in December saying that they
were struggling with being becoming aware of a patient needing and a drug
emergently or at least quickly within one to two weeks
typically these come into play on a Friday night Saturday Sunday when they
have a really heavy load and it was a barrier to them to get this drug
available to the patient so we wanted to work with them to limit those various
barriers and then ultimately get the drug to the patients
so when we met with dr. Alexander and dr. Chet Patel with orh Q and docker we
really heard their difficulties in getting this through into the IRB and
the patient as quickly as they would like to so we have reached an agreement
between D UHS and the school of medicine so that we can submit them these
applications for them so or aq is specifically assisting with obtaining
the sponsor approval and performing the IND submission and then maintaining that
submission and then docker has organized a or is organizing a core group of
regulatory coordinators and clinical research coordinators who have worked
with these invs in the past to get these into the IRB for the faculty and we are
also working on creating a redcap database so that we are consistently and
in a streamlined and getting these these patients
registered and documenting the process so that everyone is alerted when they
need to be so that we can get that a keep track of that information and get
even better at the process so first we looked at what we’ve been doing in the
past and we discovered that on average we’re doing between twelve and eighteen
inds per year at Duke both emergency and non-emergency primarily the departments
that are submitting these are in infectious disease solid organ
transplant and oncology so like I said we met in December of 2016 and as we
discuss the process it was realized that we needed to include orh you daugher IRB
and investigational drug services and OCR C which is now o RC office of
research contract and then we are working with a redcap designer in in
docker who is helping us actually get all of this into a workflow and this is
what we have as of now and in fact it’s been updated a little bit since so the
way it starts is the faculty has decided discovered that they need to get an IND
to a patient quickly so what they’ll do is they will be routed to the o ra q
website and we’ll do this through some ways that we’ll talk about in just a
little bit but they’ll be directed to the o ra q website and there will be a
link on that website it’s not there yet because we’re not active but when that
when that is created when we’re ready to go live there will be a link there where
the faculty will be able to go in and submit some basic information that
includes their contact information and some basic information about the
patients and how that they want the patient to be treated and whether they
believe this is an emergency or a single IND or aq we’ll let me back up a little
bit so that will generate an email to O ra q
and to this core of research coordinators and regulatory coordinators
and like I said before where we’ve taken a pool of coordinators who have done
this work in the past and first we reached out to their managers and asked
them if this was reasonable for us acceptable for us to approach those
coordinators based on either their current workload or their ability to
perform work that is outside their current job description this would be
additional work if their manager agreed to that presumably spoke with that
coordinator that was decided that they could participate we followed up in an
email to that research coordinator and asked them to engage in some training
with us and have been clear with them about the expectations as far as
timelines and time spent doing these studies so those two teams are alerted
that the faculty has submitted an IND and the regulatory coordinator can then
at least open up the IRB applications and and we decided to do that as early
on as we did just so that it can be a common place to house the information
and if anyone has any questions they can go into the IRB and see see where we are
in the process or if you will look at that information that the faculty
submitted and do a determination on whether it truly meets criteria for
emergency or if it sits as single and then that will generate and an email
that’s up that top blue box up there that will generate an email to the
faculty that the IND has been picked up by or a queue and what the status is
whether it’s determined to be emergency or single so then coming back down off
of that green down to the yellow or aq will then work to get sponsor approval
and then once our aq does get sponsor approval that will generate an email to
all parties that I told you about earlier including the faculty the
faculty expressed that they want to be included in the community
Asian along the way and not much work will be done at this moment because we
still have to wait to see if the FDA will approve this inv so or aq will work
on filing that submission and then if it’s not approved and I guess it’s
actually not ever not approved I’m learning too it’s just put on hold and
which may be indefinite but I think that’s a fairly rare situation so
assuming that the FDA approval is yes or aq will enter that approval into the red
cap which will generate a notification to that core group of coordinators and
to in the investigational drug services who can then get the drug prepared once
they receive it and the regulatory or research coordinators will go into the
IRB and actually work on getting the complete application submitted and then from there information is entered into
the red cap that is really mostly HR related but this is just a good
communication stream for the team to get the process moving through the system as
far as the regulatory core of coordinators we had decided since it’s
coming from those three specialties typically what we’ve asked or what we’ll
train the coordinators to do is if it is their specialty for them to pick it
first and so that’ll be some internal
communication for the coordinators just so that that process is a little bit
easier so what we’re doing now is we’re we’ve largely built the red cap already
and we’re testing it and making sure everyone’s receiving their emails and
that everyone is in the loop that needs to be and we’re training the staff on
the workflow we have met with all of those parties that I talked with you
about already and once we know that all of everyone’s in that needs to be
included we’re going to have hopefully one or two training sessions that should
last between two and three hours we’ll provide the education on all parts
of it so where we are now is making sure that we get the word out so that the
faculty do know where to go and so that both on the research side and the non
research side we know how to direct the faculty and so that they know where to
go onto that Oh our HQ website that will include just making sure that like
investigational drug services and the IRB have the information to tell those
faculty where to go we’ll also advertise you should be in
hopefully the July ERU update update I am the leadership
bulletin and faculty flash will be information about this coming and again
this is not necessarily research this activity is going to happen on the
clinical side it will often include some research personnel so we’re hoping that
any research staff and here can help us get this message to the faculty on the
clinical side we’ll communicate this in all of our research meetings and the
faculty director meetings we’re going to meet with the IRB directors next week so
that they have the information as well and that’s it any questions on the
process okay thank you

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