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
Arthur H. Kibbe, Ph.D., Chair
Hilda F. Scharen, M.S., Executive Secretary
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
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.
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.
C O N T E N T S
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
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
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
C O N T E N T S (Continued)
Committee Discussion and Recommendations 234
Bioequivalence Testing for Locally Acting
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
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
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
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
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
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
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
Dr. Fackler is employed by Teva
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
DR. KIBBE: Thank you.
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
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
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
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
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
measure something, you cannot improve it. So,
measurement and metrics would be a key factor of
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
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
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
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
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
reviewers and sponsors, then, you have to build the
time for that, and so forth. That has to be
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
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
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
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
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
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
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
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
In some ways, FDA could play that role of
coordination, as Viad declared yesterday,
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
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
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
DR. KOCH: Marvin, just before you--I
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
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
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
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
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
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
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
DR. KIBBE: Anybody else would like to
make a comment?
DR. SINGPURWALLA: Yes. I
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
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
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
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
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
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
I am thinking primarily of industry and
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.
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
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
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
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
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
Just to bring out my experience with the
journal, the APS on-line Pharmaceutical
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
Before they left, they had eight or nine
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
collaboration between FDA and NIH may help in doing
DR. KIBBE: Thank you.
Ken, go ahead.
DR. MORRIS: Thanks, Art. Welcome to your
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
DR. SINGPURWALLA: The lawyers made them
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
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
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
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
The second point is it look
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,
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
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
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
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.
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
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
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
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
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
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
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
DR. SINGPURWALLA: Mr. Chairman, I have a
few thoughts. Ajaz, back.
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
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
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
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
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
problem with the situation in industry, but I am
not sure FDA is going to be able to do anything to
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
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
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
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
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
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
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
So, we welcome the work and we welcome the
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
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
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
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
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
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
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
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
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
So, he did something unique which I don't
think any of the companies would do
today. He got
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
supposed to, they said what's in here, it wasn't
quinine, it was something else, I don't know what
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,
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.
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
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
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
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
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,
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
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
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
At that time, Tetracycline came
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
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
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.
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
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
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
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
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.
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
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
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
So, we need to go in the direction of what
is truly a harmonized or internationalized
regulation of quality. We need to somehow control
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
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.
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.
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.
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
How many of us would be willing at the
ends of our days to become virtual us in a virtual
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
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
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?
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
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
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
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
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
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,
Does anybody want to throw a few cents'
worth in while we are prognosticating?
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
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
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
scientific gaps, and Jon will identify some of the
policy gaps and how we intend to sort of fill those
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
DR. KIBBE: That means you are passing the
ball to Helen.
DR. HUSSAIN: Yes.
DR. KIBBE: Let's see how you follow my
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
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
DR. KIBBE: There appears to be a gap in
the computational problem, too.
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.
MS. WINKLE: As I said, I am going to talk
about the organizational gaps and
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
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.
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
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
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
There is a difference in products and
regulatory requirements and review
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
Actually, we have chemists in
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
Part of what is adding to that workload
and to the backlog is that we get too
supplements. We require supplements on little
changes that really have no significance in the
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
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
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
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
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
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
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
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
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 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
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
So, that is a question that we need to
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.
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
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
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
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
Training. This goes to the question Mel
asked, training, training, training is
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
The last thing I have on
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
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
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
the Review folks in those inspections, and also a
better way of getting the findings from those
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
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
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
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
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
We are implementing a Quality Systems
approach. One of the things, too, that ONDC is
doing, is they are developing a mock NDA
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
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
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
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
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,
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.
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
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 is the fundamental aspect that I think is
going to be a significant challenge in how we
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
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
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
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
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
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
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.
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
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
Product specifications based on
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
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
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
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
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
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
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
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
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
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
So, initial conditions for screening
experiments and then experimental conditions are
then dependent on this prior knowledge and risk
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
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
What is a robust design? A robust design
is not removing the source of variability, but
designing a process or product to reduce the
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
pharmacists, formulators, and so forth, a long
period of time, but we never captured that as a
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
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
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
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
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
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
should be why, why do you need that dissolution
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
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
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
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
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
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
size, morphic form, and so forth, to address these
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
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
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
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
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
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
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
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
So, say what you do to FDA, is your
pharmaceutical development information
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
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
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
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,
and efficiency. These are typically
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
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
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
There are signs that I
see. The phone
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
We have gone to the molecular
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
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
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.
Team building and communication will be
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
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
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
In the GMPs for the 21st Century, some CMC
guidance documents are out of
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
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,
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
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
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
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