1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ADVISORY COMMITTEE FOR PHARMACEUTICAL
SCIENCE
CDER Advisory Committee
Conference Room
2
PARTICIPANTS
Arthur H. Kibbe, Ph.D., Chair
Hilda F. Scharen, M.S., Executive Secretary
MEMBERS
Patrick P. DeLuca, Ph.D.
Paul H. Fackler, Ph.D.
Meryl H. Karol, Ph.D.
Melvin V. Koch, Ph.D.
Michael S. Korczynski, Ph.D.
Marvin C. Meyer, Ph.D.
Gerald P. Migliaccio,
Ph.D. (Industry
Representative)
Kenneth
R. Morris, Ph.D.
Cynthia
R.D. Selassie, Ph.D.
Nozer
Singpurwalla, Ph.D.
Marc Swadener, Ed.D.
(Consumer Representative)
Jurgen Venitz, M.D., Ph.D.
SPECIAL GOVERNMENT EMPLOYEES SPEAKERS
Judy Boehlert, Ph.D.
Gordon Amidon, Ph.D., M.A.
FDA Staff
Gary Buehler, R.Ph.
Lucinda Buhse, Ph.D.
Jon Clark, M.S.
Jerry Collins, Ph.D.
Joseph Contrera, Ph.D.
Ajaz Hussain, Ph.D.
Monsoor Khan, R.Ph., Ph.D.
Steven Kozlowski, M.D.
Vincent Lee, Ph.D.
Qian Li, Ph.D.
Robert Lionberger, Ph.D.
Robert O'Neill, Ph.D.
Amy Rosenberg, M.D.
John Simmons, Ph.D.
Keith Webber, Ph.D.
Helen Winkle
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C O N T E N T S
PAGE
Call
to Order
Arthur Kibbe, Ph.D. 5
Conflict of Interest Statement:
Hilda Scharen, M.S. 5
Committee Discussion (Continued) 8
Science in Regulation - Visionary
Overview
Arthur Kibbe, Ph.D. 43
The "
Regulatory Policies
Ajaz Hussain, Ph.D. 74
Organization Gap Analysis
Helen Winkle 75
Scientific Gap Analysis
Ajaz Hussain, Ph.D. 103
Policy Gap Analysis
Jon Clark, M.S. 135
Generic Pharmaceutical Association
Perspective
Shahid Ahmed, M.S. 152
Pharmaceutical Research and Manufacturers
of
Gerry Migliaccio, Ph.D. 164
Committee Discussion and
Recommendations 182
Pharmaceutical Equivalence and
Bioequivalence
of Generic Drugs
The Concept and Criteria of
BioINequivalence
Concept of BioINequivalence
Criteria of BioINequivalence
Qian Li, Sc.D. 222
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C O N T E N T S
(Continued)
PAGE
Committee Discussion and
Recommendations 234
Bioequivalence Testing for Locally Acting
Gastrointestinal Drugs
Topic Introduction
Scientific Principles
Gordon Amidon, Ph.D. 275
Regulatory Implications and Case
Studies
Robert Lionberger, Ph.D. 308
Committee Discussion and
Recommendations 324
Conclusion and Summary Remarks
Ajaz Hussain, Ph.D. 341
Helen Winkle 349
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P R O C E E D I N G S
Call to Order
DR. KIBBE: Ladies and gentlemen, I would
like to call the meeting to order. The first item
of business is the reading of the
Conflict of
Interest Statement.
Conflict of Interest
Statement
MS. SCHAREN: Good morning.
The following
announcement addresses the issue of conflict
of
interest with respect to this meeting and
is made a
part of the record to preclude even the
appearance
of such.
Based on the agenda, it has
been
determined that the topics of today's
meeting are
issues of broad applicability and there
are no
products being approved. Unlike issues before a
committee in which a particular product
is
discussed, issues of broader
applicability involve
many industrial sponsors and academic institutions.
All Special Government
Employees have been
screened for their financial interests as
they may
apply to the general topics at hand. To determine
6
if any conflict of interest existed, the
Agency has
reviewed the agenda and all relevant
financial
interests reported by the meeting
participants.
The Food and Drug
Administration has
granted general matters waivers to the
Special
Government Employees participating in
this meeting
who require a waiver under Title 18,
Code, Section 208.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
Agency's Freedom of Information Office,
Room 12A-30
of the
Because general topics impact
so many
entities, it is not practical to recite
all
potential conflicts of interest as they
apply to
each member, consultant, and guest
speaker.
FDA acknowledges that there may
be
potential conflicts of interest, but
because of the
general nature of the discussions before
the
committee, these potential conflicts are
mitigated.
With respect to FDA's invited
industry
representative, we would like to disclose
that Dr.
7
Paul Fackler and Mr. Gerald Migliaccio
are
participating in this meeting as
non-voting
industry representatives acting on behalf
of
regulated industry. Dr. Fackler's and Mr.
Migliaccio's role on this committee is to
represent
industry interests in general, and not
any other
particular company.
Dr. Fackler is employed by Teva
Pharmaceuticals
employed by Pfizer, Inc.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which FDA participants have a
financial
interest, the participants' involvement
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any firm whose product they may wish to
comment
upon.
Thank you.
DR. KIBBE: Thank you.
8
Yesterday, we concluded with a
suggestion
that we might want to continue our
discussion about
the questions that the Agency has raised,
and I
think Dr. Meyer has asked Dr. Hussain to
come up
with a straw man, and we have it ready,
so I think
we should go there first and then go back
to the
scheduled agenda.
Ajaz.
Committee Discussion (Continued)
DR. HUSSAIN: Good morning.
I think the
discussions towards the end of yesterday
started
honing down on some of the key challenges
we face
in the designing of a Critical Path
Initiative in
OPS.
I think, reflecting back on the
discussion
yesterday, clearly, I think we have a
wide range of
research capabilities and programs
already in
place, and the challenge would be to sort
of direct
these in a very focused way to help the
Critical
Path Initiative, keeping in mind that all
of our
research will not be focused on critical
path,
there are other aspects that we have to
focus on.
9
I will sort of reflect back on
the PAT
Initiative and how that sort of
evolved. Clearly,
if you recall, the PAT Initiative led to
the GMP,
and there is a whole sequence of
initiatives that
have occurred. The PAT Initiative was a model and
we can learn some things from that as a
model also.
I will sort of summarize my
thoughts here
with a hypothesis statement that Jerry
proposed
yesterday, that Critical Path Initiative
will
improve the efficiency and effectiveness
of drug
development process. That is the hypothesis that
sort of really we are engaged in trying
to fulfill
or trying to confirm.
The challenge would be then how
do we
measure efficiency and effectiveness of
drug
development. That is one of the keys, how do you
measure drug development in terms of the
failure
rate, or the time it takes, or the cost
of drug
development.
All of these are relevant metrics, but for
the purposes of a hypothesis, what and
how should
we approach and define that, because
unless you can
10
measure something, you cannot improve
it. So,
measurement and metrics would be a key
factor of
that.
The second aspect then would be
what are
the root causes of low efficiency and
effectiveness
in all the three dimensions. A number of factors
were put up looking at 1999 or 1991 or
2000, and so
forth.
They were indicators of what
may be
happening, but you have to keep in mind
that is
partial information, information
available to FDA
and available in public is just limited
because the
companies have far more information about
the root
causes, and so forth. So, you have to sort of
factor that into our decisionmaking.
The next question is who is in
the best
position to address these root cause
factors that
we identify, what is the role of FDA,
what should
FDA do and what should some industry,
academia, and
other agencies should be doing is the key
there.
I think based on information and based on
experience at FDA, clearly, we are in a
good
11
position to identify many of the
problems, not all
of the problems, but many of the
problems, and FDA
has the responsibility to communicate
these
findings in some way or form.
If you look at John Simmons'
presentation,
he laid out, as a part of the critical
path,
strategic meeting points during the drug
development process. That is one aspect,
communication between sponsors of
applications and
our review scientists, if that is timely
and in a
coordinated manner, that is one effective
means of
that.
So, communication through
meetings for
specific drug applications, broader
communications
with workshops, and then eventually
guidance
documents outlining FDA's current
thinking on a
given topic are the communication
mechanisms that
we have.
For that, clearly, I think you
have to
think about resources and how do you
facilitate
that process. If you want to sort of move towards
more meetings and more interactions between
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reviewers and sponsors, then, you have to
build the
time for that, and so forth. That has to be
considered, too.
Workshops and guidances also take
a
significant amount of effort, and so
forth, so as
we improve our communication channels,
where will
we find the resources and time to do that, I think
that is also a management aspect that has
to be
discussed.
FDA's knowledge base, I think was
clearly
an asset in the sense we have a lot of
information.
If we are able to create a knowledge base
that can
be useful, not only for identifying
problems that
we see, but also for improving of a
predictive
ability in all three dimensions, safety,
efficacy,
and industrializations, what are the
practices that
lead to success, what are the practices
that may
not be as efficient, and so forth.
So, this knowledge base would be useful
for that purpose, but again I will remind
in the
sense we have to be cautious, there are
limitations
of that knowledge, because we don't
always have all
13
the information, so you have to factor
that in.
But based on our knowledge base
and based
on communication, and so forth, I think
the
laboratory and the research functions
clearly have
to
focus on improving methodologies. There
are
many aspects of laboratory work that only
FDA is in
a good position to do, and others either
don't have
the interest or don't have the focus to
sort of
address some of the challenges.
For example, in the case of
regulatory
decisionmaking, risk-based
decisionmaking, the
decision process itself often needs
support of
science, and so forth, so that is where
the
research really could focus on.
Also for development and
validation of new
methodologies, standards development,
methodology,
validation, say, from biomarker to any
new
technology, unless FDA has a role in
achieving
that, it may not be fully appreciated
within the
Agency, and some of the Agency concerns
would not
be addressed if it is done totally
outside, so
there has to be some means of linking our
14
laboratory work to standards development,
validation of new methods, and so forth.
Our postmarketing experience
again is
unique because that is where I think we
have a lot
of information, how do we capture that as
lessons
learned and how do we use that. You saw some
examples of how we were learning from
that and
going retrospectively and said how could
we have
improved the process. Those experiments would be
very valuable.
One aspect is in terms of
innovation, in
terms of new technologies, what is an
important
aspect of standard setting? Standard setting and
guidances are slightly different in my
opinion.
For example, in the PAT Initiative, we
opted to
move towards ASTM International as the
body for
standard setting.
What that does is allows
industry,
academia, every stakeholder to be part of
that, and
actually identify what standards are
needed, and
actually develop those as quickly as
possible.
That relieves the burden on
FDA, and FDA
15
simply adapt or adopt those standards
after
evaluation, so that might be an option
that seems
to be moving forward in the PAT
Initiative for new
technologies, new methods, and so
forth. So, that
could be considered at the same time.
But at the same time, I think as
we look
at FDA's role, what is the role of
industry and
what is the role of other agencies and
academia
really have to sort of come together.
The role of industry I think is
knowledge
sharing. Clearly, it has far more
information, and
reluctance to share knowledge will
inhibit the
progress, and how do you do that is a key
challenge.
At the same time, I think in
order to
bring all of us together, focused on a
given goal,
we really I think have to define clearly
the
metrics, the desired state, and so forth,
and come
on the same page, so that we can
coordinate all of
these activities.
In some ways, FDA could play
that role of
coordination, as Viad declared yesterday,
not only
16
from the prospective of we are not
competing in
this arena, eventually, we have to be
involved, so
coordination function for FDA would be an
important
function for all these activities.
If we have a clear
understanding of what
are the issues and what are we trying to
achieve,
then, the coordination and synergy would
sort of
evolve naturally.
So, those are the sort of
thought process
that I could capture.
DR. KIBBE: Anybody?
Marvin? You asked
for the straw, you got the straw man.
DR. MEYER: The virus, are you talking
about that later?
DR. HUSSAIN: No, that is a very specific
example.
DR. MEYER: I thought I had more time to
think then, since I was waiting for the
virus.
DR. KIBBE: Does somebody else want to--
DR. MEYER: No, no, I have something to
say.
DR. KOCH: Marvin, just before you--I
17
think I need a point of clarification
because some
of what came out yesterday was the desire
to have
either shorter development time, more
compounds
coming out that could be effective, new
pharmaceuticals, and it seems to be a
push towards
industry to try to become more effective,
et
cetera, but I saw a couple times
yesterday where
things developed within the Agency to
improve the
ability to go after materials through
some of the
databases and things were certainly ways
to help
that process.
The other thing, though, is
that when you
looked at that chart that showed an
increase in
cost of materials and a few other things,
toxicity,
you know, is something that shows up
there, and I
think something a little bit insidious
over time
has been with improved technologies and
increased
concerns over pharmaceuticals, there are
new tests
that come in that prolong the evaluation,
that
anything the Agency can do to pull things
together
to make those things, immunogenicity or
other
things that have, you know, you go back
two
18
generations ago and if you come up with a
new
material, would you put it through all of
the same
tests, so anything that can be done to
simplify and
do more predictive studies in that
regard, I think
would help.
DR. HUSSAIN: Definitely, that is an
important point. For example, I think as we move
towards more complex materials, the
material cost
is, as you saw, is already showing up,
and so
forth.
Introduction of new excipients
or new
adjuvants, and so forth, is a significant
challenge, and as we go towards
nanomaterials,
nanodevices, and so forth, if we still
have to rely
on the traditional pharmaceutical
excipients, it
would be a very limiting aspect, so I
think that
that is clearly on our agenda.
One aspect that I do want to
mention, as
we think about this, the patient has to
be foremost
in our minds, what are the unmet needs,
and as we
sort of develop this, I think clearly,
the patient
needs have to be kept in mind as we move
forward,
19
because there are many diseases, many
aspects where
we don't have effective drugs, and so
forth, so we
shouldn't forget that aspect.
DR. KIBBE: Marvin, are you ready now?
DR. MEYER: Yes. I
was just thinking of a
simple example where the Agency I think
played a
major role and really expedited drug
approval, and
that was back when we were battling over
assay
method validation.
The hypothesis was if we had a
better way
of validating assays or a uniform way of
validating
assays, things would get approved without
recycling
and redoing, and, in fact, FDA then, and
APS and
others, convened several workshops, had
white
papers, ultimately put out a guidance,
and I
suspect that hypothesis has been tested,
that there
are much fewer problems in the local
methodology,
so I think that is a good model, and you
alluded to
that.
DR. KIBBE: Anybody else would like to
make a comment?
DR. SINGPURWALLA: Yes. I
repeatedly hear
20
from individuals like yourself asking
industry to
share more information with you. What is the
incentive to the industry to do so,
because there
is a penalty to do so? Recently, those of us who
read the Washington Post can see the
number of
pages devoted to the Merck and also to
Pfizer
having a similar drug going to be tested,
and
things like that.
So, unless the legal pressures
that are on
industry are defused or removed, industry
is going
to be foolish to share all the
information with
you.
I wouldn't. It's like me going to the IRS and
saying look, this is how I have cheated,
catch me.
It doesn't make sense, does it?
DR. HUSSAIN: No, I think it is not in the
context of sort of cheating, and so
forth. This is
in the context of how much we know and
how much we
don't know, to start filling the gaps
where the
knowledge exists. Clearly, that is the aspect, and
it is complicated by the fact that the
way it gets
entrenched into the legal and political
scenarios,
those are significance challenges, no
doubt about
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that.
DR. SINGPURWALLA: What is the industry's
response to this?
DR. MIGLIACCIO: Well, it is complicated
by obviously, intellectual property
rights, which
is the life blood of a commercial
business, but it
is also complicated by--you just used the
word
"trust."
I will give an anecdote
here. I went to
an internal FDA meeting to provide
training, and
during that training, provided knowledge
about
products, which normally, would not have
been made
available.
The reaction was the
traditional
predictable reaction, not the forward
thinking
reaction, by certain elements of the
audience. So,
that was a risk, that was a poorly
thought-through
risk on my part.
We have to reduce the risk
associated with
sharing knowledge. That is the fundamental issue
is if we share knowledge and expose
ourselves to
compliance action where that knowledge is
22
essentially reflecting what is the
scientific
truth, and we can now measure that, we
can now see
that where we couldn't before, and if you divulge
that knowledge and risk compliance action
versus
scientific discussion, then, the
knowledge will not
be transferred.
DR. KIBBE: Ajaz, anything?
DR. HUSSAIN: No.
DR. KIBBE: Anybody else?
Let me just put
three things on the table and perhaps you
can think
about them as how they respond to the
questions we
were left with yesterday.
One is that I think I heard
from around
the room that the Agency has a limited
resource
base, and it truly should focus on those
aspects of
the critical path that only the Agency
can do, that
no one else has the wherewithal or the
capability
or the information to do that.
Secondly, that we try to get
others who
are even more capable of responding to
certain
aspects of the critical path to take on
that
burden.
I am thinking primarily of industry and
23
perhaps industry/academia together
looking at those
aspects of it.
But the third thing that I
think that the
Agency and both the industry will have to
look
forward to is that the rate of
technological
advance is such that 10 years from now,
the
questions that you are trying to answer
now will be
ancient history, and the questions that
you are
running into are going to be dramatic and
clearly
different, and I really look forward to a
paradigm
shift in the way we approach therapy, and
I would
recommend to the industry that they
change their
name from drug companies to companies
that provide
therapeutic agents and processes, because
they
could be caught up in the same system
that the
railroads did. They were railroad companies, and
not transportation companies.
I don't know how the Agency can
respond
effectively without having some type of
internal
committee that is constantly looking at
four or
five years out and the technology that
they are
going to have to deal with then.
24
So, that is where I think the
critical
path kind of initiative ought to be
looking.
DR. DeLUCA: Let me just comment. I made
some notes here from yesterday, and I
think that
this is based on collaboration, I think I
am going
to really focus on that, and as Jerry
mentioned, I
think trust. Certainly, trust is essential in
collaboration, and as we get into talking
about the
science-based approach here and research,
research
is a search for the truth.
I would like also to commend
the Agency in
their research efforts. I mean yesterday was, I
think, I would say overwhelming to learn
the type
of research that is going on and the
collaboration
with NIH, so I really have to commend the
Agency
for this.
I would like to also talk about
the
presentation by Monsoor Khan where he
talked about
critical path research and some of their
efforts,
and I think Gerry Migliaccio had
responded that
industry takes this approach.
I have to say that that is true
from my
25
experience to an extent. I know, I am involved in
the novel drug delivery area and the
research in
that area, and working with a company
that was
scaling up or transferring some
technology, that
that approach was taken, the critical
path approach
was taken, and worked with them, and they
did solve
the problem at hand, but there were other
things
that still needed to be done to define
some of the
process variables, that once the problem
was
solved, they went on, they didn't want to
go any
further with that.
So, I think there is a limit to
where they
go and I think this is where
collaboration is
important, and I think there is a need to
continue
on and to search those things out, and
probably the
place for that is in academe.
I don't know if it was Jerry
Collins, when
he talked about the science-based
approach to
critical path issues and the research,
that it is
probably essential that the research that
is going
on, that it is going to be hypothesis
driven. I
think this is something that many times
the
26
research that takes place, and if it is
in an
industrial setting, may lack the
hypothesis driven
type of research, and that probably I
think is
important.
I guess my feeling is in
hearing all the
things, and I think what Art had said,
FDA can't
really overreach, I mean there is a limit
resourcewise, but I think more
importantly is the
idea that they can't do it alone, so I
think that
collaboration is important.
The FDA has been collaborating
more with
NIH, and I think translational research
issues,
taking the drug product development, that
portion
of it along, but I think there is a gap
there with
the critical path, in the formulation and
taking it
and the manufacturing science, and I
guess I think
that the collaboration has to be there
between
academe, industry, and FDA, and FDA could
really
set the stage for this. I think there is a very
important role.
Just to bring out my experience
with the
journal, the APS on-line Pharmaceutical
Science
27
Technology Journal, that the submissions,
we get
about 50-50 from abroad and the United
States, but
about 90 percent of the submissions--now,
this is
in the Pharmaceutical Technology Journal,
and you
would really think that you would get
more from
industry--but about 90 percent of the
submissions
come from academe.
I have to acknowledge that
probably in
about 40 percent of those, there is a
collaboration
between academe and industry, so that
there is a
tie-in and that it is all those being
submitted
from the academic institution, the
industry is
involved in it.
But I think that this kind of
sends a
message, and I have tried to encourage
more, more
submissions from industry, and there is
intellectual property situations involved
in that,
but I think there is a need.
I know, being in academe and
graduating
Ph.D.'s, the majority of them will go
into the
industry, few of them publish after they
are in
industry.
Before they left, they had eight or nine
28
publications, and then they went in and
stopped
publishing, so, I am not sure that is a
good thing.
What I wanted to emphasize here
is that
there is an essential need for
collaboration. I
think the whole science-based approach to
the
regulatory arena is great, and I have to
commend
the Agency in this, but they just can't
do it
alone, and I think there is an essential
need that
this collaboration occur.
It may be that with that type
of
collaboration, you know, for a long time
in
academe, we have talked about the NIH and
trying to
get them involved with supporting drug
product
research and development to little avail,
so maybe
now is the time.
Certainly, I think it is
essential that
this type of approach be taken in the
manufacturing
sciences, because it certainly will benefit,
I
think, our society, so I think it is in
the
interests of the country, so that
hopefully, the
NIH will look a little bit more favorably
on
supporting this type of research. I think the
29
collaboration between FDA and NIH may
help in doing
just this.
DR. KIBBE: Thank you.
Ken, go ahead.
DR. MORRIS: Thanks, Art.
Welcome to your
last day.
A couple of things I wanted to
say first
to Nozer's point. In the face of the data that I
think Merck generated or was generated
and then
shown to Merck, I don't think they would
need the
Agency to tell them that they needed to
pull the
drug or to modify it. They are really very
responsible about that sort of
thing. I understand
your point.
DR. SINGPURWALLA: The lawyers made them
do it.
DR. MORRIS: Well, the lawyers made them
do it, but the drug companies in general,
the
innovators of generics, when they see
problems like
that, are still I think honor bound and
have
historically done a good job of
monitoring
themselves with respect to public health when
there
30
is a clear and present public health
injury issue.
But beyond that, let me just
comment, if I
can, I have just five points here,
relatively
short.
The first is, is that the
unique
opportunity afforded by the FDA massive
database, I
think is absolutely invaluable and needs
to be
exploited to the maximum. I mean that, in my mind,
is perhaps the number one initiative in
terms of
getting down the critical pathway with
all due
deference to proprietary data, of course,
as we saw
yesterday.
There are some issues I think,
for
instance, tox, where the database would
probably
not be nearly as good as even the
sampling of the
Big Pharma companies' databases on tox,
because you
don't have the tox information on
compounds that
never made it to filing, so they may
actually have
a bigger database there, which would
really help in
the really interesting work we saw
yesterday on
modeling.
The second point is it look
from a
31
nonbiological and obviously blue collar
tablet
smasher, that there is a fairly large
disparity
between the amount of internal biological
research
versus product development research. I am not
really in a position to judge what the
priorities
in the biologicals should be. It is all obviously,
very high-caliber research.
I am not in any way commenting
on that,
nor am I capable of it, but I think it
does point
out the fact that there are developmental
research
agendas that probably would be better
handled in
part at least, or at least administered
through the
Agency, that aren't being, and we can
talk about
specifics, and have with John and you and
others,
of course.
But I think that points out an
opportunity
if you were on the critical path, and
that is the
prioritization that I was asking about
yesterday,
is that given the breadth of projects and
the
dearth of resources, I think the
prioritization,
particularly the internal research
projects,
becomes your biggest challenge and one
that I think
32
could be helped by the committee, and I
think has
been in part, hopefully, in these days.
It also points out, to
reinforce Pat's
point, and this is a little bit
self-serving, but
the amount of research that doesn't or is
not as
logically done within the Agency, needs
to find
federal support in terms of public health
initiatives, as well as the obvious
advance of just
basic science.
To address a question that
Gerry had
raised with respect to the possible
putative
consequences of sharing information,
there is a
mechanism that we have been sort of
developing,
which is to, through blinded
intermediates, to be
able to discuss general topics without
filtering.
I am not talking about
filtering data or
hiding data, but to bring data to light
to the
Agency in a blinded manner to say, you
know, is
this the sort of data that would be
useful, or is
this the sort of data that would give you
cause to
think that there was no particular reason
to review
it, and it would just be a waste of the
Agency's
33
time.
So, I think there are mechanisms to do
that.
They are not formal mechanisms, but through
consultants and whatnot, I think you have
already
got that as an opportunity, so you can't
be too
specific, of course, because once you are
too
specific, then, you have already revealed
what it
is you are asking about.
Finally, with a question of
metrics, I
think the suggestions you made yesterday,
the
multiple review cycles I think is a great
metric.
That was what the Manufacturing
Subcommittee, at
Judy's last meeting, we talked about the
idea that
in the new or the desired state, instead
of having
minimal data that the reviewers have to
try to
piece together into some sort of
Frankenstein
rationale, if you get the rationale in a
piece from
the companies with summarized supporting
data to
make it a compelling argument, then, the
reviewers
just have to assess the sufficiency of the
rationale as opposed to trying to piece
together
one on their own.
34
So, I think the review cycles
are an
excellent metric. The time to approval, of course,
is a low hanging fruit there in terms of
a metric
although it is not independent, and for
generics,
of course, that is compounded by the
workload
itself.
Maybe you could normalize it by
normalizing the time to approval to the
number of
pre-filing and pre-approval meetings, the
off-line
meetings that John talked about
yesterday, John
Simmons talked about yesterday.
The other one--and I don't know
if we have
talked about this before--is to track FDA personnel
turnover.
I think it is not a bad metric to look
at retention of the FDA reviewers
themselves. I
mean it is a very high-pressure job, it
is not all
that celebrated a position, but obviously
of key
importance.
I think that does two
things. One is it
gives us a metric of how effectively the
program
works, and the other is that it gives an
internal
metric for the personnel management, so
you don't
35
burn out your best and brightest.
DR. HUSSAIN: Ken, the whole aspect of the
critical path was in a sense that review
cycles
have really come down, so that review
cycle is not
the rate-limiting step in the critical
path. So,
there are different metrics for that
purpose.
DR. KIBBE: Marvin, do you have something
else?
DR. MEYER: A quick comment. Helen was
saying last night that on the ANDA side,
that the
generics are now, or shortly going to be,
required
to submit all studies they did, not just
the 1 out
of 12, the test.
Maybe, and this is terribly
naive because
I don't know all of the complications,
but maybe
there is some way down the line of having
the NDAs
be accompanied by a synopsis, at least,
of what
they tried and what failed, a one-pager
perhaps.
We tried doing virus filtration
this way,
and it failed because, we think it
because, and
this might be attached with the NDA, but
reviewed
independent of the NDA. There might be a
group at
36
FDA that evaluates failures, if you
will. So, some
way of getting the data to the Agency
that wouldn't
impact on the NDA and yet would provide
the Agency
with I think some valuable information.
DR. KIBBE: I am concerned that as much as
we in academia value getting all the
information,
industry values having information that
their
competitors don't have, and if they have
a lot of
failures they corrected, and they know
what
mistakes not to make, they generally
think they
have an edge on doing it right, and they
are not
really excited about turning that over to
someone
else, let them make their own mistakes
and figure
it out.
I think the time that we will
actually be
able to share all the information about
all the
drugs that have ever been approved is
when Glaxo
finishes buying everybody or Pfizer has
merged with
whoever is left, and there now is
International
Therapy Development Company.
DR. KIBBE: Ajaz, anything to wrap up
with?
Okay.
37
DR. SINGPURWALLA: Mr. Chairman, I have a
few thoughts. Ajaz, back.
[Laughter.]
DR. KIBBE: It's okay, Ajaz, you can
escape if you would like.
DR. SINGPURWALLA: Ajaz, you asked three
questions here. To be quite honest with you,
yesterday, I couldn't focus on these
because I
couldn't get my mind straight as to what
we are up
to and what is happening.
But subsequently, I think I can
answer
some of your questions very directly.
I looked at TR Critical Path
Initiative
Challenges document, and to be quite
honest with
you, I think you are on the right track,
and I
think you are thinking along the proper
lines.
Two, three things come to my mind. Your
mention or at least the mention of design
of
experiments that was discussed is one of
the right
ways to go about things.
You also mentioned the use of
bayesian
ideas. That is the best way to reduce time cycles
38
because you are taking advantage of all
other
sources of information, but you don't
want to use
that only for clinical trials, but you
want to use
it throughout the entire process. Again, you have
highlighted it, so I think again you are
on the
right track.
The one thing is you cited
examples from
manufacturing. That is fine, but I seriously
consider you also look at the area of
weapons
development. They face problems very similar to
yours and you may want to see what they
are doing
and how they are developing their
particular
processes, and the weapon development
process has
much in parallel. The two communities are very
alien to each other, but I urge you to
look into
what they are doing, and I think I can
say that you
are on the right track. You are focusing on the
issues that I would focus about, that is
all. I
wanted to reaffirm it.
DR. HUSSAIN: Thank you.
DR. KIBBE: Paul.
DR. FACKLER: Let me just offer a couple
39
of thoughts to those questions, you know,
are you
on the right track. Of course, I am speaking for
the generic industry, but it is difficult
to give
people help when they haven't asked for any,
and I
can't speak for PhRMA, and I don't know
if PhRMA
has come to the Agency and said, help, we
can't
develop new drugs.
So, I think you face a very
difficult
challenge trying to assist a process that
maybe the
people actually doing it don't feel is
broken. The
economics of drug development in 2004 is
significantly different than it was in
1994.
You know, if you have a company
selling
$50 billion in drugs a year, and they
want to grow
by, say, 5 percent, which isn't
acceptable by any
means, they need to get an additional $2
1/2
billion in revenue out of the new drugs
that they
are developing.
So, you know, a product that
has some
marginal value, say, 50- or $100 million
that would
benefit society probably just gets put in
an
envelope somewhere, and not brought
out. It is a
40
problem with the situation in industry, but I
am
not sure FDA is going to be able to do
anything to
assist that.
Let me speak to the generics
because there
was a presentation yesterday, and
speaking for the
generic industry, we have communicated
with FDA
where we think we need help. We have asked about
topical products, we have asked about
inhaled
products, biologics, of course, are an
issue, and
time to approval is a real issue for us.
So, the question was are you on
the right
track, and at least from the generic
perspective,
the answer is yes. I think you are trying to
overcome the hurdles that we face, that
would
assist us in bringing products to the
market
earlier.
I know it is not really the
main thrust of
the Critical Path Initiative, but for our
portion
of it, the answer is yes.
DR. KIBBE: Thank you, Paul.
DR. HUSSAIN: I think just the point
generics are equally important for us, so
they are
41
part of the critical path from an OPS
perspective.
DR. KIBBE: Gary.
MR. BUEHLER: Well, we have had a number
of mentions of our workload. It is significant.
We did receive 563 applications I believe
the last
fiscal year, 449 the year before, and 361
the year
before, so we are increasing by about 100
a year.
It is a bit scary, but we are
dealing with
it, and we are communicating with the
industry
significantly on what we can do to make
their
applications better and to make our
responses to
them more predictable, so that they know what
we
want.
As part of the critical path,
and we are
trying to work in providing the
information that
the industry needs to develop their
products, and
this is through the dissolution methods
and the
bioequivalence methods that we get tons
of letters.
We got over 1,000
correspondence last
year, over half of them requesting what
is the
bioequivalence method for a particular
drug, what
is the dissolution method for a
particular drug, so
42
we can begin to develop our products.
We are trying to get that up as
a
web-based program, so that they can
actually access
these methods. We have people working full time in
our office to research this information,
so we can
make it available to the firm.
Now, this isn't revolutionary
stuff. This
is stuff that we have always provided
them. We
just want to provide it to them
faster. We want to
make it easier for them to access this
information,
and we don't want to get as many
letters. The
letters that we get obviously take up our
resource
time, and we want those resources to be
put toward
application review.
We hope to be able to get these
up soon.
I know I promised them I think six months
ago to
the industry. Things are never as easy as you
would like them to be in the Agency. A lot of
people have to sign off and make sure
that we are
not giving away the farm, and we don't
want to give
away the farm, but we do want to give
away
information that is needed by the generic
industry.
43
The generic industry is a very
viable,
very robust industry right now. A lot of new
players are getting into it, a lot of
people want
to put applications in as evidenced by
our
workload.
We welcome that workload, we are glad.
This country needs generic products. A lot of
people out there can't afford
prescription drugs
out there.
So, we welcome the work and we welcome the
challenge.
DR. KIBBE: Anybody else?
Okay.
We have an opportunity now to
hear from an
absolute genius. They asked me to give a talk on
visionary overview, and I will get up
there, then,
I will pontificate for half an hour, and
I hope you
all enjoy it.
Science in Regulation -
Visionary Overview
DR. KIBBE: I need a soapbox. I have six
slides.
This is to reduce some of the slide
overload that we are suffering from. You all have
copies of these slides. You can tell that the
slides are really informative because
they are
44
filled with words. I look at slides and I say,
hey, there are 22 slides and each one has
180
words, how am I going to get through it,
so I put
up a couple of simple slides.
First, the title was given to
me by the
Agency.
I looked at it and I said Visionary
Overview, I guess they think I am a
visionary, why
would they think that. So, I thought long and hard
about why they think I am a visionary,
and I
realized it was because I live in
Pennsylvania,
which is the home of the world's most
well known
and renown visionary, the seer or all
seers, the
procrastinator for all good things,
Punxsutawney
Phil, who comes out and tells you whether
you are
going to have winter for another six
weeks or not.
I also would like to make a
disclaimer, we
do lots of disclaimers. All the ideas that I
express today are strictly my ideas, and
I would
not saddle anyone in the scientific
community and
industry over the Agency with any of
these
cockamamie ideas. So, they are all mine and
hopefully, they will stimulate your
thinking
45
without putting you completely to sleep.
So, what has the FDA and we
been doing for
the last few years? I actually went out and got a
copy of the agenda for the first meeting
I was at,
and there wasn't PAT mentioned in the
agenda, but
when you looked through the agenda, you
saw the
beginnings of what was I think a
wonderful three-
or four-year push in an area that can
significantly
impact industry's bottom line, and
hopefully, the
industry will be in a mood of generosity
and have
that bottom line, some of those savings
reflected
in the cost of goods produced.
The effort I think was an
opportunity for
me to view the way that scientists from
industry,
both the generic and innovator companies,
scientists within the FDA, and scientists
from
academia, and those consultants who serve
all of
us, could get together, look at a
problem, develop
a reasonable approach to it, something
that would
work in the community that we work in,
and really
come up with something worthwhile.
I could go on about the
successes we have
46
had, but they don't make great news, and
the news
media always wants failures and disasters
to report
on, and so I will move directly into
those.
First, is it the Agency's role
to apply
science to regulation? Of course, we all agree it
is.
The application of the scientific method to
goalpost generation for the industry is
extremely
important, and I am going to try to look
at what we
have done and where we are going, and
perhaps make
some projections out.
If we are going to regulate a
science-based industry with science,
then, we need
to use a scientific approach to where we
are going.
We all are familiar with linear
regression, and we know that there is a
certain
amount of error associated with it, but
in order to
project beyond the data that we already
have, we
have to have a significant amount of data
going
backwards to draw a line through, so that
as we go
out in the future, we get closer to the
truth.
We know that the further out in
the future
we can project, the less reliable the
answer is,
47
but we do it anyhow, and I am going to do
that.
So, where have we been in terms
of
regulating the quality of drug products
and
therapies in the United States? Of
course, we start
in 1817 with Dr. Spalding, and he decided
that we
ought to get the physicians together and
say why
can't we have quality products to give to
our
patients, let's set up some standards,
and the USP
was formed.
So, we started the regulation
of the
quality of how we treat our patients by
getting the
health care providers who treated
patients together
to decide what quality was and how to
arrive at it.
After the Civil War, the
pharmacists got
together and decided that while the USP
had
standards for individual ingredients, it
really
didn't have standards for how to mix them
together
and make them useful, so they decided to
publish
the National Formulary, and I was
instrumental in
the first edition, and I brought my copy
with me.
This is the sum total of how to
make
pharmaceuticals in 1888, and compare it
with what
48
we know today and how many shelves it
takes up, and
how controversial each little, tiny issue
is. Of
course, we also know that you have to
learn Latin
to use this, so it's dead along with the
dead
language that it is written in.
At the same time, the industry
actually
regulated itself. There was a comment made here a
little while ago, which said that lawyers
make them
do things. I would argue that in the current
litigious society, companies act slower
to remove
drugs from the market when they have
worrisome data
than they would if there wasn't a
litigious
society.
I think they worry more about
what it
means to their future class action suits
to
actually admit that there is a problem
until they
have all their lawyers lined up, so they
know how
to defend themselves, and if they weren't
worried
about the fact that the American public
has an
exaggerated misconception of what drugs
do and
work, they would act quicker.
I think the American public in
general
49
expects drugs to be safe and effective,
and they
don't recognize that drugs can be safe
and
effective if used correctly, but in the
wrong way,
are dangerous and shouldn't be used, and
they don't
get that.
They just don't get it.
I put E.R. Squibb down because
I know a
little bit about E.R. Squibb as an example
of the
leadership that the industry had back in
the 19th
century.
Dr. Squibb, a physician, wanted a higher
quality ether for anesthesia. This was an
extremely important drug in those days,
and so he
founded a company for the express
purposes of
making sure he had high quality ether.
He built it in Brooklyn, and
then his
company started making other things and
then he
noticed that there were other companies
that were
copying his products, calling them the
same thing
and putting them out there less
expensively, and he
said the public might be at risk if they
aren't
made correctly.
So, he did something unique
which I don't
think any of the companies would do
today. He got
50
all his formulas together, how he made
everything,
and he published them in the Journal of
the
American Pharmaceutical Association with
the
proviso that if anybody wanted to make a
product
that E.R. Squibb sold, they should make
it the way
we make it, so it would be of the same
quality, so
at least the public would have a good
quality
product, and if they could make it less
expensively
than we could, good luck to them.
Well, I wonder how many
companies are
ready to jump into that game. At that same time,
of course, Eli Lilly was producing well
over 100
generic products. It was the largest generic
manufacturer in the United States. It produced
everything that could be made that was
listed in
the USP or NF, extracts, and what have
you. It was
an interesting time.
Now we get into government
regulation.
Now, why did the government get into
regulation?
Well, it bought quinine that wasn't
quinine and it
got upset. So, in 1848, with the troops attacking
Mexico City, their quinine didn't work
like it was
51
supposed to, they said what's in here, it
wasn't
quinine, it was something else, I don't
know what
it was.
They said that's terrible,
terrible,
terrible, and so we needed to find a way
to make
sure that when something was labeled
quinine, it
really was indeed quinine. That was the first shot
out of the cannon.
We finally had the Food and
Drug Act of
1906, which really just said that if you
are going
to sell something and call it a drug, and
name it,
it ought to be what you call it. Right about that
time we got into the concept of
misbranding, which
was putting something in something and
calling it
something that it wasn't, and that is
basically
what misbranding is.
We have a lot of meetings for
misbranding
now, but the bottom line is that it is
not what it
is supposed to have been.
The Agency wasn't really
founded then, but
the government said that if we wanted to
take
action against the company that
misbranded a drug,
52
that it was incumbent upon the government
to prove
that the drug was indeed not what it said
it was,
and that there was intent to
defraud. If you do
that to the government, we can't enforce
any
quality on anybody, because we don't have
any
information to use for it.
But I want you to remember that
concept
that came about in the early 1900s,
because when we
get to the end of the 1900s, we have
another law
that brought us right back to that place.
So, 1938, we killed a bunch of
kids in the
New York City area with antifreeze as a
sweetening
agent in a sulfa drug preparation. That was the
end of a company's reputation, and well
it should
have been, and everybody was in an
uproar, so we
now have a new regulation. You will notice the
trend here - disaster, new regulation,
disaster,
new regulation. It's kind of a recurring theme.
So, we know said, okay, it has
to be what
it says it is, it has to contain what it
says it
contains, and it has to be safe, but it
doesn't
have to work.
53
Homeopathic remedies are
exactly that.
They are 1 to 100 dilutions of something
done 1,000
times.
You end up with a bottle of water, which
they claim contains the essence of the
power of
whatever drug was in the first bottle of
1,000
dilutions before. All right.
So, we can claim it
works, and it contains a diluted,
diluted, diluted,
fine, that is what it really
contains. You can't
find a molecule because you have diluted
more than
Avargordo's number, so we have products
on the
market.
By the way, the Food, Drug, and
Cosmetic
Act says specifically that drugs are
things that
are contained in the homeopathic
pharmacopeia,
which means that they are precluded from
acting
against products that are in the
homeopathic
pharmacopeia even though we know they
don't work.
We are still working with
things that are
just safe, but at least they are branded
right, you
know.
Nowadays we have people who claim that water
solves medical conditions. What the heck, you
know, 1938, that would have worked, put a
label on
54
water, say, if you will bottle water and
pay for it
at a rate higher than you pay for
gasoline, then,
it is better for you than the water you
get for
free out of the tap, and you will do
better.
Well, I don't know, I wonder
about things
like that. I have a problem my students always
complain about. I have one of those minds that
kind of wanders, and so I do that.
Let's get back to misspelled
words and
regulation. So, in 1951, two pharmacists
got
together, a guy named Carl Durham and a
guy named
Hubert Horatio Humphrey--I love his
name. They
were pharmacists. One was in Congress and one was
in the Senate. Hubert came from Minnesota. He
ultimately became vice president, ran for
president, didn't make it.
I often wonder what would
happen if the
president of the United States was really
a
physician or a pharmacist, a health care
worker,
what difference that would make in their
approach
to the health care problems.
So, they got together and they
said, you
55
know, there is a lot of drugs out there
that are
pretty dangerous, that the average person
really
can't understand, and maybe we ought to
have
somebody help them figure out what to
take, so they
established two criteria, prescription
drugs and
over-the-counter drugs. We still, by the way,
don't have to have them work. You know, God
forbid, they actually should work.
We are a unique country among
the
developed nations of the world. We only have two
categories of drugs. Most of them have
many more
categories of different levels, and, in
fact, I
like the Australian system. They are listed in the
group of things they call poisons, so we
clearly
know where they belong, right? They are the poison
list.
In 1962, we finally got around
to hoping
that we could figure out that the drugs
were both
safe and effective, so in 1962, we said,
okay, new
drugs have to be safe and effective. The Agency
was kind of curious. It said, but you can't tell
people that this is an approved drug,
because that
56
gives you a marketing advantage over the
drugs that
haven't been approved by us, and then we
don't know
are effective. Hmm, that's interesting.
Then, Congress, in its infinite
wisdom,
jumped right in there with DSHEA, and
DSHEA says
that if you aren't really a drug, but
kind of imply
that you are a drug, then, you can go
back to the
1906 regulation which says that it only
has to be
what it says it is, and it doesn't have
to be
proven to be safe or effective, and if
there is any
problems with it, the Agency has to
compile the
data before they can make you take it off
the
market.
I just love that, you know, retrograde
regulation, I just wonder about the
wisdom of that.
I am sure it has to do with the need that
the
public has for unsubstantiated claimed
herbal
remedies.
All right. Here is where we really get to
where the rubber meets the road, and that
is the
cost of drugs. I grew up in a pharmacy family. My
father was a pharmacist, my uncle was a
pharmacist,
I became a pharmacist because I didn't
know
57
anything else.
I grew up in a drugstore, and
when I was
at
a young age, I worked in my father's drugstore
as a soda jerk. Some people think that I
have never
gotten over the second half of that.
But in those days, the average
cost of
drugs that my father filled--he has a
wonderful
ledger, handwritten in ink pen where he
wrote down
the name of the patient, the
prescription, the
physician, and then the cost--and if you
look at
it, you will find that the average charge
to his
patient was $1.75.
I asked him one day, being a
nosy
teenager, how do we make money to live on
at the
store here, and he says, "Well, I
charge $1.75, but
it costs me about 25 cents of
goods." So, I said I
thought that was pretty good.
Of course, nowadays, the
average charge of
a prescription can be in the $50 or $60
range, and
the pharmacy gets $3.50. There has been a shift
here somewhere.
At that time, Tetracycline came
out. It
58
was about 50 cents a capsule. The price of
Tetracycline has gone down dramatically,
but we
keep bringing out new drugs, and I think
each time
we bring out a new drug, we say what was
the price
that we charged for the last new drug,
and we
multiply by 1.5.
You also understand that there
is
absolutely no relationship between the
charge for
the drug and the cost of actually
manufacturing it,
and that they factor in all of the other
costs to
maintain the corporate entity that
creates new
drugs.
So, they need to have this huge inflow of
money in order to float all of the
research and the
marketing, and all the other efforts that
go on,
and so that there is some disconnect.
Waxman and Hatch got
together. We
recognized back in the 1980s that the
cost of
health care was going up quickly. Uwe Reinhardt
has a wonderful graph that he puts up, a
Princeton
economist, that shows the gross national
product
and its rate of increase and the cost of
health
care and its rate of increase, and then
he predicts
59
some date in the future where the two
will meet.
Then, he has a cartoon where he
has two
physicians lying in beds in the hospital
together,
prescribing for each other, and he said
that is
going to be the entire productivity of
the United
States is going to be this.
So, we know that there is a
disaster in
the future and what are we going to do
about it,
and we have a culture in the United
States where we
don't regulate the price of drugs. We are again
unique.
Very few developed countries have that
compunction. So, we try to regulate it through
competition.
So, the Waxman-Hatch Act or the
Hatch-Waxman Act, depending on whether
you are a
Republican or a Democrat, came into
being, and it
was a compromise that was supposed to
benefit the
innovator companies by ensuring them a
reasonable
patent extension or exclusivity time
frame in order
to recoup the investment to bring the new
drug to
the market, and established rules and
regulations
for the development of generic drugs.
60
It seems to work in some areas
and we hope
for the best. However, it is not going to be the
end of the issue, and if we start to make
projections out in the future, we are
going to have
to do more than that in terms of cost,
but it was
the first time that the FDA was an active
participant in controlling costs.
I think I see that as something
going
forward.
We have a problem, of course, with other
issues associated with cost, and, of
course, here
comes re-importation, and we are going to
get into
that in a little bit, but I don't want to
beat a
dead horse.
My wife is Canadian and my
inlaws are in
Canada, and they see the U.S. news come
across that
says that Canadian drugs are bad for
American
citizens, and they say, oh, and they call
their
son-in-law, the expert, and they say,
"What's wrong
with Canadian drugs?" Of course, i am hard pressed
to say anything about it, because there
is nothing
wrong with Canadian drugs. So, that makes an
interesting argument. I think we can go down that
61
road as long as we want.
I think the next level of
regulation is
going to be the line on top. People are going to
want information that shows that the next
new drug
is not only safe and effective, but
better. I
don't know how long it is going to take for
Congress to do that, but that is what is
coming.
We have a history of producing
lots of
drugs that might be different, but not
necessarily
an improvement, where are we going to go,
and I
think both the industry and the Agency
should be
prepared to think about how they would
handle that
situation.
Remember that we are trying to
regulate
according to best science, and sometimes
we lose
track of best science. There are some classic
equations that we use that we depend upon
to help
us decide what is good science. One is the
Noyes-Whitney expression. The Noyes-Whitney
expression describes dissolution profile,
and it
was developed by these gentlemen using a
very
interesting standard material. It was a fused
62
cylinder of material.
So, their apparatus and how
they did it
were standardized based on one solid hunk
of an
individual chemical in the cylindrical
form, so
they could accurately determine the area
exposed to
the fluid and therefore, from it,
determine all of
the
equations. Nowadays we use a
standardized
compressed tablet. I would argue that the
dissolution apparatus is probably less
variable
than an individual tablet coming off a
tablet run.
If you wanted to standardize an
apparatus,
you ought to standardize it with
something which is
less variable than the apparatus you are
standardizing. I wonder about that. I guess we
could ask our colleagues down the street
what they
think about that, but let's go back to
the basic
science and figure out what is going on.
The other one I like to talk
about
occasionally is Arrhenius. Arrhenius developed a
relationship between temperature and rate
of
reaction that was developed for reactions
that
happened in dilute solutions.
63
We apply them, same rules, too,
tablets,
ointments, creams, and lotions. We put things
aside for three months at elevated
temperature, and
we say this is going to predict what is
going on in
two years. We will give you two years, just send
us the real data later. I would argue that if we
went through the data that the Agency
has, that we
would be hard pressed to get a
correlation
coefficient much over 0.3 for that data.
The other thing is what is the
rule and
regulation. When a rule or regulation gets out
there and purports to be doing something, and
it
doesn't, it makes you wonder. We have a regulation
that says you have to do accelerated
stability at
40 degrees and 75 percent relative
humidity, but
you can take the humidity and temperature
chamber
and you can put in it a tablet container
that is
sealed with a descant in it and do the
study.
That is kind of like saying
let's see how
fast ice cream can melt in the kitchen,
but you are
allowed to put it in the freezer. I wonder, you
know, I just wonder. I am just kind of curious
64
about those kinds of things. You sit around in an
academic office, you are a tenured full
professor,
what are they going to do. You wonder about those
things.
I think that there is going to
be a lot of
international regulation. I think that we are at
the stage where the companies are truly
international. The largest provider of generic
drugs in the United States is in Tel
Aviv. Most of
the big developmental innovator companies
are
really housed everywhere.
In fact, the numbers of workers
at
pharmaceutical plants in the world has
shifted from
the United States out. If that is true,
then, we
really have to have cooperative control
on quality.
I am sure that England and Germany and
France want
the same high quality of drugs as we do,
as the
Canadian Health Protection Branch insists
that they
do.
So, we need to go in the
direction of what
is truly a harmonized or
internationalized
regulation of quality. We need to somehow control
65
the cost to the consumer, and if we don't
find a
way to do that, it will be imposed on us.
One of the problems I have with
all of
this is that drug costs to consumer seems
to make
the news way more than the cost of a bed
in the
hospital.
Now, I will just ask you, how much does
it cost to be in a hospital bed. Does anyone know?
No, but you sure know how much it costs
for a
bottle of Viagra--oh, excuse me.
DR. SINGPURWALLA: I don't.
DR. KIBBE: Oh, there is a man with
confidence.
[Laughter.]
DR. KIBBE: The reason is that most of us
in the public are covered by some
insurance plan
that covers the cost of the hospital bed,
but we
aren't covered by drugs, and drugs
represent 8 to
10 percent of the total cost of health
care in the
United States, and if you look at it, it
is much
cheaper to give reasonably expensive
drugs to
patients than to put them in a
hospital. But the
patients don't pay for it out of pocket.
66
I wonder why the huge lobbying
efforts of
the pharmaceutical company isn't applied
to getting
drugs covered by Medicare and Medicaid
instead of
anything else. If they could ever do
that, they
could forget about the arguments in the
newspaper
about the cost of drugs.
I am sure there is lots of
economic issues
associated with that.
The last three things I have
are
continuous quality improvement, PAT, and
federally-funded efficacy testing. I don't know
whether we are going to get the right to
demand
that you do an efficacy test against
seven or eight
of your competitors in order to get
approval, but I
think that the world deserves a chance to
look at
what is those relative efficacies in an
abstract or
at least impartial way.
PAT has been fun for me. I think it's a
wonderful initiative, it has its own
journal now,
those of you who are interested in
it. It has got
a forward written by--oh, my
heavens--Ajaz. It has
some beautiful pictures in here.
67
I went through it immediately
and wanted
to see if I knew anybody that actually
was involved
in PAT, and there is a whole bunch of
really pretty
pictures of all sorts of people that were
actually
on the committee with it, if anybody is
interested
in
it. I thought that was pretty neat.
I think that there are things
in the
horizon that really threaten the way we
do business
both at the industrial level and at the
regulatory
level.
One of them is the development of
nanotechnology and computational power.
We are looking forward to a
singularity in
computational power, a point beyond which
we cannot
predict or even understand the
future. In
approximately 2014 or 15, the computer on
your desk
will have not only digital computational
power, but
parallel processing, and will be able to
think
better than you can. We will be able to process
data, come up with new ideas, and, in
fact, at some
point in time, it will be the most
intelligent
being on the planet, and we humans will
relegate
ourselves to second place.
68
When that happens, what do we
do about
health care? And let's look at nanobots and what
they can do. If aging is truly a degradation of
the DNA strand within people, if we can
inject
nanobots who know how to count DNA
strands and
repair them, how are we going to age?
If we have the capacity to scan
individual
molecules and relationship in the neural
net, can
we then scan down a person's entire
knowledge base
and personality, and shift it from a
carbon-based,
short term, to a silicon-based, long term holding
facility?
How many of us would be willing
at the
ends of our days to become virtual us in
a virtual
environment?
Where are we going? Challenges to the
FDA.
In our experience over the last several
millennium, an ever- increasing rate of
new
technological development. It was 20,000 years
from the time we developed hand-held rock
until we
actually made a bow and arrow with a
processed
rock, and the rate at which we develop
things now
69
is astronomical.
We need to have improved
productivity in
the industry, but that needs to be
related to an
improvement in the cost of goods sold to
the
American public, and the Agency needs to
maintain
public confidence. It needs to not say things that
are clearly difficult to defend in the
public
environment.
It needs to be responsive to the
public needs and realistic, so that the
public
understands the expectations of drugs.
If there was any advertising
that the
Agency could do, that I think would help
in the
long run, it is to get the American
public to
understand that drugs are not safe, that
they can
be used safely.
The American public has an
unrealistic
expectation for their medications and an
unrealistic expectation of how they
should feel as
they go through life, and they expect
that these
little pills will do it for them, and it
won't, and
we need to get them to stop thinking that
way.
We need to maintain and improve
70
international cooperation in both
regulation and
harmonization, and we need to, in the
final
analysis, decriminalize Grandma. When she crosses
the border to pick up drugs, she needs to
understand that we don't think that she
is
committing a heinous crime against
society, that we
understand that the economics are driving
her to
it, and we need to find a way of making
it happen
for
her, so that she can get the drugs she needs at
the price she can afford.
Does anybody have any
questions?
[Applause.]
DR. KIBBE: Thank you, Dr. Kibbe, for that
exhilarating presentation. I am sorry, I just love
those kinds of things.
Now, we are going to get into
some serious
stuff here, because Ajaz is going to get
up to the
podium.
DR. HUSSAIN: Could we just take a break
now
and then start after the break?
DR. KIBBE: I am still fired up, you know,
whatever you want to do. You know the energy level
71
after making a presentation. I really want to
complain about the lack of a
soapbox. I asked for
a soapbox up there because I knew I was
going to
get on my soapbox.
Ajaz wants to take a
break. Let's try to
get back and get back to work at two
minutes to
10:00.
[Recess.]
DR. KIBBE: We have comments on my talk
that some members would like to make, and
then I am
going to be more than happy to add to my
talk a few
other issues, so we might have a lot of
fun today.
As is the tradition with this
year's
committee, Nozer has a comment.
DR. SINGPURWALLA: I don't have a comment,
I have a question for you. The question is what
would your reaction be to the idea of
nationalizing
the drug industry?
DR. KIBBE: That is a wonderful question
and I think the answer to it resides with
our
colleagues over there. I know that if they ever
did that, I would volunteer to be drug
czar. There
72
are a couple of issues that I didn't hit
on in my
thing.
One of them is direct-to-consumer
advertising. I think the issue of why the public
has the misconception that drugs are not
safe can
be tied directly to direct-to-consumer
advertising.
Many years ago, in my one
opportunity to
appear on the Today Show, I was
interviewed by
Debra Norville on the topic, and I was
debating an
industry representative, and I said that
it would
completely change the dynamics of
prescribing and
using of drugs in the United States, and
I think it
has.
Two days ago, I was sitting at home
watching TV, and for an hour and a half,
every
single ad on TV, every single ad was for
a
prescription drug, and it just has to
have a
dramatic effect on the way patients
interact with
their physician and how they get health
care. I
think it was a mistake, but we can
comment on that,
too.
Does anybody want to throw a
few cents'
worth in while we are prognosticating?
73
MR. CLARK: You mentioned something about
E.R. Squibb challenging the world to meet
his
efficiency in his products that he
manufactured. I
was just trying to point out that while
he
challenged the world, that challenge
could prove
fatal today, because today, Mr. Squibb or
Dr.
Squibb would be required to freeze his
manufacturing technique, whatever it may
have been,
and that while his challengers came in
with new
techniques, he would be burdened with an
approval
process that would slow down his ability
to
compete, and we should be able to create
a
regulatory environment that protects the
public as
it still encourages innovation, and not
just
encourages the innovation for
innovation's sake,
but encourages applying it to the
products and to
improve the entire environment.
DR. KIBBE: Clearly, he couldn't do what
he did then now, because the Federal
Government is
in his business now.
MR. CLARK: Exactly.
DR. KIBBE: And that has happened after
74
World War II. Before World War II, the Federal
Government stayed out of everybody's
business, and
that is a dramatic change in the way we
do business
in the United States.
We need to get to the desired
state--I
recommend Pennsylvania, far less
hurricanes--the
desired state, however, is going to be
defined by
Ajaz.
The "Desired
State" of Science and
Risk-based Regulatory
Policies
DR. HUSSAIN: I will do it from here. In
a sense, what we wanted to do, sort of
build on the
Manufacturing Committee discussion that
was
reported quite elaborately by Judy
Boehlert, the
chair of that committee, but to sort of
now do a
gap analysis, what we see as gaps between
the
current state and the desired state from
an
internal FDA perspective, what are the
challenges
we face internally, and get your feedback
on that.
So, what we have are three
presentations,
one, Helen will sort of look at the
organizational
issues, I will try to identify some of
the
75
scientific gaps, and Jon will identify
some of the
policy gaps and how we intend to sort of
fill those
gaps.
If you could sort of give us
feedback on
are we missing in our gap analysis, it is
a
preliminary gap analysis right now, and
then how we
proceed, and then this will be followed
by
discussions and presentations by PhRMA
and GPhA
perspective on how they see the progress
we have
made and some of the challenges that
remain.
So, that is the discussion for
this
morning.
DR. KIBBE: That means you are passing the
ball to Helen.
DR. HUSSAIN: Yes.
DR. KIBBE: Let's see how you follow my
act.
Organizational Gap
Analysis
MS. WINKLE: Believe me, in 100 years, not
only could I not only follow your act, I
wouldn't
know where to begin, and my topic is so
boring
anyway.
76
I am going to talk about
organizational
gap in the Agency right now as far as the
desired
state is concerned, and as Ajaz said,
this is sort
of a follow-up to some of the things we
talked
about at the Manufacturing Subcommittee,
and I
think it is really important that we look
at these
gaps and talk more about them, and sort
of discuss
how we can possibly fill some of them.
I have some ideas on filling on
some of
them, but I think there is a lot more
that we will
need.
DR. KIBBE: There appears to be a gap in
the computational problem, too.
[Pause.]
DR. KIBBE: We are passing around a
transportation note for people who need
help to get
to the airport.
MS. WINKLE: Is everybody leaving now?
Gosh, you could at least have given me a
chance.
[Laughter.]
MS. WINKLE: As I said, I am going to talk
about the organizational gaps and
reaching the
77
desired state, and I wanted to start off
with, just
a second, showing you the organizational
chart of
OPS, because I think as I talk about
organizational
gaps, you need to know a little bit about
what the
organization looks like, and I think you
have a
good idea, but I just wanted to point out
we do
have four offices.
You actually heard from all
four of those
offices yesterday, but you say, in
yellow, where
the CMC is done in all four offices, so
almost
every part of the organization in some
way is
affected by the changes that are being
made by the
new paradigm and what we are trying to
accomplish
with the desired gap, which complicates
the issues
somewhat.
It is very important as we look
at the
organizational gaps that it is
multi-dimensional,
it goes across all of the
organization. It is
between organizations and it is within
organizations. There is lots of gaps here and we
need to look at all of these gaps and
figure out
how we are going to handle them.
78
It is outside of OPS and other
parts of
CDER.
We really do a lot of work with products
with devices with CBER, so we need to be
sure that
those gaps are closed as we move forward
in trying
to accomplish the desired state.
So, basically, what I am going
to be
talking about here is what we need to
consider and
resolve in our process or processes
before we can
adequately implement regulatory direction
and
support through applications process and
review of
what we are calling the desired state.
I also want to point out as I
talk, and
you will see this a lot, that the
organizational
gaps that I am going to point out really
intersect
with the science gaps that Ajaz is going
to talk
about and the policy gaps that Jon is
going to talk
about, and you probably can't really
address any of
these separately although that is what we
are
making an attempt to do here. But again as I go
through the organizational gaps, you will
see a lot
of the intersections.
What constitutes the gap in OPS
and what
79
are actually the process issues for
implementing
the desired state, and how we will review
at
different levels? This is really some of what we
need to talk about.
One of the big problems here is
the
appropriate utilization and focus of
available
resources. I am reading it wrong. This is why I
am having problems. It is the resources. We have
a lot of human resources. You have already heard
some of the issues that we have had with
how to use
our best resources and how to focus those
resources
on those issues that are most
important. So, that
is really one of the things that we have
as part of
the gap.
We are not always focused on
those issues
which are the most important, and we
don't always
have the science expertise available to
focus on
the gaps or focus on the issues
correctly. So,
this is a big gap that we have across the
entire
organization.
There is a difference in
products and
regulatory requirements and review
processes. We
80
are regulating ANDAs, NDAs, and BLAs, and
BLAs even
fall under a different act than the ANDAs
and the
NDAs.
So, there are some complications and some
gaps there that we are going to have to
look at and
determine how best to handle.
The organizational structure,
the way it
is set up really creates a really large
gap in how
we are going to move forward.
I think we have made it clear
in the past
that in ONDC, I know Moheb has talked
about this at
different times, Dr. Nasr has talked
about this at
different times, that we have chemists
from the
Office of New Drug Chemistry that are
located in
the different clinical divisions, so that
we lack
consistency in how they make decisions often,
because it is done outside of the whole
chemistry
structure, so to speak. It is done within the
Clinical Division, and we also lack the
flexibility
of being able to use our staff and to
utilize the
science and the staff because of these
collocations.
Actually, we have chemists in
18 different
81
teams across the Clinical Divisions, and
they very
rarely interact with each other, so it
really
causes a lot of complications in how we
do our
work, and it will cause even more
complications
when we get into the new paradigm.
I think one of the main gaps is
that we
are very process driven, not science
driven. This
goes back to the earlier comment by Dr.
Kibbe. We
are regulating a science industry. It is a science
industry that we are regulating through
process.
Some of the things that contribute
to this
is PDUFA in generic drugs, first in,
first
reviewed.
We have a tiered approach to our
reviews.
We have heavy backlogs. I think
that
Gary has made that point several times to
this
committee. The workloads are big, the backlogs are
big.
So, that is really driving us, too, to focus
more on process than science. So, this is causing
us to really have to rethink how we want
to do
things.
Part of what is adding to that
workload
and to the backlog is that we get too
many
82
supplements. We require supplements on little
changes that really have no significance
in the
manufacturing process.
Also, part of the gap is the
interaction
with inspection. We have a lack of appropriate
reviewer involvement, and we get no
feedback. We
do not get copies of 483s. Once they have been in
to the industry with the observations, we
don't
even have any correspondence in most
cases with the
inspection people on things that they
find when
they go out on inspections.
So, how you are supposed to
really have
knowledge about the products that you are
reviewing
in the future or where you can use that
knowledge
that has been gathered and incorporate
that into
your thinking about reviews and products,
you can't
do, so that really creates a lot of gaps.
One of the things that is going
to create
a gap in the future is the possibility of
having a
two-tiered system. As we talk about the
desired
state, as we talk about the things that
are
required under the desired state, we
don't have
83
regulations that are going to require
manufacturers
to submit pharmaceutical development
information.
We don't have regulations that are going
to require
them to do this thing or that thing, and
in some
places, I am not even sure we have the
carrot to
encourage them to do that.
So, you are going to have some
companies
that are naturally going to submit this
stuff, or
naturally going to move toward PAT and
toward other
aspects of improving on their
manufacture, but you
are going to have companies that don't,
so what we
are looking at is the possibility of having
a
two-tiered system which is going to
create a gap
even within one reviewer.
He is going to have to be able
to look at
both tiers and make decisions, and this
is going to
complicate issues a lot when we move
ahead.
We use guidances to accomplish
consistency, and those guidances are
sometimes very
prescriptive, and this adds to the whole
gap, and
also not only are we using guidances for
consistency, they are also up for
interpretation.
84
Unless they are prescriptive, they are
interpreted
differently by different people, so
obviously, we
have some concerns about this.
Organizational components are too
reactive, and not proactive. Now, this is caused
by workload, and the workload continues
to
perpetuate the problem.
You have to be reactive because
you have
so much work piled up in your In box that
that is
what you have to focus on, and it is very
hard to
be creative and innovative and think
about those
issues and problems that you are going to
have down
the road, think about, as Dr. Kibbe was
talking,
new therapeutics that are coming along or
new novel
delivery systems or different things like
that, too
busy moving the freight from day to day.
Use of available scientific
expertise and
scientific collaboration. Often within especially
in ONDC, because they are broken up
according to
the clinical divisions, you may not have
the
necessary scientific expertise to look at
an issue,
to look at a problem, to know really what
the right
85
direction is for making a decision on a
product.
Also, we do not go out and use
a lot of
scientific collaboration. I mean we have a lot of
SGEs, we have several in this room that
are helping
us on different scientific issues of a
broader
nature, but we could be taking advantage
of some of
those and calling and getting more
information in
the future.
There is a challenge in focusing on the
appropriate questions or what are the
right
questions. Reviewers have a tendency--and this is
not any kind of negative against
reviewers--but
they do have a tendency to look at all
the data
that is provided, and we have not focused
down on
what the appropriate data is, and,
therefore, the
appropriate questions that we need to
have
answered.
We have a lack of utilization
of
appropriate tools. We could be using statistics
more, all of us, to get better answers to
some of
the questions that we have around
review. There
are other tools, as well, that we could
be using
86
that we are not. One of the big areas I think that
causes a gap is the lack of communication
between
disciplines, but I do want to add to
this, there is
also a lack of communication between
organizations
or
components of the organization, and this is one
of the things that we need to focus on to
help
close the gap.
So, I did take a look at what
we had done
so far for closing the gap, because I
think it is
important to emphasize some of the stuff,
because
we do realize that we have some big gaps
here.
I do want to upfront say,
though, that
these are not all of things that we need
to do. I
know that there is a lot more down the
road that is
going to come along, and I am really
looking for
advice from the Advisory Committee as to
some of
the things that we need to be thinking
more
carefully about, or make suggestions for
some of
the things that we could be doing to help
close
this organizational gap.
One of the things we have been
doing is
making some structural changes in the
organization
87
In
the Office of New Drug Chemistry, which Judy
talked about yesterday for the
Manufacturing
Subcommittee, we are reorganizing the
Office of New
Drug Chemistry. We are actually doing away with
the collocation and making one Office of
Chemistry
when we move to White Oak.
We feel that this is going to
give us a
lot of consistency or at least more
consistency,
and give us the opportunity to have more
flexibility as to how we look at the
review
process.
We feel that this is going to have some
real advantages to us.
We are also, in our Office of
Generic
Drugs, we have set up a third division
for doing
chemistry. The workload is so heavy in the office
that we felt like if we had more
divisions where we
could spend more time and focus more on
some of the
issues, that we could help in some of the
gap
problems, having reviewers on inspections
or as
consultants to inspection, so have
complete
knowledge on products and the results of
inspections.
88
This is something that we have
been
working on. We have been working with our Office
of Compliance and with our field
component. We
feel like we would like to have reviewers
on
inspection. We think it is very important for them
to go out and provide some of the
scientific
knowledge to the inspectors as the
inspections are
being done, but I don't think that part
of the
question even came up yesterday on
resources to do
this.
This is a resource issue. You are taking
people away from their desk to go and--we
have
already talked about the workload being
high--taking people away from the desk to
go out on
inspections and spend time away from
their desks,
but also this is costly, and like it or
not, we are
not flush with money, so we won't be able
to do
this in every inspection.
But I do think it is important
that before
the inspections are done, even though the
reviewers
can't go out, that they provide
consultation to the
inspectors and talk about some of the
issues that
89
they have seen in the reviews of these
particular
companies and give them some advice on
what they
may want to focus on more in the
inspections.
One of the big things that is
really
necessary, in my mind, to closing the
gaps, and
again this sort of goes across the whole
concept of
the science gap and the guidance gap, and
our
policy gap, as well, is that we have a
lot of
questions we still need to answer and
address.
This is only a few of them, but
I think
there is a lot of things that we have not
come to
grips with on manufacturing science and
how that is
going to affect our review and what our
review
process is going to be to handle these
things in
the future - things like quality overall
summaries.
Dr. Nasr talks about
incorporating this
into the process of ONDC. We have not come to any
conclusions on this. We are still in the proposal
stage.
We need to decide, if this is the direction
we want to go, what is the benefit of it
to us, to
the industry, and what we really need to
see in
that QOS.
So, that is a question that we need to
90
look at.
What we need in the way of
pharmaceutical
development information. There is a lot of
information that these companies have in
the
pharmaceutical development arena, and do
we want
all of that information. If we get that
information, what are we supposed to look
at, what
would we focus on. We need to answer those
questions, it is very important, before
we start
asking for this information.
We have to have addressed that
before, I
think, companies are going to feel
comfortable in
providing it. I think many companies see this as
just more information they are sending us
to look
at and more questions they are going to
get from
us, so we really have to develop our
processes.
We also need to look at things
like how
industry will determine critical
attributes, so as
we look toward the desired state, that we
are able
to regulate that and include those in our
process,
and we need to know in all these cases
what we will
do as far as reviewing these.
91
This is just a small part of
the
questions, I think, that we need to be
addressing.
Also, as far as closing the
gap, we need
to have a better understanding of what
constitutes
the design space across all products, and
once we
have a good feel about that, or
understand that, we
need to know when notification to FDA is
necessary
for change in manufacturing.
We have not reached these
conclusions yet,
and we need to have working groups,
whatever it
takes, to really develop our own internal
thinking
on this and work with industry to make
sure that
the direction we are going is going to be
useful to
them.
We need to have a better
understanding of
what risk for a product is and develop a
systematic
risk approach to review processes. I keep seeing
time and time again, people talk about
risk
management or risk processes, and stuff
like that.
I think when you talk about risk
management, you
are talking about something different for
every
person.
92
I mean what is in my mind, what
is in
everybody else's mind in this room could
be
entirely different, and we at the Agency
need to
narrow down as far as review is
concerned, decide
what that means, how we are going to use it,
and
have a very, very concise program for
ensuring that
we do look at this in a fair and
equitable way.
Guidances. Again, Jon is going to talk
about guidances, but it is really
necessary for us
to go back. This will help us close the
gap, but we
need to go back and look at our
guidance. We have
many guidances out there that are
outdated, many
guidances that are overly prescriptive,
many
guidances that don't fit into the new
paradigm at
all.
Jon is in the process, he and
his staff,
of going through the guidances, removing
some,
redoing some, and looking at what
guidances we will
need for the future in order to
incorporate some of
the changes.
Training. This goes to the question Mel
asked, training, training, training is
necessary
93
here.
We have so much to train. We are
doing some
training, and I will talk about some of
that, but I
think it is really important and part of
what we
need to do to close the gap, is determine
what
really training our reviewers need and
what
training is necessary for the industry,
and I don't
think we have come to those conclusions
yet.
We need to determine how we are
going to
work under a two-tiered system if, in
fact, that is
the direction that we go, and we need to
have
developed the processes for doing
that. We need to
develop an internal system for handling
differences
in Review Divisions.
I met a couple of months ago
with PhRMA on
a RAC Committee on a dialogue session,
and this was
one of the things that came up was the
need for a
dispute resolution process, some kind of
mechanism
where, when there are differences in
review, that
we are able to handle those decisions and
get
information out as to how these issues
are
resolved.
The last thing I have on
here--and
94
actually, I wrote this slide before we
even had
some of the conversations yesterday--was
what is
really important is we need to have
appropriate
metrics for measuring things.
Today, in the review, we
measure by what
we accomplish, how many supplements we
get. Well,
let me tell you when you are measuring
supplements,
and that is an indication of how good you
are doing
your job, you are going to want more
supplements.
We have got to really back off
of the
metrics that we currently have and look
for those
appropriate metrics to help close these
gaps.
So, some of the current steps
we have
across OPS, we mentioned before that we
are setting
up a working group under the
Manufacturing
Subcommittee of the Advisory Committee to
begin to
address many of these questions that we
have. We
are also setting up some CRADAs to get
some case
studies to help us, too, in getting a
better
understanding of these issues and how we
are going
to handle them in our processes.
ICH, too, is going to be an
important part
95
of helping us handle some of our
organizational
decisions especially Q8 as it looks at
the desired
state and implement some guidelines on
it.
We are doing some
workshops. We have a
Workshop of Specification Setting and
looking at
how we need to have a mechanistic understanding
of
setting specifications in line with the
direction
that we are going.
That particular workshop is set
up in
March, but I will be upfront with the
fact that I
think there is still going to be issues that
come
out of that workshop where we are going
to have to
look more specifically at some of the
specification
areas and really dig deeper into them, so
I really
anticipate more workshops than this just
in the
area of specifications, but I think a
number of
workshops are on the horizon in order for
us to be
able to address many of these questions.
I actually think, too, one of
the things
that we are probably looking at having a
workshop
on is quality overall summaries. If that is the
direction we want to go, I think we need
input from
96
the industry and others, so that we have
a better
understanding of what we need for using
that type
of process and what it means to us in the
industry
when we do.
We already have some
collaboration with
academics. As I said, we are involved in
several
CRADAs or in the development of several
CRADAs. I
think these are going to be very helpful
for us in
getting a better understanding of some of
the areas
that we need to, or some of the questions
we need
to, answer, so that we can fill some of
those gaps,
and we have been doing some work with the
Product
Quality Research Institute.
As I already said, we have an
internal
review of our current guidances, which is
very
important to helping us have the
appropriate
guidances out there. We are developing a program
for team interactions for inspections.
We are sort of basing this on
how we have
handled PAT and the team approach, and we
are
working with Compliance in the field to
develop a
better way of handling inspections and
including
97
the Review folks in those inspections,
and also a
better way of getting the findings from
those
inspections.
Training for reviewers. We have already
had a number of scientific seminars. We have
started that, especially, OGD has one
every six
months or so, and those seminars have
been very
beneficial to our staff in helping us have a
better
understanding of where we need to go, but
we need
more seminars and we need, again, really
a set
training program for all of our
reviewers.
We did form an OPS Coordinating
Committee
within the immediate office, and
actually, Keith
Webber and Gary Buehler are the chairs of
that
committee, and we will be looking at all
the issues
that come into OPS to try to ensure that
we have
consistency throughout all of OPS on
handling
these.
One of the other things that we
are in the
process, I think, that will help with the
gap is
finalizing the guidance on comparability
protocol.
Also, in ONDC, as I said, we
are really
98
changing the organizational structure,
but much
more than changing the organizational
structure, we
are changing from a review program to an
assessment
program, and that assessment program will
focus on
quality attributes of the manufacturing
including
chemistry, pharmaceutical formulation,
and the
manufacturing process.
So, the significant thing here
is that we
will be looking at much more the
chemistry, the
CMC, and that is where the assessment
program is
focused.
We have the proposed QOS. We have also
implemented a team approach. We are establishing a
peer review process. We have already done this on
a limited basis to provide more
scientific input to
our scientists in their review processes,
and
helping everyone have a better
understanding and
sharing the knowledge that they learn
from the
reviews.
We are implementing a Quality
Systems
approach. One of the things, too, that
ONDC is
doing, is they are developing a mock NDA
under the
99
new paradigm, under the desired state
paradigm, so
that they will have a better feel for
some of the
questions and issues that can come up,
and they are
looking at reducing supplement
requirements.
OGD has reorganized, as well. As I
mentioned, they have an additional
Chemistry
Division.
They are looking at changes in the
supplement review and evaluation to
determine if
some of the supplements can be eliminated.
They have also taken on the
team approach
on some applications, so that they have
better
utilization of scientific expertise and
ensure
consistency across similar product areas,
and they
are also looking at efficiencies in
review to
eliminate redundant or non-essential
review
activities. So, they are very much involved, too,
in some of the things that we need to be
focused on
in order to eliminate the gap.
OBP, which is, of course, our
newest
review organization, is looking at
supplement
requirements to determine where we can
eliminate or
reduce supplements.
100
Some additional steps. I think we need to
involve stakeholders in the review of
guidances.
Maybe under the Manufacturing
Subcommittee we need
a group that looks at some of the
guidances. I
don't know how we need to do this, but I
think it
is a step we need to do.
We need to determine how to
handle the
two-tiered approach, if we do it at
all. I have
mentioned this before, and I think it is
going to
be important to involve industry and
others in
doing that.
We need to have external
workshops,
develop a dispute resolution
process. One of the
things, too, besides looking at regular
GMP
inspections, we really need to look at
better ways
to
handle pre-approval inspection process.
I would really like to see
reviewers more
involved in making some of the decisions
on whether
to do pre-approval inspections and to set
better
criteria for getting those done plus
participate on
the inspections if we feel they are
necessary, and
develop appropriate metrics. These are things we
101
haven't started on, but are obviously
necessary,
and I am sure there is others.
Just to finish up, observations
and
conclusions. I think we need to continue to
address and analyze the organizational
gap issues.
I think they are going to be really
important to
us, to have determined what they are and
to resolve
how we are going to handle them in the
future in
order to move in the direction that we
need to do
to be able to regulate under the desired
state.
One of the things I think that
is very
important that we need to think about is
culture.
When I talk about culture, I am talking
about the
culture within FDA, and I am talking
about the
culture outside of FDA.
There are a lot of changes that
need to be
here.
I realize that the culture is always a
different area of thing to handle. I thought
Jerry's example was an excellent example
of how the
culture is a problem in some of the
things that we
are trying to do, and this is one of the
things
that we have got to manage and figure out
how best
102
to handle.
All of this, all of this, the
changes in
the organizational gap will take time,
and we need
to be dedicating the time to make it
happen.
Also, as I said, a lot of this
depends on
resolving some of the science gaps that
we have.
We need to include stakeholders in making
some of
the decisions and developing some of the
procedures. We need to work closely, I think, with
the stakeholders or we are really not
going to have
the answers that we need.
The training of reviewers is
important,
and the thing I think that is going to be
something
that we have got to be open to is that as
we move
forward, we are going to see other gaps
that we
haven't anticipated, and we are going to
have to be
ready to fill those.
That is all I have. Thank you.
DR. KIBBE: Thank you, Helen.
Should we take questions or you
want to
move to the--
MS. WINKLE: Let's go through all of it,
103
yes.
DR. KIBBE: I will hold my really tough
and incisive questions until later.
Scientific Gap Analysis
DR. HUSSAIN:
Last night I had a phone
call and I couldn't answer that, but this
morning,
at 7:00, I had another phone call from a
company
which recently got an approval for an
inhalation
product, and they were ecstatic. They had
submitted
a complete development pharmaceutics
report, and
that process went extremely well. This was a
one-cycle review approval for an
important product
including all the development report.
So, I think that is a wonderful
example
that shows ONDC has already moved and
things are
moving in this direction already. We probably will
make a case study out of it, and so
forth.
Anyway, I would like to sort of
focus on
the
scientific gaps. I will use some
background
information. I know a number of members on this
committee who are new, so I thought I
will spend
some starting with the basics.
104
I think, as Dr. Woodcock had
come to the
Manufacturing Committee, her articulation
of what
is quality has really come to almost
fruition, and
she is publishing this article soon. The
definition of quality is fundamental as
we move
forward, and there are some challenges as
we move
forward.
Good pharmaceutical quality
essentially
means an acceptably low risk of failing
to achieve
the desired clinical attributes. That is the goal
of achieving quality.
The challenge has always been,
and you
heard many of the discussions yesterday,
saying the
weakest link--and the weakest link is
what we have
to strengthen and address--how do we link
measurements and risk?
I think what we believe quality
by design
approach that we are developing under ICH
Q8 is a
way to help that. It is a multivariate
model. It
is characterized during development. You have to
think about, when you think about quality
by
design, the clinical is a confirmation of
that.
105
That is the fundamental aspect that I
think is
going to be a significant challenge in
how we
achieve that.
At the same time, you have to
remember
that development is only one part of
it. You
essentially have to make sure you have a
quality
system.
The final link between product and
customer-driven quality attributes really
means you
have a good quality system for
manufacture that
brought us consistently also, that
requires
integrated product and process knowledge
on an
ongoing basis, because you don't stop
learning at
the time of approval. In fact, you learn quite
significantly after manufacturing status.
You have to assure ongoing
control, and
you have to enable continuous
improvement.
In summary, I think Dr.
Woodcock
articulated this at our ONDC scientific
rounds on
October 6th. The future definition of quality
should be probabilistic in nature. That
is the
fundamental aspect, and we are not there
yet.
106
Science management, risk
management, and
quality management are critical aspects,
and I
think we really would like to be leaders
in this,
and I personally believe that we are.
But let me take a look
backwards from
beginning with the end in mind. Since we started
the PAT Initiative, the cGMP Initiative,
our focus
has been on looking at the entire system,
and we
have been looking backwards from a
manufacturing
end to the entire discovery development
product,
and it is what do we learn from that.
But before you look, before you
measure,
it
is always good to make sure your measurement
system is good, so you get your eyes
checked. That
is the symbol there.
The reason I was so sensitive
to that is I
think the dissolution variability from a
manufacturing end, we really fully
appreciate it
when we are putting that white paper
together, that
today, companies don't have the ability
to document
lower variability than that of the
calibrated
tablet, and which is made with the
conventional
107
method, and so forth. So, that was I think a stark
reality that a lot of us fully understood
during
this process. Art mentioned that, and so forth.
So, what are the challenges
here in the
sense the challenge is organizational
communication, and knowledge sharing and
information sharing. If you work in silos, the
boundaries between organization, which I
call
interface, the quality of the interface
between
functional unit, that means the
effectiveness and
efficiency of the process, the interface
can be
handoffs between functions, and often is
in need
for better coordination, and that is what
we
learned through our GMP Initiative.
The rapid and broad movement of
information and knowledge sharing is
necessary for
process optimization between
organizations, within
any organization itself, so we have to
move from
technology transfer to knowledge
transfer.
But just toward the stage,
reliability is
a phrase that we often don't use in
pharmaceuticals, but reliability has a
very
108
distinct body of information, body of
knowledge
associated with that.
So, if you look at this figure,
you have
performance, you have life, shelf life,
and you
have a desired specification on both
sides, on the
performance.
The first, Figure A is good
performance,
but poor reliability because the
performance
changes significantly over time, and the
variability of the spec changes, too.
The second one is good
performance and
good reliability over the life.
The third is poor performance
below spec.
So, I think the key is when we
think about
performance, we are thinking about
performance of
the shelf life, the bioavailability, and
so forth,
remaining unchanged throughout the shelf
life.
Just to keep that in mind.
In the current state, today,
chemistry,
manufacturing, controls, design
information
available in applications is limited and
varied.
Our reviewers have a high degree of
uncertainty
109
with respect to what is critical and what
sort of
process controls are necessary.
Our reviewers have significant
doubt on
the level of process validation and
process
understanding. So, they have no option but to
focus on in-process and product
testing. So, in
the pharmaceutical manufacturing from an
engineering sense, testing is control,
but in an
engineering sense, control is very
different. It
is a dynamic method. We don't do that.
Risk coverage post-approval is
a
challenge, and supplements are a means
for risk
mitigation. That is the way we have approached it.
Traditional use of market
standards--these
are the pharmacopeial standards--as
release tests
are not effective for process
understanding and
continuous improvement. In fact, by definition, if
you have attribute data or so-called zero
tolerance, continuous improvement is
impossible by
definition. That is the definition in QS 9000,
because we can only have continuous
improvement
when the product is already in spec.
110
If you have zero tolerance
criteria, by
definition, the product is not in
spec. So, that
is the fundamental thing. Also, we understood and
wrote about that in our Manufacturing
Science white
paper.
We have variable test methods
for physical
characteristics, less than optimal
systems
perspective and approach, low efficiency
and high
cost of drug development and
manufacturing, and
continuous improvement is difficult, I
would dare
to say not possible.
So, the success of the cGMP
Initiative was
to get a consensus desired state
statement, so I am
not using the exact words that we
developed. They
are modified and the desired state
statements
adopted by ICH, these are the ones.
Product quality
and performance are achieved and assured
by design
of effective and efficient manufacturing
processes.
Since we are looking back from
the
manufacturing side, manufacturing goals
are kept
first.
Product specifications based on
111
mechanistic understanding of how
formulation and
process factors impact product
performance, and an
ability to effect continuous improvement
and
continuous "real time"
assurance of quality.
Now, let's start looking at
this in the
sense what are the gaps and how do you
fill those
gaps.
Information and knowledge for
regulatory
assessment and decision process based on
the
desired state is information related to
quality and
performance and how the design impacts
that. So,
we need to know impact of formulation and
process
factors on performance.
We need information to judge
and develop
specifications based on mechanistic
understanding.
We need information to evaluate and
facilitate
continuous improvement, and continuous
"real time"
assurance of quality.
The focus is on design, and if
you are a
formulator, especially one trained a few
years ago,
or if you have been in the design
business, this is
simply logical extension, so this is
nothing new
112
about this, but if you are not, then, you
have to
think differently the design process.
Design is about doing things
consciously,
and not because they have always been
done in a
certain way. It is about comparing alternatives to
select the best possible solution. It is about
exploring and experimenting in a
structured way.
So, that is what design vocabulary brings
to us.
So, in the context of drug
product
development, design is about doing things
consciously, so you start with the
intended use.
That is the fundamental issue. You cannot forget
the clinical use of the product that you
are
designing. That includes route of administration,
patient population, and all other things
that
impact on the intended use.
That intended use defines for
you what the
product design should be. You have options to
select, and you select a product
design. That
design leads you to design
specifications, and
those design specifications define the
manufacturing process and its control
necessary to
113
develop those design specifications back
to deliver
the intended use.
So, you have product
performance, design
specification that reliably and
consistently
deliver the therapeutic objective, and
you have
manufacturing capability, ability to
reliably and
consistently deliver the target for a
design. This
is straightforward, logical, no rocket
science, and
we have been making and doing this for
100 years.
So, that was the basis that we
said we
will develop the ICH Q8, and ICH Q8
document, which
will go to Step 2 in Yokohama, I am
confident about
that, will essentially bring this type of
information.
It will not deal with the drug
substance
manufacturing part of it, but it will
start with
drug substance characterization.
So, it will bring in
characterization of
components of drug product. It will bring in
aspects of manufacturing compatibility,
and so
forth.
Much of this information is sort of missing
or varied in the current submission, and
we are
114
hoping, although the sections in CTD-Q
(P2) are not
ideal, we have to live with that because
that is
how everything goes in green, we felt
that the
sections provide enough room for bringing
all the
information to bear on that.
So, we have made significant progress,
and
I think the draft 4 we are working on has
captured
most of this.
What is the importance of
design thinking?
Design thinking makes the user paramount,
ensuring
that services we end up will do the job they
are
supposed to, as well as delighting the
customer.
Design thinking and methods
provide new
routes to better public services that
meet people's
needs and deliver value for money. That is the
key.
We have been making tablets for 100
years
or more.
It is a design problem. We
essentially
have not used the vocabulary, we haven't
brought
that in.
Tools, such as pre-formulation
characterization, and so forth, literally
have
become [inaudible], but that information
often is
115
missing in our assessment.
So, if I distinguish between
conventional
and novel design for the sake of
distinction in
terms of how we use prior knowledge, the
key aspect
of this design and quality relationship
is utility
of prior knowledge. For similar drug products, you
have probably more prior knowledge, and
for novel
designs, you have to rely more on the
experiments
you generate, but prior knowledge is the
key.
If you are going to come with a
new tablet
formulation, and you have 300 similar
tablet
formulations on the market, how much more
information do we need? If you leverage the prior
knowledge correctly and characterize your
drug
substance in a way to say all right, this
is the
way it is, you can leverage that
knowledge.
Level of mechanistic understanding will
depend, will vary. Pre-formulation programs, many
good pre-formulation programs get to the
mechanism
of degradation, get to the mechanism of
absorption
including Bioform Classification System,
characterization, that is the
fundamental. That
116
defines literally every aspect of the
manufacturing
process and other things.
So, if you have that
information, if you
will not be mechanistic completely, but
you have
valuable information, that moves forward.
The challenge I think is to
think about
design during drug development. As you develop
your characterization and your
development program,
you have to keep in mind the ability to
reliably
predict performance, confirm as you
progress.
Every experiment you do next, say, a
scale-up, is
adding to your knowledge base, is a means
to
evaluate the predictability of your prior
knowledge, and so forth.
So, if you think about
designing the
entire development project from a design
prospective, and capturing your
predictability, you
actually have an opportunity to move forward
very
quickly in terms of regulatory aspects,
as well.
So, level of understanding
increases over
time, and I think we have to recognize
that.
Structured empirical approach is often
necessary
117
because you often are not mechanistic.
Use of prior knowledge to
identify and
select a design space for
characterization is
fundamental, and I think Ken Morris
mentioned this
yesterday. People often jump into design of
experiments without knowing what design
space they
want to explore.
If you miss the prior
knowledge, you
actually increase your workload, you
increase your
cost by not being intelligent enough to
say what
are the critical variables upfront, and
sort of
exploring the design space. You cannot approach
this in a blinded fashion.
For example, now, if you have
multiple
number of variables that you have to
study,
obviously, you cannot study all of
them. That is
where risk comes in. Prior knowledge and risk
assessment is the way to address that,
for example,
failure mode effect analysis would be a
means to
say all right, these are the critical
variables, at
least these are potential critical
variables, these
are the ones we will select and move
forward.
118
So, initial conditions for
screening
experiments and then experimental
conditions are
then dependent on this prior knowledge
and risk
assessment.
Impact of formulation and
process factors
on performance, why can't we leverage and
be more
intelligent about our clinical trial
material
itself, and how do we design clinical
trials,
because that is where the connection
between
quality and clinical comes together, and
I will
show you an example as we go.
Similarly, with shelf
life. If you are
getting mechanistic understanding, and so
forth,
prior knowledge and shelf life, I think
is a
wonderful opportunity which we don't
utilize today.
Just to give you an example,
these are
standard procedures in industry. Here, is a work
from Amgen in a sense how do they address
the large
number of variables as they go through
process
characterization, pre-characterization
experiments,
is to bring the prior knowledge to bear
on this.
So, process characterization
studies start
119
with pre-characterization work, screening
experiments, interactions, and
combinations of key
parameters leading to process redundancy.
They sort of covered that with
a formal
risk analysis. So, these are standard procedures,
and in many, many aspects, the
formulation
development process has built in robust
approaches,
but it is not formalized, it is not well
understood.
What is a robust design? A robust design
is not removing the source of
variability, but
designing a process or product to reduce
the
variability.
A very simple example that in
pharmaceuticals we have, is we know
magnesium
stearate is a wonderful lubricant, but it
has a
drawback of affecting dissolution, we
know that.
Half of the formulations that
we have in
our submissions actually have a robust
design built
in.
They will use a smaller model on sodium lauryl
sulfate.
That negates the negative effect of
magnesium stearate. We have known that as
120
pharmacists, formulators, and so forth, a
long
period of time, but we never captured
that as a
knowledge base.
If you are making a tablet, you
are
compacting. Compaction has an effect on
dissolution. If you have right amount of
disintegrating agent, you remove the
effect of
compaction force. It's as simple as that. That is
what a robust design principle brings to
bear on
that.
What is troubling often is, if
you look at
the SUPAC guidance, and if you look at
the way we
have regulated, the way we have done
experiments
often is to define our input or
independent
variables in terms of equipment. Say, for example,
if you look at the SUPAC guidance, we say
equipment
of same design and operating principles,
you can do
this, and so forth.
That is not a
quantifiable. It is an
identifier. So, we know that performance
of a unit
operation depends on material
characteristics,
particle attributes, equipment design, and
121
operating conditions.
Instead of sort of defining of
input as
equipment A, equipment B, and equipment
C, and then
doing a design experiment, if you are
smarter, you
will say all right, what are the forces
acting on
the particle irrespective of the
equipment design.
That removes that and improves your
ability to
generalize. So these principles have been there
for 60 years.
Let me explain, in a sense, I
think the
key aspect here is risk-based
specifications.
Here, is an ICH Q6A decision tree. Let me walk you
through this.
What specific test conditions
and
acceptance criteria are appropriate for a
conventional or immediate release dosage
form?
Now, Professor Nozer corrected
me before,
so I will correct myself again. He said this is
not a decision tree, this is an event
tree.
Question 1 is: Dissolution significantly
affects bioavailability? That is the Question 1.
If the answer is yes, develop
test
122
conditions and acceptance criteria to
distinguish
between unacceptable bioavailability.
But if the answer is no, you go
down. Do
changes in formulation or manufacturing
variables
affect dissolution?
If the answer is no, go
down. Adopt
appropriate test conditions and
acceptance criteria
without regard to discriminating power,
to pass
clinically acceptable batches.
The first question is how do
you know
dissolution significantly affects
viability. Most
NDAs, not all, have a simple test that
they do. It
is called a "Related bioavailability
study." They
will compare a solution with a solid
dosage form,
and often you see they are superimposable. That
means dissolution is not rate
limiting. So,
dissolution is not likely to affect that.
Do changes in formulation
variables affect
dissolution? Yes, all of them do, most of them do.
If the answer is no, for
heaven's sake, if
you can find a formulation that doesn't
have that,
but you still put a dissolution
test. The question
123
should be why, why do you need that
dissolution
test?
So, some of the questions, how,
why, and
what really have not been addressed
adequately, and
our dissolution specification setting is
one, two,
three, these were your three batches,
this is your
specification. Often, it is limited to that.
I want to remind you that
variability is
inherent, and I did include a paper in
your packet.
This was published recently from
Cambridge
University and Pfizer.
It said if you don't account
for
variability and you assume that meeting
specification means you are
bioequivalent, that may
not always be true. In fact, if you do this
analysis, if your specifications are not
set right,
you have a 50-50 chance whether you are
bioequivalent or not, or whether you meet
specification or not.
So specifications for
dissolution are not
likely to be the ones ensuring
bioequivalence. It
is the entire control process that does
that, but
124
we focus so much attention on just one
test, we
miss the whole point.
Let me come back to this
decision tree. I
think in a quality by design thinking,
this is what
are my questions. So, dissolution significantly
affect bioavailability is a product
design issue.
You start with your pre-formulation, your
biopharm
classification, the solubility,
permeability, and
all that aspect, and you have an
anticipation
whether it will be affected or not, so
when you do
your related bioavailability study, you
are
conforming your past prior knowledge.
So, postulate-confirmed based
on mechanism
or empirically, and that can apply to the
question
dissolution significantly affect
bioavailability or
do changes in formulation affect
dissolution or
not.
But Jurgen points out, the key
question is
we have a mind-set 80 to 125, and that is
the magic
number.
Where did that magic number come from?
I
think this is where the clinical
relevance comes
in, what is a relevant acceptance
criteria to judge
125
whether an acceptable bioavailability is
there or
not, and that is a clinical pharmacology
question.
That is where we link to the clinic.
If you have a good PK/PD
assessment, and
so forth, you have far more information
available
to make a more rational judgment, and
that is the
question there.
So, design of manufacturing and
controls,
and the question is how reliable those
are, do
changes in formulation and manufacturing
variables
affect dissolution? If the answer is yes,
Are these
changes controlled by another procedure
and
acceptance criteria?
If the answer is yes, we come back
and put
a dissolution test. My question is why? If the
dissolution test itself is variable, and
so forth,
why would you want to put another
test? You have a
series of tests, and so forth, your
chances of
failure keeps increasing.
So, the questions that we need
to ask are:
How good or how reliable are your design
and
controls that you have put in place for
particle
126
size, morphic form, and so forth, to
address these
conditions?
So, overall risk-based CMC
would ask why
for these questions, but also, so
what? If
dissolution is not rate-limiting, the
question
should be so what, why do we need a
dissolution
test, and so forth.
So, this is how it all sort of
comes out.
So, quality by design thinking brings an
overall
CMC systems approach, for example, link
to morphic
form, particle size, stability failure
mechanisms,
and so forth, to address this in a
systematic way.
Continuous improvement is not
possible
today, because any movement is a
change. This is a
direct cut-and-paste from our SUPAC guidance.
Level 1 change, definition of change is
this
category includes process changes
including changes
such as mixing times and operating speeds
within
application/validation ranges.
If you need to have validated
those
ranges, any movement within that is a
change today.
So, it requires to be reported. If you change
127
outside those ranges, you not only have
to report
it, but then you have to do a Case B
dissolution,
which is a profile comparison, and the
supplement,
and the stability, and so forth, so
today, it is
not possible.
Our law and our regulations
provide
provisions for those approaches, and this
is a
Section 506A of the Act and 314.70 that
we issued.
We are required to make decisions based
on
potential to have an adverse effect on
identity,
strength, quality, purity, or potency of
the drug
product.
We have used the phrases
"substantial,"
"moderate," and
"minimal." They are not very
useful, they are not probabilistic, and I
think
that is where we have to work at.
But also, if you look at CFR
314.70, there
is a provision no change means no
reporting beyond
the variations already provided in the
application,
and that is where the design space comes
in.
So, what is this design space? The design
space is simply a space of knowledge or
information
128
where you know you will not affect your
bioavailability, you will not affect your
stability, and you will be in
specification, but
you are improving the manufacturing
efficiency, you
are improving the manufacturing process
through new
equipment, better controls through
process
adjustment in response to incoming input
variables,
and so forth.
So, that is what continuous
improvement
is, and Box defined this years ago as
evolutionary
operations.
So, that is how ICH Q8
information that
brings reliability to your deliver design
information, ICH Q9, which will develop
the failure
mode effect analysis and risk
communication, too,
all of them come together to define a
design space
for continuous improvement, and that
design space
will depend on the company's information
that sort
of comes about.
You will know which area is the
change,
which area is not a change, and that is
the map of
Maryland, a weather map, so you shouldn't
be in the
129
red area.
That's about it.
Yesterday, Steve showed this
slide that I
had developed for thinking about the
entire system,
how do you connect the dots. I am not going to get
into that, but I think the key aspect
there is the
knowledge space, and the knowledge space
in
relation to the clinical knowledge space
and in
relation to the manufacturing knowledge space
all
have to come together to sort of address
this.
A personal learning that I had
going
through the GMP process is a better
appreciation
for quality system. I am still an academic at
heart, and when you put me into a
documentation
mode, I get nervous, and great mounds of
paper is
something I want to avoid.
The quality system that we have
worked out
in the GMP Initiative is actually quite
nice and
simple.
It says say what you do, do what you say,
prove it, and improve it. Those are the
fundamental
principles.
So, say what you do to FDA, is
your
pharmaceutical development information
that you
130
share with us? If you say this is all I know, so
that is what you are going to get. If you say this
is how much I know, and so forth, you get
benefits
from that, but then you have to do what
you say
consistently. You have to prove it, and if you are
unable to prove it, you have to ask why,
and you
have corrective actions.
If you are unable to ask why,
unable to
answer why, then, there is a risk profile
that
increases. And prove it is more optional, there is
continuous improvement in innovation sort
of comes
in there.
The challenges, I think in
pharmacy, in
pharmaceutical education, we have been
doing this
all along. What has been missing is a
formal
structure and communication tool.
I draw some similarity
here. If I look at
what has happened in chemical
engineering, and now
I think chemical engineering is going
through
soul-searching activities to redefine
themselves,
but this is how chemical engineering
evolved.
It started with industrial
chemistry, unit
131
operations, material and energy balance,
chemical
engineering thermodynamics and control,
applied
kinetics, process design, transport
phenomena,
process dynamics, process
engineering. Now, they
are in molecular transformation,
multi-scale
analysis, and systems view.
So, they went from industrial
chemistry to
unit operations, to chemical engineering
science,
to system engineering.
Industrial pharmacy is still
industrial
pharmacy in the U.S., not as well in Japan,
China,
Europe, it's a pharmaceutical engineering
degree
literally. So, we are still in that, and I think
we can catch up on that, going to bring
some of
those principles.
It is important to do that, it is
important to bring a systems engineering
perspective because not only we have to
deal with
the traditional goals of quality, the GMP
Initiative offered new, non-traditional
goals, that
is, risk-based, flexibility, robustness,
scalability, continuous improvement,
innovation,
132
and efficiency. These are typically
non-traditional goals.
The characteristics of these goals are
complexity and uncertainty associated
with that. The
relationship between goals and
characteristics
that we are seeking is knowledge and
information
centric relationships.
There are fundamental issues there,
because if you don't get to this, our
quality
system will continue to be a paper chase
exercise,
and not really get to the heart of it,
because we
don't want to be lurching from fact to
fact, from
one quality system to another. Unless this process
is in the same sciences there, this will
not
happen.
I will skip that and focus on
where we
are.
My assessment is this. This is
not rocket
science, this is straightforward and simple
for
those who have been in this area for
quite some
time.
For those who are not, there is a need for
education training.
There are signs that I
see. The phone
133
call this morning from a major company,
and, in
fact, I should have asked that I can
share the name
or not.
Their positive experience with the
development report already in a
four-cycle review
is a good example that our folks can
manage this
process well, but consistency and making
sure it
happens consistently is a challenge.
So, the immediate education
need that I
see going through the PAT training, and
so forth.
Now, for a broader training is
introduction to
statistical quality control. That is fundamental.
We are missing that, and I emphasize it
is not
biostatistics. There is a distinction between
statistical quality control and
biostatistics,
hypothesis testing, and where we keep
missing that.
I meet with the PhRMA
Statistics Group,
and so forth. It comes back we are missing the
quality dimension here. We have to understand
variability. We have to focus and put training
programs on molecular pharmaceutics and
biopharmaceutics.
We have gone to the molecular
level in
134
most of those areas. Engineering principles is a
key aspect. Risk assessment and communication
would be a program. All of this will come together
quite nicely with the ICH Q8/Q9 training
program
itself, but I think we would like to add some
additional training.
I know Ken has been working
with us quite
constantly on focusing on what the right
questions
are for the review process, but I think
we can put
a
more formal training program on all of these
aspects.
I would like to say systems
approach and
thinking is important. Unfortunately, most of the
training programs that we go through, our
BS/MS/BA
programs actually takes us away from
systems
thinking to focus as narrowly as
possible, and so
forth, but in an applied area in the
regulatory
setting like this, systems thinking is
important.
Unfortunately, I go and talk
about Deming,
many people in the industry have never
heard of the
name Deming. I think we need to introduce
people to
Deming and others.
135
Team building and communication
will be
the key.
I will end my talk saying that
coming
together is a beginning, keeping together
is
progress, working together is success.
The GMP Initiative brought us
together. I
think the PAT Initiative took us further,
and a
smaller group is actually making
progress.
I am fairly positive. I went through a
quite depressive cycle in some of the
challenges,
and so forth, but I am fairly positive
that I think
we are on the right track, and we will
achieve this
rather quickly.
Policy Gap Analysis
MR. CLARK: I am going to deliver a talk
about something of the policy gap, but
what I will
really be talking about is a guidance
development
process and some changes that we have
done there.
My talk will be quite pedestrian and
quite short,
which I hope to be some relief.
I noticed in the agenda, at
10:30 we were
supposed to break, but now it's after
11:00, and
136
were this agenda an application, we would
be found
in violation of an agreement, and if we
showed a
pattern of being late, well, we might
just be under
a consent decree. So, I think we are at some risk,
so I will move us along and try to get us
back on
the path of righteousness, and such.
I want to point out that
somebody
mentioned earlier today about failure,
about
failure data, I am sorry I didn't quite
catalog who
it was that brought it up, but the
failure of data
to point stayed in my mind.
One of the things that we will
be talking
about in Yokohama in Q8 is what role that
plays in
an application, and to help define a
design space,
is there a place for us to use that in an
evaluation of an application, and if you
have
determined where your system fails, can
that offer
you some relief as to where you
operate. I wanted
to just bring that point up as I start in
this
speech.
In the GMPs for the 21st
Century, some CMC
guidance documents are out of
synchronization with
137
that rollout that you all have seen by
now, but the
guidance process that developed these
documents has
strong and weak points, and one of the
main
strengths of this is the technical input
from our
staff, from our review staff.
One of our weaknesses is in the
decisionmaking process for actually
moving the
documents from step to step and getting
them out,
which causes it to be very slow.
I would like to really dwell on
the
strength.
One of the things that we need to take
away from our previous guidance
development process
is that these deliberative processes are
well
meaning, and these people are highly
trained, and
they are experts at what they do. At every step,
they are trying to articulate the things
that are
on their minds and how to get
applications approved
in
the best way.
They may have become
proscriptive and
prescriptive, but that is not a failure
in their
attempts to articulate the best way to
get an
application approved.
138
We believe that there may be a
better way
to articulate that point, and obviously,
with the
rollout, and you compare the rollout to
the
documents that we have on our guidance
page, there
is
the gap, and most people know that, that are
familiar with the two sets of documents,
so I will
move on from there.
The draft cycling that was the
weak point,
I will point out this is the old draft
cycling, and
you
will see that there was a CMCCC working group
assigned from a CMCCC committee
body. That CMCCC
would define a group to work, and we will
call that
the body for now, to develop a document.
They would go ahead and develop
a
document, and this might take six months,
and it
might take two years, and it might take
five years,
but they would develop an articulation of
the areas
of interest for that document.
They would then proceed to take
that and
go through each review team, through some
kind of a
hierarchical structure in the
organization. Those
review teams would then have comments,
not unlike
139
the public comment system, and those
comments would
go back to that review group, and they
would
redraft the document, which might take
another year
or two.
Because these people are not
dedicated to
that task, they are also reviewing drugs,
they are
also involved in a lot of other efforts
like ACPS,
and they are also involved in guidance
development.
So, they go back to the review
teams, goes
back to that CMCCC body, and then it goes
back up
to the working group or back up to the
committee
for review, and then from the committee, it goes
to an OPS editor.
Now, that process, those steps
might take
as much as six months, it might be a
year. The OPS
editors then have a go at making sure
that the
legal language is current with the
desires of our
legal staff, and they might pass it on to
the legal
edit if their suggestions are minimal, and
so on.
If not, if the suggestions are
strong and
get into the body of the document to a
large
degree, it might actually go right back
up to the
140
body and have to go all through all that
stuff I
just mentioned all over again, and were I
mean-spirited, I could go through it a
second time,
but I won't.
Well, you go to the legal edit,
then, it
goes out to public comment. Then, you have public
comments dockets come back. You might have 1,000
comments if you are lucky. It might be a
couple
inches thick if you are lucky, and it
might be a
foot high if you are not so lucky.
If that happens, well, it will happen,
then, you have to catalog all those
comments,
address each of them somehow, address
them by
groups or individually, and then if you
have to
make substantial changes to the document in
order
to address those comments, go back up to
the top,
and if I were extra mean-spirited, we
could go
through this whole thing again.
I think you can understand that
that could
be a laborious process, and that is my
excuse for
why guidances take so long to get out of
the
Agency.
141
When somebody says that a
guidance will be
available soon, they may think it is
going to be
available soon, because they think they
are near
the end of the process, or what they
don't maybe
not understand is that there is an
iteration that
they hadn't predicted. So, that is something we
have been dealing with over the years.
This is a slide that puts into
words some
of what we just discussed, but it also
points out
that there is a rapid change in FDA
thinking over