So we have found, as an office, that
with the flux of the field and also the commonalities between cell therapy
products that in general broader guidances are generally -- we get good results
with them and we hit more of our target audience that way.
DR. TAYLOR: Thank you.
CHAIR URBA: Thank you very much. We'll move on to the next presentation about
the guidance development program with Dr. McFarland.
UPDATE-OCTGT GUIDANCE DEVELOPMENT PROGRAM
DR. McFARLAND: Thank you, Dr. Urba. I'm very happy to be here this morning to
give you and the Committee an update on the Office's guidance activities
because I think we really have a good story to tell on our activities over the
last two years, and how we've used the input from the Committee to work into our
guidance program.
First, though, I'm going to
spend a few minutes describing the
process by which FDA develops and publishes guidances, and then I'll go through
the guidances that we've published and/or finalized over the last two years and
highlighting a particular draft guidance that we published last summer.
This came up, was sort of alluded
to, in the questions after Dr. Benton's presentation. FDA develops guidances under what's called
good guidance practices. Good guidance
practices really ensure the proper development, formatting, processing, routing
and use of FDA guidance documents. It
was mandated by the Food and Drug Administration Modernization Act, known as
FDAMA, and has been codified in the Code of Federal Regulations, and with CBER
we have a SOP to follow, which is available.
One of the things inherent in good
guidance practices is the public notification of the agency-wide Annual
Guidance Agenda which actually gets published right now through, actually, a
biannual guidance agenda in the Federal Register and what I will be
concentrating on is when I get to the presentation on the guidances or the
guidances that we have published since the last issuance of the Guidance Agenda
in 2006.
Guidance documents are prepared by
FDA staff and they describe the Agency interpretation of a policy or a
regulatory issue or they relate to the processing, content and
evaluation/approval of submissions or to the design, production, manufacturing
of regulated products and we have some guidance documents that cover all of
those areas.
What aren't guidance documents,
which is important to know. They're not
internal FDA procedures, not reports, not general information provided to
healthcare professionals or consumers, not speeches. We don't make policy from the podium. They're not media interviews, not journal
articles, whether they be articles about our general regulatory process or
scientific articles that come out of our research laboratories. They're not warning letters, memoranda of
understanding, any other communications or documents related to specific public
health emergencies.
What they are is, they're intended
to represent our current thinking on matters discussed in the documents once
they are final guidances. CBER staff
departs from guidance documents only with appropriate justification and
supervisory concurrence, and when we get consistent deviations from guidance
documents where we have to deviate from them, that's really a strong signal
that we really should spend some time revising those documents.
Most FDA guidance documents are
called Level 1 documents. Level 1
guidance documents, typically we have a Federal Register notice announcing the
availability of the draft and a specific public comment period. They are placed on our website and on the
Agency's website.
After reviewing the public comments,
then we revise the guidance or we may revise the guidance and we issue a final
guidance. Only when we issue the final
guidance does it represent our current thinking. Although we have specific time frames in the
Register, we'll accept comments on documents, be they draft, final, be they
implementation guidance documents which are at any time.
Immediate implementation allows us
to issue guidance documents both in Level 1 and Level 2 guidance documents when
we think that due to a reason, due to a statute, due to a public health
emergency, that it's appropriate to issue them not in draft initially.
What are Level 2 guidance
documents? Well, everything that isn't
Level 1. But Level 2, really you could
think of as setting forth existing practices or minor changes or interpretation
or policy or minor updates to Level 1 guidance documents.
This was kind of alluded to during
the question from Dr. Benton's talk. How
do we communicate with the public during the guidance development? Well, when we're considering the development
of a guidance, we can discuss the issues with the public. Frequently, when we have topics that we bring
to the advisory committee, they are things that we are considering. They're issues that I think are worthy of
public input and anything of general principal, anything that we bring public
input, is something that at least potentially could become a guidance.
If the issues that are addressed are
particularly appropriate or controversial, we hold a public meeting and this is
mentioned in the advisory committee. We
frequently use this advisory committee for issues that are controversial. Yesterday is a good example.
Before drafting the guidance, once
the preparation of the draft guidance has really begun, the specifics of what's
in the guidance we can't discuss to the public in order to keep the process
fair and unbiased and so everyone has equal knowledge of what the Agency is
working on.
Once a guidance document is issued
in draft, then we can certainly discuss the issues related to that particular
draft guidance. One of the things that
we really don't talk about with any specificity once it's issued in draft is
what our plans are in terms of finalization, in terms of timetables, in terms
of which comments we've gotten and how we're evaluating those comments. And as I said, we accept comments on any
guidance at any time.
The next few slides, I'm going to
discuss the guidances that we have published or finalized in the last two
years, since, well, 18 months since the issuance of the most recent guidance
agenda on September 1, 2006.
The first guidance here that we've
published is the umbilical cord blood guidance
which we published in draft in 2007.
We've had advisory committee discussions long before the guidance was
drafted in 2003 on this general topic and then, of course, last March, we had
discussion of the cord blood guidance during the comment period after the draft
guidance had been issued.
Another guidance that we issued last
year is the guidance for the products for cartilage repair. I'm going to spend a little more time on that
at the end of the talk. So I won't belabor
it here, but to mention that it was the topic of an advisory committee in 2005.
This guidance is a validation of
rapid microbial methods, a guidance document to facilitate validation of rapid
microbial methods in our cell and gene therapy products for investigators. It was published in draft in February. And, although we haven't had a specific
meeting related to that topic, the issues of rapid microbial methods has come
up at various points during our discussions in the advisory committees over the
last five years or so.
Guidance that we published in
January, certain HCTPs recovered from donors who were tested for communicable
diseases using pooled specimens or diagnostic tests, this is a guidance that we
issued for immediate implementation which was final, to deal with specific
issue related to the implementation of the tissue-ables. It has relatively limited applicability, but
it is important for everyone who has products that might fall into this
category to get the same advice.
In addition to the guidances that we
published that are in the guidance agenda, these are the topics that we
anticipate working on guidances over a two year period. Other issues come up during these two years
and that we publish guidance on that may or may not make it into the guidance
agenda, and on the next couple slides I'm going to list those guidances.
This first one is also related to
implementation of the tissue rules and has a very helpful question-and-answer
format. It answers very common questions
on implementation of the tissue rules and it was an immediate implementation in
August of 2007
The next guidance, the eligibility
determination for HCTPs is also directly related to implementation and
exploitation of the tissue rules. It's
quite comprehensive and it was issued, finalized, I'm sorry, in August of 2007.
The third guidance on the list here
for cell selection devices for point of care of minimally manipulated,
autologous peripheral blood stem cells deals with an interpretation of a
provision in the tissue rules in terms of same surgical procedures. It was issued in draft in July of 2007.
The last one is a Class II special
controls guidance for cord blood processing, systems and storage. It was issued with immediate implementation
in January 2007 and I think it was also discussed briefly in March at the day
on the other cord blood guidance document.
This is related to a 510(k) submission and actually outlines the special
controls that manufacturers would need to meet in order to gain a marketing --
to market these particular devices.
Continuing with our additional guidances
we've published in the last 18 months or so and this guidance, I think, was
mentioned yesterday during the discussion as potentially a model for thinking
along topics with embryonic stem cells, is the gene therapy clinical trials:
observing subjects for delayed adverse events, known as a long-term followup
guidance and was finalized last November -- November 2006. Multiple advisory committee discussions
touched on these issues and I listed the four most prominent ones, although I'm
sure it has been mentioned, at least in passing, in various other advisory
committees.
The guidance underneath it, the
supplemental guidance for testing of replication competent retrovirus in
retroviral, vector-based gene therapy products and during follow-up was issued
as an immediate implementation 11/2006, which is a revision to the supplemental
guidance that was issued in 1999 and issued at the same time as a long-term
follow-up guidance, so that our published guidance on retroviral vectors and
general long-term follow-ups would be consistent. So, many of the same advisory committees
related to that and it's worthy to note that Carolyn Wilson was instrumental in
getting these two guidances through the process and issued at the same time, so
that we'd have consistent guidance to the industry.
And as Dr. Benton mentioned, the
recently finalized guidances this week, she mentioned the first one, The human
somatic cell therapy investigational -- the CMC guidance for cell
products. On the same day, we also finalized
the CMC guidance document for gene therapy products this week and really the
advisory committee discussions for both of those topics are really too numerous
to mention on the slide. But, suffice it
to say, because these two documents represent primary guidance for the
chemistry, manufacturing and control for the two large, overarching classes of
products that are regulated through the biologics license applications, these
topics have been discussed at numerous meetings in the last decade or so.
I'm going to spend a little bit of
time now concentrating on the cartilage guidance. It's important to look at the title
here. It's the Preparation of IDEs and
INDs for Products Intended to Repair and Replace Knee Cartilage.
Now what's significant in that is
that, as IDEs are for investigation of devices and INDs are for regulations of
biologics and drugs. So inherent in the
title is really the cross-center nature of this guidance. It was written by a cross-center team with
experts from Center for Devices and Center for Biologics, reflects closely the
advisory committee input on the meeting in March 2005, which CDRH was
completely involved in planning that guidance document. It also leverages an ASTM -- several ASTM
guidelines which points to the agency's leveraging of using of outside
resources to provide guidance in our standards development process which we did
in connection with CDRH. So we
participated according to the FDA policy for dealing with standards development
organizations, in the planning of the ASTM document and then were able to
leverage into an FDA document.
I'm going to go through a little bit
through the scope. As I said, it's for
both devices and biologics to repair or replace articular cartilage of the knee
and also for combination products, that is, products that have device and
biologic components. It excludes several
other areas and we wanted to focus primarily on articular cartilage and mainly
focal lesions and it excludes the 361 products which are human tissue products,
because you don't typically need IDEs and INDs for those.
There's a brief section on
manufacturing and CMC information. But
much of that information for manufacturing is either in other device guidances
or in our newly finalized CMC document.
The guidance document has two major
sections, one on non-clinical data and testing, and we go through explaining
what we see as the purposes of animal studies within the context of development
of products for cartilage repair; durability of response that we expect;
toxicology and dose response and mechanical testing; biocompatability, here
leveraging both an ISO standard and an ASTM document.
And a large part of the non-clinical
data and testing in terms of surveying the potential animal models that are
available, the cartilage defect locations in those models, descriptions of
their limitations and aspects, much of that was discussed in this ASTM
document, Standard Guide for the In Vivo Assessment of Implantable
Devices. You should read that as
implantable medical products intended to repair or generate articular
cartilage. Being able to leverage that,
in addition to communicating with industry during the development of that
standard; it used the expertise in industry to have the details of the
multiple, different models that would be more time-consuming for FDA to have
written by itself.
The rest of the guidance document
really deals with clinical study protocols, which stress the importance of
exploratory trials of both the design features of those trials and using the
knowledge learned on the exploratory trials for your confirmatory studies, so
that we expected -- we recommended randomized control trials; double-blinded,
bounded evaluation; evaluations of major endpoints, but mentioned that
alternative study designs would be considered but they need to be supported.
Study endpoints: we went through
study endpoints and we stressed that we would recommend clinically meaningful
endpoints as primary in confirmatory studies -- improvement in pain and/or
improvement in physical function.
We went through what we would expect
for examples of secondary endpoints that might be considered in development of
these trials. It's a long list and we go
through in some detail in the guidance itself.
It also has a section we point out
that we would expect, in terms of the submission for IDEs and INDs, a detailed
description of the procedures of the product administration, the surgical
technique and the plans for the post-operative rehabilitation. We think that those are important to describe
in the IDE and IND in some detail.
We mention our recommendations on
follow-up, a length of follow-up to be based on in vivo and in vitro studies
and a two year follow-up for, at least, a subset of the subjects in the trial.
We go on to recommend our adverse
event reporting in addition to reporting for the regulations for the IND or the
IDE. There are somewhat different
regulations. We wanted to stress our
recommendation for reporting subsequent surgical interventions, revisions,
removals or re-operations, as that applied to these products, and it's
something that we'll take into consideration in these products when we're
evaluating them.
We'll say just that, that is a draft
guidance at this point and we've received comments and we're in the process of
finalizing it. So it doesn't currently
represent our thinking, but this is our draft.
Similarly, to Kim's slide on
resources on the web, there's the reference on the regulatory process that is
updated periodically and, given all the recent guidances that we've published,
I'm sure there's probably an update we need to do on it. However, until that occurs and even when it
doesn't occur, our cell and gene therapy guidances can be found at that link
and our tissue guidances, also, at the link underneath. I will point out that for cell therapies it's
helpful to check both the cell therapy link and the tissue link, because there
are some general ACTP guidances that also apply to cell therapies.
So a quick summary, I went over
quickly what GGP was, what our FDA guidance process is and how it's governed by
regulations. I went over very briefly
our recent guidances that we've finalized and issued in draft, both in the
Annual Guidance Agenda and those that have come to meet needs in the interim,
and went into some details on the cartilage repair product guidance.
So in conclusion, I'd say that I
think we have an active guidance development program in the Office now that
includes both strategic planning -- guidance planning -- which is reflected in
our annual agenda, but also is able to respond to changing needs as times go
on.
We leverage many things in terms of
our guidance development input from the advisory committee, other public
meetings we have, notably the FDA Advisory Committee, at the NIH, workshops
such as the ones that were mentioned by Dr. Epstein earlier, industry liaison
meetings that we have, our cross-center efforts within CDRH -- within FDA, to
CDRH and to CDER in terms of informing our guidance process and participation
with the standards development organizations.
And one thing that is so obviously
that is so much of the DNA of the Office that I left it off the list, which was
leveraging our research. Our research
reviewers, we had some discussion earlier about research reviewers and review
load versus research load. I would like
to just stress their expertise in the relevant research. It's really essential in many of these
guidance development programs. It helps
ensure that we have the most up-to-date science underlying our guidance
recommendations, particularly in those guidances that reflect specific product
areas and development of applications.
And although I don't have a thank
you slide, I do thank you for your participation and your advice over the
years.
(Applause.)
QUESTIONS AND ANSWERS
CHAIR URBA: Dr. Allen.
DR. ALLEN: Yes, I have a -- actually, I have three
questions but they relate to the draft guidance with respect to cartilage. So I guess my first question is I understand
it's not the arena of the FDA to tell sponsors exactly what to do and what will
be acceptable. But over the course of
the time since this draft guidance has been released, I've had, I think, three
calls from sponsors in this country and one from overseas asking essentially
what they should do in order to get preclinical data.
So one of my questions is just in
a general sense with the guidance
deliberately be somewhat vague and loose on exactly what is required, what is
the distinction with these cell-based therapy or cell based and combination
therapies? What determines whether the
FDA is actually going to require a GLP
study or not, understanding that doing a GLP study in a horse for a year is
probably far from trivial and I think there are probably three places in the
country that can do it? That's my first question.
DR. McFARLAND: Okay.
The answer is GLP studies are not necessarily required. It's been a longstanding policy at the Office
to understand that GLP studies may not -- number one, they're impractical for
many of our types of products, simply because they're not always able to get
the technical expertise to conduct the study in the GLP setting and GLP labs,
and sometimes those are not completely overlapping subsets.
So we certainly would accept
preclinical data that's not GLP. It
needs to be -- they need to be robustly done, however, and there is a
regulation that says that if you are going to say that a study is GLP, they
expect for that entire study to be GLP, and if there are sections of a study
which aren't, those need to be demarcated.
So that's the general answer to the
question. We're really interested in
getting the best data, regardless of where it comes from that's applicable to
the product and the pharm-tox branch will frequently answer that question, as well,
in our pre-IND interactions or with sponsors where they will typically have
done some preliminary work, submit their plan for preclinical data and that's
frequently a question that comes up as one of our standard comments.
DR. ALLEN: Okay.
So my second question then relates to efficacy and -- I noticed in the
draft guidance again and obviously I was at the discussion back in 2005, but we
place fairly strong emphasis on the fact that you could do essentially proof of
principle, biological principles, in a small animal model. But for the durability of response and the
efficacy, a large animal model is preferred and desirable, and so I was struck
yesterday in the meeting in the discussion about ES cells that we were not, I
think, as stringent with respect to the large animal models and understanding
there are problems with large animal models, with using autologous cells.
I noticed in the guidance here for
cartilage we allow latitude and we say that, for example, with large animal
models where it's not feasible to use human cells because of issues of
immunosuppression, that if you have an autologous or allogeneic product from
that animal and it is being characterized with respect to the human situation
that that would be accepted.
So I guess I'm concerned that there
are some inconsistencies between cell-based products and embryonic stem cells.
And I guess that brings up my third
question which is, if I have an embryonic stem cell and I differentiate it in
vitro to the point of it being essentially a cartilage progenitor cell, then,
which guidance do I go with. I mean, can
I take that cell and put it into this and say it's a product which now has to
follow this guidance or am I constrained by the other, by the ES cell
guidance? And I just worry that we're
placing an extra burden on ES and also, and most especially, we have a
stringent requirement, I think, for demonstrating long-term efficacy and with
that in those model's safety for cells like MSCs that are potentially less
risky and yet we seem to be not so concerned.
We seem to just say it's hard to do in a large animal. So we shouldn't worry.
But I would be much more concerned
potentially about the known and the unknown risks of ES cells and I would
strongly urge the FDA to really reconsider as they formulate draft guidance,
look at the importance of doing even allogeneic experiments long-term,
one-year, let's say, large animal models.
So I'm just trying to understand the
science and to get coverage on this information because I think it's critically
important. I'm just -- I'm concerned
there's just not consensus across these two documents, potentially.
DR. McFARLAND: I guess the only comment to that is, we've
heard your comment and we'll take it under consideration. I think -- I guess the other comment is, in
these areas that are emerging, which is true for the cartilage and for the ES
cell which would -- really, the indication, the general indications in general,
a lot of these differences in risk assessment gets initially done in terms of
interactions with individual sponsors, and it's frequently a question in our
pre-submission interactions, which are similar to the concerns that you issued
and that's how we initially gather information and gather information on risk
assessment as things are just beginning.
DR. GERSON: I wonder if I could just ask for some
clarification on what I view as sort of the guidance gap, if you will, and that
is that, in the process of going from the formal regulation to the guidance
documents and, in the process of going from the conceptualization of the need
for a guidance, the developments of information gathering, sort of a discovery
period, and then the development of a draft and you showed us the detail on the
cartilage, to the final document which we've just seen the process of the
earlier presentation on somatic cell therapy and the CMC for that recently
issued, and your very last statement during your formal presentation,
next-to-the-last statement, about the current thinking of the draft document. So, okay, so now I'm an investigator, a
research entity, a commercial entity, and I know there's a regulation and I
know there's a guidance document that's some years old and now there's a
lingering draft document and I want to do it right. What am I supposed to do exactly, and how can
the agency help that gap period between the old, former guidance, the new draft
and the final guidance? So how do you
operate in that sphere of limbo?
DR. McFARLAND: The guidance gap, I kind of like that
term. Okay, there are multiple questions
packed in. Let me see if I can address
them all and, if I miss some, let me know and I'll go back. What are sponsors supposed to do in the
situation that they have an old guidance, they have a draft guidance, which
isn't formally the thinking of the agency or the field is moving and changing
since the guidance?
What an individual sponsor entity
should do is, if they have those questions, direct them to us and in that
specific way, either in a formal pre-IND session, pre-submission session, or in
a more informal session if they're a little earlier in their development and
that, I think, is what a specific sponsor should is come talk to us and put
that on the table as a specific question.
I have X product. You have X
guidance. It doesn't seem to fit in with
where the science is right now, or ,we won't be able to tell you exactly where
we are in terms of working on things, but we will be able to tell you what our
current practice is in review specific to that product.
The other thing that I think is
helpful for sponsors to do is, we frequently give outreach presentations at
scientific meetings, industry-type meetings, where we outline what our current
thinking is in a particular area and topic, and those typically are helpful in filling
that kind of gap in the general sense.
What are we doing to reduce the guidance gap, I suppose, is the implicit
question behind it.
At the agency level and at the
Center level and at the office level, we are working on improving our processes
for prioritization of guidances, of streamlining our processes in terms of
generating the first draft of the guidance, which is sometimes a long haul when
things aren't moving quickly or when we have had other, competing priorities as
well as decreasing the time in the area of the guidance getting sign-off and
the guidance at the various levels of administration throughout the Center, the
office and the agency. At all levels, we
are working on some internal processes to do that.
One of the things that Dr. Witten
has done which we hope has helped is develop the Office of the Associate
Director of Policy. That is, all the
product offices in the Center now have an associate directors of policy and one
of our jobs is to work on decreasing the guidance gap, moving things forward,
helping to facilitate guidance development by taking lessons learned from one
guidance and bringing them back to review teams that are writing guidances.
One of the things that happens is
that any individual reviewer may have a limited number of experiences in their
career writing guidances. Some of the
roadblocks that come up in writing the guidances are not unique to a specific
guidance. So one of the roles of the ADP
and the regulatory policy staff at the Center level is to help the review teams
understand where they're going to come up to roadblocks and help them get
around those.
The other thing that we do is meet
at the Center level to coordinate policy development and to make each other
aware of guidances in our individual offices, so that concerns that may arise
in one office about a guidance that potentially slows things down, are
incorporated early on. I think the
derivative of the guidance development in the center is positive right now, but
it's an ongoing process. I think it, in
some way, reflects similar issues that it's happened in the research realm.
DR. WITTEN: Can I add something to what you said,
Richard?
DR. McFARLAND: Sure.
DR. WITTEN: I just want to mention that Dr. McFarland has
highlighted the role of the advisory committee in helping us with our guidance
document development. But it is also
possible for outside individuals in organizations, not as members of the AC but
in your other world or other people that you know to contribute in the
following sense and one is that this guidance document agenda, I mean, people
can propose topics. They could comment
to that guidance document agenda that's published with suggestions for where
they think there are specific gap areas.
In other words, Richard has gone
over the way to comment to specific guidance documents to the public and
comment to the docket when there's a draft published and provide feedback and
input on a guidance document that we've put out either in draft or in final
form. And in addition anyone is free to
make suggestions for guidance documents that they think would be worth
developing and there's even a procedure for them to propose background or information or even some type
of draft.
Now we can't work with an outside
organization in developing a guidance document, but I think we can take
nominations including some fairly substantive background. If someone is interested in doing that, we
would be glad to explain how to do that and we'd welcome that because our own
agenda setting is based on what we see is our needs and the fields' needs.
Putting a guidance document out is a
nontrivial effort. As Richard said, a
lot of thought and time goes into it.
But I think there is a role for outside groups if they think carefully
about it, what our needs are and what we would need.
DR. TOMFORD: Thank you.
I appreciate the amount of work that goes into a guidance document and
the fact that the FDA works hard to make it fair and equitable. My question involves -- I don't want to pick
on this particular guidance document. If
you read it, it says preparation for products intended to repair/replace knee
cartilage. But the primary endpoint is
not replacement of knee cartilage. The
primary endpoint is improvement in pain and improvement in physical function,
two of which to me at least as an orthopedic surgeon are secondary
endpoints. The primary endpoint is what
it says, replace knee cartilage.
So I want to ask about this sort of
deliberately vague concept because that seems pertinent here. How is thst chosen? I was thinking about the embryonic stem cells
yesterday. It would be unlikely that the
FDA would approve a process where an embryonic stem cell that's replacing a
cell in the retina isn't that cell. It
turns out to be a kidney cell or something.
So I guess I'm concerned about this
because this is a very controversial area in orthopedics as you know. Why is this deliberately vague? Why is not the title of the guidance document
supported by the primary endpoint?
DR. WITTEN: Do you want me to answer that?
DR. McFARLAND: Well, if you want. I don't care.
It doesn't matter to me.
(Laughter.)
DR. WITTEN: Yes.
I'd just say I wouldn't really focus on the title that much. The titles of these generally describe what
the product is, I mean, a lot of our guidances and I don't think any real deep
reading of it is actually intended. If
somebody wants to develop one of these products, they'll know from the title
that might be something useful to look for and I just wouldn't try to read any
meaning into it. I think that the titles
are just supposed to tell somebody that this is a place to look. So I don't think we have a deeper meaning to
explain with that and the guidance document describes the kinds of endpoints
we'd want to see for this type of product.
CHAIR URBA: Dr. Gunter.
DR. GUNTER: Thank you.
DR. CHAPPELL: Go ahead.
DR. GUNTER: Okay.
First of all, I don't want any of my comments to be perceived as
critical because I think the guidance program the FDA has, that CBER has, that
this office has, is actually really world class. When you look in other regions of the world,
there is virtually no guidance on especially this class of products.
So the FDA and CBER should be
commended for their efforts and achievements so far and I think Dr. Witten
actually partially addressed my question already. But I'll ask it anyway and that is I think
stakeholders in the field would be interested in knowing what guidance
documents are planned and he did mention an agenda of guidance documents and I
know, Dr. McFarland, you've presented in some meetings what guidance documents
were planned.
So my first question is is there
opportunity for stakeholders in the field to look to see what guidance
documents you're planning and have input on that. And then a second part to the question is
have you ever considered some kind of formal survey of stakeholders as to what
their needs for guidance documents are in a systematic way.
DR. McFARLAND: Okay.
The formal way to see what we've officially planned is the Biannual
Guidance Agenda which it comes out roughly every two years and the last one was
September 2006 and that is the formal vetted way for the agenda to look and, as
Dr. Witten said, comment directly that and it will get to us if you have
guidance documents that you think we should write.
In terms of a formal way to do a
survey, doing a survey raises lots of issues with OMB and paperwork and doing a
survey from the Federal Government for that is not a trivial undertaking and I
think to go through the process to do a formalized survey would actually take
away resources that could better be used in developing the guidances.
What we do do to use the term that
came up in the research presentations, we do a lot of horizon scanning in concert
with the research program and the regulatory program on things that we see in
the future that might be issues.
We take comments, informal comments,
from every industry meeting. Almost
every time we do an outreach, someone is suggesting something that we should
write on. We take those all back and
frequently, although not all the time, we are already sort of thinking about
it. I hope that answers your question.
CHAIR URBA: Dr. Allen and then Dr. Chappell.
DR. ALLEN: I just had a question really for
clarification and I guess that is with respect to these guidance documents when
public comment is invited do we, the Committee, or does the public, sponsors in
the public at large, have access to those public comments. I mean we can see the response to public
comments, but are we seeing that the FDA is being responsive to those public
comments in a specific way? And I have
no -- This is probably from a sense of ignorance, but I have no idea how many
public comments, for example, would be garnered by a draft guidance document on
IND. I imagine a lot. It may not be. But could I just get a sense of the magnitude
of a response to a typical document and whether that information is publicly
available even after the finalized version has been produced?
DR. WITTEN: The public comments are public, although I
have difficulty finding them on the web.
I mean I've been told you have to go in person to see them.
DR. McFARLAND: Yes, they're not particularly easy to find.
DR. WITTEN: Yes.
DR. McFARLAND: But we've just gone to a new eGovernment
system across the government in terms of accepting comments and we're told that
they'll be easier to access.
In terms of how we have dealt with
the comments when we issue a final guidance, we issue with it a notice of
availability in the Federal Register where we discuss the comments, the
number of comments, the depth of comments and what we have, in addition to
changing the guidance, we have frequently specifically -- we have some guidance
that suggests being issues with study endpoints or small animal use and these
particular phrases and this is what we did with that. So there is a formal process to get feedback
on that.
DR. CHAPPELL: I just wanted to observe with regards to Dr.
Tomford's comment that it relates to yesterday's repeated pleas for surrogate
variables for early phase studies and that when we talk about endpoints,
primary endpoints, we should always explicitly state for what phase of research
we want those endpoints.
For example, surely the eventual
goal of cartilage knee replacement is to improve quality of life and minimize
pain and a Phase III trial I would recommend that. But also for early phase trials as we
discussed yesterday, I think we want surrogate endpoints. Yes, we want to know that the cells there are
cartilage or cartilage progenitor cells or the eye example eventually I want to
see better. But my early goal is a surrogate one of just being assured
that the appropriate cells are implanted into the retina.
So my more general plea is to state
primary endpoints and then say for which kinds of studies you think those
primary endpoints are important and I say that because I've seen in the past
statements that surrogate variables are inappropriate which was true at the
time for Phase III trials at least in that context and yet it was applied to
early phase trials and also visa versa.
So when guidances recommend
endpoints, I think they should be put in explicit context lest those reading
them for one reason or another take them out of context and apply them to
situations for which they were not intended.
CHAIR URBA: Other questions or comments? Thank you.
DR. GERSON: Just a point of clarification. These slides are very, very helpful. Are they, since this isn't a public meeting,
now -- Will they be on the web for general consumption?
DR. McFARLAND: Yes.
MS. DAPOLITO: Yes, but will they be easily accessible?
(Laughter.)
CHAIR URBA: They're in your package.
MS. DAPOLITO: Yes, they will be posted on the FDA Advisory
Committee website and they should be easily accessible.
CHAIR URBA: Dr. Witten, do you have any final comments?
DR. WITTEN: I'd like to again thank the Advisory
Committee for their participation today and a special thanks to you, Dr. Urba,
for chairing this meeting. I know this
is your first foray and we really do appreciate it. Thank you and thanks to all the FDA people
who prepared for today as well.
CHAIR URBA: Thank you for your kind words and I want to
thank Gail and all her staff for making the meeting run so smoothly and for all
the Advisory Board members who took time out of their schedules to make this
happen and for the FDA people who are working hard so that we can all do better
things for our patients. With that,
we'll adjourn. Thank you.
(Whereupon, at 10:53 a.m., the
above-entitled matter was concluded.)