1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ADVISORY COMMITTEE FOR
PHARMACEUTICAL SCIENCE
Volume II
Wednesday, May 4, 2005
8:30 a.m.
CDER Advisory Committee
Conference Room
5630 Fishers Lane
Rockville, Maryland
2
PARTICIPANTS
Charles Cooney, Ph.D., Chair
Hilda F. Scharen, M.S., Executive
Secretary
MEMBERS
Patrick P. DeLuca, Ph.D.
Paul H. Fackler, Ph.D., Industry
Representative
Michael S. Korczynski, Ph.D.
Gerald P. Migliaccio (Industry
Representative)
Kenneth R. Morris, Ph.D.
Marc Swadener, Ed.D. (Consumer Representative)
Cynthia R.D. Selassie, Ph.D.
Nozer Singpurwalla, Ph.D.
SPECIAL GOVERNMENT EMPLOYEES
Carol Gloff, Ph.D.
Arthur Kibbe, Ph.D.
Thomas P. Layloff, Jr., Ph.D.
Marvin C. Meyer, Ph.D.
FDA
Gary Buehler, R.Ph.
Kathleen A. Clouse, Ph.D.
Jerry Collins, Ph.D.
Ajaz Hussain, Ph.D.
Robert Lionberger, Ph.D.
Robert O'Neill, Ph.D.
Keith O. Webber, Ph.D.
Helen Winkle
Lawrence Yu, Ph.D.
3
C O N T E N T S
PAGE
Call to Order
Charles Cooney, Ph.D. 5
Conflict of Interest Statement
Hilda Scharen, M.S. 5
Parametric Tolerance Interval Test for
Dose
Content Uniformity
Current Update on the Working Group
Robert O'Neill, Ph.D. 8
Quality-by-Design and Pharmaceutical
Equivalence
Topic Introduction
Ajaz Hussain, Ph.D. 10
Using Product Development Information
to
Extend Biopharmaceutics
Classification
System-based Biowaivers
Ajaz Hussain, Ph.D. 30
Using Product Development Information
to Address
the Challenge of Highly Variable
Drugs
Lawrence Yu, Ph.D. 79
Using Product Development Information
to Support
Establishing Therapeutic Equivalence
of
Topical Products
Robert Lionberger, Ph.D. 140
Summary of Plan
Ajaz Hussain, Ph.D. 169
Committee Discussion and
Recommendations 192
Criteria for Establishing a Working Group
for
Review and Assessment of OPS Research
Programs
CBER Peer Review Process for
Researchers/Reviewers
Kathleen A. Clouse, Ph.D. 221
CDER Peer Review Research
Jerry Collins, Ph.D. 243
4
C O N T E N T S
(Continued)
PAGE
Committee Discussion and Recommendations 258
Conclusion and Summary Remarks
Ajaz Hussain, Ph.D. 273
Helen Winkle 280
5
P R O C E E D I N G S
Call to Order
DR. COONEY: I would like to call the
meeting to order this morning.
Conflict of Interest
Statement
MS. SCHAREN: Good morning.
I am going to
be going through the Conflict of Interest
Statement.
The Food and Drug
Administration has
prepared general matters waivers for the
following
Special Government Employees: Drs. Charles Cooney,
Patrick DeLuca, Carol Gloff, Arthur
Kibbe, Michael
Korczynski, Thomas Layloff, Marvin Meyer,
Kenneth
Morris, Nozer Singpurwalla, who are
attending
today's meeting of the Pharmaceutical
Science
Advisory Committee, to:
1. Receive an update on current
activities of the Parametric Tolerance
Interval
Level PTIT Work Group;
2. Discuss and provide comments on the
general topic of considerations for
assessment of
pharmaceutical equivalence and product
design;
3. Discuss criteria for establishing a
working group for review and assessment
of Office
of Pharmaceutical Science Research
Programs.
6
The meeting is being held by
the Center
for Drug Evaluation and Research. Unlike issues
before a committee in which a particular
product is
discussed, issues of broader
applicability, such as
the topic of today's meeting, involve
many
industrial sponsors and academic
institutions.
The committee members have been
screened
for their financial interests as they may
apply to
the general topic at hand. Because general topics
impact so many institutions, it is not
practical to
recite all potential conflicts of
interest as they
apply to each member.
FDA acknowledges that there may
be
potential conflicts of interest, but
because of the
general nature of the discussions before
the
committee, these potential conflicts are
mitigated.
With respect to FDA's invited
industry
representative, we would like to disclose
that Dr.
Paul Fackler and Dr. Gerald Migliaccio
are
7
participating in this meeting as
non-voting
industry representatives acting on behalf
of
regulated industry. Dr. Fackler's and Dr.
Migliaccio's role on this committee is to
represent
industry interests in general, and not
any other
one particular company. Dr. Fackler is employed by
Teva Pharmaceuticals, Dr. Migliaccio is
employed by
Pfizer.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which FDA participants have a
financial
interest, the participants' involvement
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any firm whose product they may wish to
comment
upon.
Thank you.
DR. COONEY: Thank you, Hilda.
I am Charles Cooney, the
chairman of the
committee, and will preside over the
schedule
8
today.
We have several topics on the schedule.
The first of these is a current update of
the
working group Parametric Tolerance
Interval Test
for Dose Content Uniformity by Robert
O'Neill, who
I believe has just come in.
Parametric Tolerance Interval
Test for
Dose Content Uniformity
Current Update on the Working
Group
DR. O'NEILL: I am here to just update you
on what we promised you from the last
meeting on
October 19th. As you know, there is a technical
working group that has been put together
with folks
from FDA and folks from the IPAC group.
We have been working diligently
since
then.
We thought we would have some
recommendations for you today. We do not, but we
have had approximately eight
get-togethers, five
telecons and three face-to-face meetings,
the last
of which was about a week, week and a
half ago.
What those discussions have
been about is
the agreement of the statistical
formulations of
the problem. There were a number of
discussions
9
regarding the coverage probability and
symmetry of
coverage, off-target operating
characteristic curve
agreements, and things of that nature.
There has been some computer
programs that
have been shared back and forth, validation of each
other's methods, and I believe there is
now
agreement on that aspect of it and that
the working
group is turning towards the agreement on
where the
operating characteristic curve ought to
be placed
and how it might handle certain
particular
situations, particularly off-target
means.
That is essentially where we
are. I think
everyone is optimistic that probably the
next time
we report to you, that there will be
actual
recommendations for you to respond to,
but that is
essentially where we are right now.
I would be willing to take any
questions
if you have any.
DR. COONEY: Any comments or questions
from the Committee? If not, thank you very much
and we look forward to the next step.
DR. O'NEILL: Thank you.
DR. COONEY: We will immediately begin
with the second topic this morning, which
is
Quality-by-Design and Pharmaceutical
Equivalence,
10
to be introduced by Ajaz Hussain.
Quality-by-Design and
Pharmaceutical Equivalence
Topic Introduction
DR. HUSSAIN: Good morning.
I would like
to introduce to you the Topic No. 2,
Quality-by-Design and Pharmaceutical
Equivalence.
We believe we have an opportunity here to
explore
and what we plan to do with you is to
share some of
our initial thoughts and hopefully,
engage the
Advisory Committee in discussion to help
us make
sure we are on the right track.
In many ways, the discussions continue
from yesterday where, in essence, we are
looking at
opportunities that have been created and
re-examining some of our current policies
and to
see how we can realize opportunities to
move
towards a desired state.
I would like to put this in the
context of
moving from a reactive to a proactive
decision
11
system for pharmaceutical quality, and
recognizing
that this is only a journey, not a
destination. I
think in the world of continuous learning
and
continuous improvement, really,
continuous learning
is your destination in some ways.
I think over the last four
years, we have
focused on discussing some of the
opportunities in
general, but if I look at some of the
reactive
examples on this chart, yesterday, in
some way, we
talked about testing to document quality,
repeating
deviations in our specification
investigations, and
in some ways we will start focusing on
the other
aspects of prior approval supplement for
process
optimization and continuous improvement,
multiple
CMC review cycles, but more importantly,
I think,
how can we leverage the opportunity of
quality by
design for demonstrating therapeutic
equivalence of
generic products.
I think we struggle often in
this arena,
and we have struggled and unable to sort
of find
ways of approving generic products and
the degree
of complexity has increased such as
topical
12
products and inhalation products, and so
forth, so
how can we leverage the pharmaceutical
development
information to seek out ways to find
mechanisms for
approving complex generic products, I
think is a
topic.
I think the proactive examples
I think is
quality by design and real time release,
right
first time, process optimization and
continuous
improvement within the facilities quality
system.
But I think in some ways,
today, we will
focus on single CMC review cycle, less
so, but I
think quality-by- design approach for
demonstrating
therapeutic equivalence of generic
products would
be a focus.
Therapeutic equivalence. The definition
from the Orange Book is as follows. Drug products
are considered to be therapeutic
equivalents only
if they are pharmaceutical equivalents
and if they
can be expected to have the same clinical
effect
and safety profile when administered to
patients
under conditions specified in the
labeling.
Pharmaceutical equivalent
products are
13
drug products are considered to be
pharmaceutical
equivalents if they contain the same
active
ingredients, are of the same dosage form,
route of
administration, and are identical in
strength or
concentration.
Pharmaceutically equivalent
drug products
are formulated to contain the same amount
of active
ingredient in the same dosage form and to meet the
same or compendial or other applicable
standards of
strength, quality, purity, and identity,
but they
may differ in characteristics such as
shape,
scoring configuration, release mechanisms,
packaging, excipients, expiration time,
and within
certain limits, labeling.
So, I think we have certain
flexibility
built into the issue of pharmaceutical
equivalence,
and one of the desired states is to
leverage that
and to say that we want to set
specification based
on mechanistic understanding, so if you
have a
different mechanism, that is perfectly
fine, but
then you set your specification on that.
The discussion yesterday was
not to force
14
the generic to a particular
specification, but
recognize that as part of that.
Today, I think I would like to
put this in
the context of risk, uncertainty, and
variability,
and I think that framework will help us
think more
clearly about the issues.
FDA classifies as
therapeutically
equivalent those products: That are approved safe
and effective, so you have to have a
reference
product which is safe and effective, and
has an
approved pharmaceutical equivalents
against the
repetition of that, and are
bioequivalent, that
they do not present a known or potential
bioequivalence problem, and they meet an
acceptable
in vitro standard, or if they do present
such a
known or potential problem, they are
shown to meet
an appropriate bioequivalence standard.
In absence of pharmaceutical
development
information and quality-by-design aspect,
we have
to assume that they present a bioproblem,
so we
often go to the second bullet in most
cases; are
adequately labeled, and are manufactured
in
15
compliance to Current Good Manufacturing
Practice
regulations.
In a sense, the last four
years, our
initiative goals have been to focus on
science-based, risk-based approaches, and
there are
certain challenges I think in our
articulation of
the problem today.
I want to sort of share with
you what the
challenges might be.
Risk-based scientific decisions
on
pharmaceutical quality is clearly our
goal. Risk
is a combination of the probability of
occurrence
of harm and the severity of that
harm. The reason
for focusing on that is an aspect that I
feel that
we often get entangled in and unable to
really
articulate the problem carefully.
Uncertainty with respect to
severity of
harm and/or probability of its occurrence
and their
modulating factors is that challenge that
we face,
what are the critical quality attributes,
and what
is an acceptable variability.
I have argued, and I think I
will ask the
16
Committee to think about this, is my
argument sort
of correct, in some ways, in the current
decision
system which tends to be reactive, one
contributing
factor for the reactive decision system
is we
confound uncertainty, variability, and
risk.
This is, by nature, how we develop
our
products to a large degree. The current paradigm
for product and process development tends
to do
this, because our entire effort in new
drug
development, for example, is focus on
safety and
efficacy of a molecule, but we use a
product to
achieve that.
The connection between product
quality and
the clinical is generally focused on the
molecules
rather than the product. So, that is a part of
this discussion.
Often intrinsic safety and
efficacy of a
new molecular entity is confounded with
its product
and manufacturing process just by the
nature of our
product development and process itself.
We have multifactorial aspects of
pharmaceutical products and manufacturing
17
processes, and there is increasing
complexity, and
if we can find a way to articulate our
problem more
carefully, this may help moving forward
more
quickly.
Establishing constraints based
on prior
knowledge and limited development
experiments that
are done in the development cycle.
What I have argued is there is a
need to
entangle or, as I call it, de-convolute
uncertainty, variability, and risk, and
then to
achieve truly a scientific integration of
these for
quality decisions, how we set specification.
Yesterday, for example, what we
proposed
was an assessment of variability,
example, begins R
and R.
That is an attempt to start characterizing
the variability and attempt to start
teasing out
what comes from what.
This may appear to be
paradoxical, and it
probably is without the concept of
quality by
design, and that sort of links to Dr.
Woodcock's
paper that we talked about.
Let me illustrate that. When we approve a
18
new drug application, we bring assessment
of all
the disciplines to bear on a decision
which says
the risk to benefit ratio of this
proposed drug
product is acceptable when used in
accordance to
the label. That is the pivotal decision criteria.
Now, that is based on the
pivotal clinical
trials along with the toxicology, and
along with
all the studies that go along with that,
but the
pivotal clinical trials play the major
role there.
What do we use for the pivotal
clinical
trials?
We use a product, and we often do not have
the opportunity or do not have the intent
to gauge
whether the product is modulating the
safety and
efficacy of the molecule beyond that of
exposure
less the bioavailability.
So, from that aspect, the
quality of the
product has to be built in before you get
into the
clinical trials, otherwise you confound
the
clinical trials with quality problems,
and
actually, I will illustrate one example
in my
second presentation of that.
As that happens, then, the
product is
19
approved and then manufacturing is
transferred to
production and you have seven production
lots, but
that goes to the patient population.
So, you see the disconnect
between
pharmaceutical quality or product
quality. I am
not talking about the safety and efficacy
of a
molecule, I am talking about how a
product
modulates that.
So, in many ways, if I look at
drug
development program, and here is an
illustration of
that, this is actually a real case
study. The only
difference I have here is I have a line
that made
it more linear. That is the only change I did, but
here is a development program.
The initial formulation was a
capsule.
Then, they went to a table, wet
granulation tablet,
and each star is a bioequivalent
study. So, they
qualified that change from capsule to
tablet using
a
bioequivalent study. Then, they add a
film coat,
then, change the site of manufacture of
the drug
substance, and so forth.
You see the changes that were
occurring in
20
this drug development program, some
before clinical
trials were initiated, some during the
clinical
trials, site changes, and so forth.
But this company actually
qualified, what
they call bridging studies using a
bioequivalence
trial.
Towards the end of the review time, to
qualify and bridge the clinical trial,
pivotal
clinical trial material with the
to-be-marketed
product, they opted to use multiple-dose
studies of
the traditional thing, and that failed at
the last
minute.
Actually, it didn't fail, it just failed
to establish bioequivalence, so they went
back and
actually repeated the study with a larger
number of
subjects, but it delayed them.
The point here is all these
changes are
being qualified on the basis of their
traditional
bioequivalence trial. In new NDAs, we generally
see from 3 to 6 clinical bioequivalence
studies,
and that was our number.
Here is a number that was
shared with us
by Jack Cook sometime, this is the year
2000, about
7 per approved compound. In a sense, if I look
21
at--this is Gary Buehler's slide--I think
in many
ways, the difference between the generic
drug
approval and the new drug approval is
minimal when
it comes to bioequivalence trial.
In many ways, we use bioequivalence
to
gauge information which we don't have in
the NDA,
but in reality, in some cases, it is
simply the two
are comparable. So, from that aspect, I think when
I look at oral products, immediate
release
products, and here is my demarcation in
an attempt
to sort of categorize what is
uncertainty, what is
variability, and what is risk.
The goal of our generic drug
approval
process is to approve a generic
product. An
approved product is expected to have the
same
clinical effect and safety profile when
administered to patients under conditions
specified
in the labeling.
Based on the previous slide, I
have shown
the characteristics of this decision
system is,
one, the first one, the product must be
pharmaceutically equivalent, and here the
questions
22
are has the applicant demonstrated that
it's the
same active, identical amount, same
dosage form,
route of administration, and so forth,
identity,
strength, quality, purity.
So, that is an assessment
process of how
good the identical methods are and how good
they
have qualified, so it's a knowledge-based
decision,
there is an uncertainty aspect associated
with
that.
Then, we have to define
acceptable
variability for that product, and we rely
on the
compendial or other standards to do that.
The risk in this case, I am
talking about
risk from a clinical perspective, is the
prior
knowledge that come from NDA.
Need for bioequivalence
assessment for
oral products is that next question, and
again the
same words from the Orange Book is if you
do not
present a known or potential
bioequivalence
problem, acceptable in vitro standard is
fine. But
you saw the debate with dissolution, we often
don't
go there, we often go to a bioequivalence
study.
If you go to in vitro standard
compendial
dissolution test method, if you go to a
bioequivalence standard, then, the
acceptable
23
variability is our bioequivalence
standard, 90
percent confidence interval for test or
reference
ratio for rate and extent of absorption
is within
80 to 125 percent.
It has to be adequately labeled
and
manufactured in conformance to cGMPs, and
in that
case, acceptable variability is what we
tolerate in
terms of deviation or specifications, and
so forth.
So, that is one way of looking
at trying
to partition uncertainty, variability,
and risk, so
that we can formulate the right
questions.
Clearly, I think the
quality-by-design
thinking is intended to focus on the
intended use,
and design is about doing things
consciously. I
showed this slide to you before.
I think what we would like to
consider is
in the context of pre- and post-approval
changes,
generic drugs, and even extending that to
the
concept of follow-on protein
pharmaceuticals, the
24
primary goal of a scientific decision
framework--I
am not talking with a regulatory
process--the
decision criteria that we bring, need to
understand
the complexity and uncertainty, but the
decision
process should be consistent.
I think that is the fundamental
basis that
we work under. Furthermore, I think our goal is
also to identify and eliminate
unnecessary human
and animal testing for this decision
framework,
keeping in mind that most bioequivalent
studies are
done in normal healthy subject
volunteers, new
drugs and so forth.
If we can avoid exposing normal
healthy
subject human volunteers, it is
desirable, and that
is part of the regulation. I will share that
regulation with you.
So, Topic 2 today, the premise
that we had
in mind was that a quality-by-design
approach via
pharmaceutical development information
can
potentially provide an excellent means to
address a
number of challenges previously discussed
at ACPS
meetings without complete or satisfactory
25
resolution, for example, bioequivalence
of highly
variable drugs, bio-in-equivalence
criteria,
pharmaceutical and therapeutic equipment
of locally
acting drug products, such as topical
products.
Today, Lawrence will bring his
thoughts to
you, and these are our preliminary
thoughts, and I
think we just wanted to put our
preliminary
thoughts on the table to engage you and
engage the
community to help us think about this, so
that as
we spend our time thinking about this, we
already
have some feedback and we are also on the
right
track.
Rob Lionberger will come
back. He
presented a decision tree to you before,
but he
will recast that decision tree for
topical products
in the context of quality-by-design.
Yesterday, we focused on
dissolution
testing, and as the past chair of the BCS
Working
Group, I took it upon myself to sort of
go back and
re-examine what were my personal thoughts
and what
held me back to make the recommendations
that you
see in the guidance and see how we can
recast that
26
discussion into the quality-by-design
thinking, so
that I can take this discussion and give
that as a
recommendation to the current Technical
Committee
on Biopharmaceutical Classification System.
Again, as I said, these are
initial
thoughts, and our goal is to engage you
in a debate
and discussion to hopefully give us some
perspective are we on the right
track. The three
topics today are:
How can pharmaceutical development
information help to extend the
applications of
BCS-based waivers of in-vivo studies for
immediate
release products?
How can pharmaceutical
development
information be utilized to address the
challenges
of highly variable drugs?
How do we use this to establish
therapeutic equivalence of topical
products?
Those are the three topics that
we would
like to present, and the general question
is are we
on the right track, but then more
detailed
recommendations on how we should proceed
with these
27
three topics or other topics that we
should have
considered instead of this.
So, that is the Topic 2.
DR. COONEY: Thank you, Ajaz.
We might pause for a moment for
any
questions particularly around
clarification of
these opening comments from the
committee. Art?
DR. KIBBE: The question I always struggle
with is how do we define highly variable
drugs.
Are we defining them in clinical
outcomes, because
then the dosage form might not be involved
in it at
all.
DR. HUSSAIN: The definition hinges on the
bioequivalence drug, the variability that
we
estimate from the bioequivalence drug.
DR. KIBBE: But that could be a function
of intersubject variability, subject
population
selection, and have nothing at all to do
or
minimally to do with the actual product
that you
are making.
DR. HUSSAIN: That is the discussion
Lawrence will bring to you, so if you
hold that
28
question for Lawrence.
DR. KIBBE: Thank you.
DR. COONEY: Ken?
DR. MORRIS: The two comments is that the
Topic 2 premise, the other part of that premise is
that the proper development information
is being
generated at the companies which, of
course, you
have limited control over, and that is
being
shared, just as a caveat.
DR. COONEY: Nozer?
DR. SINGPURWALLA: Two comments.
Slide
No. 7.
DR. HUSSAIN: I am sorry, I don't have
numbers.
DR. SINGPURWALLA: I know.
Components of
the Challenge. The second bullet. That second
bullet is wrongly worded, it has to be
changed, and
I will tell you why.
The more important reason is
you, on your
eight bullet, are talking about
confounding of
uncertainty, variability, and risk. They should
not be confounded. Who is confounding them and
29
why?
DR. HUSSAIN: The current system has a
tendency to do that. That is what I mean.
DR. SINGPURWALLA: But that simply means
that the system is not educated enough,
because
variability is the cause of uncertainty,
is one of
the causes of uncertainty, and risk is a
measure,
is
a way to measure uncertainty and its
consequence.
So, why is there so much
confusion about
these very elementary ideas in the
industry and
perhaps in the pharmaceutical community?
DR. HUSSAIN: I don't know how to answer
that.
DR. SINGPURWALLA: Well, they need to be
trained, educated.
DR. HUSSAIN: But let me propose this in
the sense, uncertainty is not risk.
DR. SINGPURWALLA: I agree with you. I
agree with what you are saying
completely. What I
am asking is, what is the cause of this
confusion,
and it is so easy to remove this
confusion?
DR. HUSSAIN: I understand the concern you
are
expressing, and my premise is for years we have
not utilized the pharmaceutical
development, and we
30
have treated that as an art rather than a
science,
and that is the way to get away from that
confusion. So, that is the premise.
DR. COONEY: Any other comments at this
point?
We will have ample opportunity for further
discussion.
Using Product Development Information
to
Extend Biopharmaceutics
Classification
System-Based Biowaivers
DR. HUSSAIN: Let me go on to the
Biopharmaceutics Classification
System. In
preparing for this presentation, I
actually went
back and reviewed all the publications
that have
occurred in this arena in this
discipline, in this
topic area for the last five years, and
there has
been a tremendous number of progress in
this area.
For example, more recently, Professor
Les
Benet's article was published on how you
can
actually start predicting metabolism, and
so forth,
31
and how you can sort of add that
additional
dimension.
There has been a paper
published in Pharm
Research on quantitative instead of, you
know,
rigid boundaries, and so forth.
But instead of sort of trying
to summarize
the progression signs, what I wanted to
do was to
go back and re-examine my own thoughts
that were
expressed to the Advisory Committee in
the year
2000, so I am actually going to repeat an
old
presentation, but in light of what we
have learned
in the last four years.
My goal here is to share with
you some of
the concerns we had when we proposed the
BCS-based
waiver guidance in the year 2000, and to
what
extent those concerns remain, and to what
extent
quality-by-design may be able to
alleviate some of
this concern, and the discussion with
you, I intend
to use that as recommendation to the
current
Technical Committee on BCS. So, that is the game
plan.
This is an old presentation
with some
32
minor modification. When I had made this
presentation, I was completely focused on
risk, and
the title was "Biopharmaceutics
Classification
System: A Risk Management Tool."
In light of the learning that I
at least
personally had, I want to sort of bring
in the
uncertainty and variability components to
this.
Since this is a presentation, probably
my
last presentation on the BCS topic before
I handed
over the reins of responsibility to
Lawrence and
Mehul, the new BCS Technical Committee
was formed,
when Helen asked me to move to OPS and
the PAT
process got started, so my focus went to
PAT for a
reason which connects back to this one.
So, this BCS Technical
Committee has been
in place under the leadership of Lawrence
and
Mehul, and they have been diligently
addressing a
number of implementation issues trying to
coordinate all the submissions, and so
forth, and
there has been significant activity on
this
guidance on the new drug side, very
little, if any,
on
the generic side.
You also heard from Mehul the
database is
now almost ready, is being audited,
database and
prospective research for extensions,
links to PQRI
33
and FIP, but the PQRI program really
didn't take
off, and our thoughts were we wanted to
explore
extension of BCS-based biowaivers to
Class III and
Class II drugs.
Further research at the FDA,
which we
completed, and we did extend the
BCS-based
biowaivers to "fed"
bioequivalence studies, and
that was part of the thing, and that work
was done
with collaboration with Tennessee.
Continuing education initiatives
and
practitioners and public, and the group
has been
busy.
International harmonization was an aspect,
but to the extent the definition of high
solubility
and rapid dissolution, we got into ICH
Q6A, the
European Guideline also adopted much of
the BCS
recommendation to some extent. There are certain
differences, though, it is not fully
harmonized.
With that as a background, let
me trace
for you the evolution of the
recommendations in the
34
BCS guidance that we released in the year
2000.
Regulatory Bioequivalence: An
Overview,
from my perspective, this is a graphical
representation of our regulation.
If you look at the dosage form
that we
deal with, solutions, suspensions,
chewable
tablets, conventional tablets, and
modified release
products, for solutions, we consider
bioequivalence
essentially is self-evident,
bioavailability is
self-evident, and biowaivers are granted,
condition
being excipients do not alter absorption,
and that
is an assessment based on historical
data.
For any product that contains
drug in a
solid form, we have a concern, and for
pre-1962
drugs, we call DESI drugs, in vivo
evaluation for
bio-problem, that was the original
biopharm
classification system, if you really look
at it,
that had many of the elements of
therapeutic index,
PK, the solubility, and so forth.
For post-1962 drugs, generally,
in vivo,
some exceptions with IVIVC. Then, we introduced a
SUPAC-IR guideline in '95, and we
introduced the
35
elements of BCS guidance, BCS system in
that to
give a waiver for minor changes and
moderate
changes that Mehul talked to you about
yesterday.
For modified release, we don't
have a
classification system, bioequivalence has
to be
demonstrated in vivo with the exception
of SUPAC
modified release for within a
product. If you have
in vitro bioequivalence, you can make
changes.
Again, Mehul summarized that.
I want to trace back the
discussion to a
bioequivalence hearing, which I did not
attend. I
was just graduating in '86, but I was
connected to
this because I made the slides of a
number of
people who presented here, so I knew what
was
happening.
This was a pivotal discussion
and I think
set the stage for what evolved as
bioequivalence
standard.
There were two comments that I want to
share with you.
One was Dr. Bob Temple. He said, after
the end of this discussion, it seems
sensible to
think that swallowing something that
turns into a
36
solution rapidly would be difficult to lead
to
differences from one product to another.
So, the clinicians were arguing
you don't
need biostudies for everything. Arnold Beckett had
made that argument years at that time, so
he said
you shouldn't go with in vivo for
everything, but
we did.
Milo Gibaldi, an eminent
pharmacokinetic
professor, "I have learned that
there is no support
here for attempting to provide such
assurance
solely with in vitro data." So, that was a pivotal
aspect, I think, and I went back and sort
of tried
to examine the thoughts and the concerns
that were
expressed at that session.
The other aspect that I do want
to put on
the table is need to reduce our reliance
on in vivo
bioequivalence studies. Why?
Ethical reasons. 21
CFR 320.25 says, "No unnecessary
human research
should be done." Science continues
to provide new
methods to identify and eliminate
unnecessary in
vivo bioequivalence studies.
Focus on prevention,
"building quality
37
into products - right first
time." So you see the
PAT initiative and how this will connect
to that
was in the thought process and why we
aggressively
moved in that direction, "right
first time," I used
before Pfizer.
Time and cost of drug
development and
review is a key, because if you see that
we have
three to six bioequivalent studies in our
NDAs. We
actually at some point said we don't even
review
some of those because they are redundant,
so why
expose normal healthy subjects to a new
drug which
is under development with all the risks
associated
with that.
So, prior to SUPAC-IR/BCS, in
vivo
bioequivalence assessments to justify a
majority of
manufacturing changes. So, this was a significant
hurdle, and that changed. In the SUPAC-IR guidance
in '95, we brought in the classification
system and
provided a tiered approach for changes
based on in
vitro.
For example, highly soluble, highly
permeable drug, the critical processes
for gastric
38
emptying, dissolution is not likely, and
dissolution is not likely to be rate
limiting, but
we said 0.1 single point, 85 percent, and
so forth.
So, you can see that for each
class, we
recommended a tiered approach for waiver
of
biostudies for minor changes, and so
forth. We
excluded the Narrow Therapeutic Index
drugs from
waiver consideration, but we never
defined what
narrow therapeutic index was, and we
still haven't.
The guidance in 2000 really
extended that
and put that as a waiver for first time
approval,
and also provided the methods to classify
your
drug, and so forth. The pivotal recommendation in
that was waiver for in vivo
bioequivalence studies.
I do want to stop here and say
the title
of this guidance was debated to the nth
degree
before we agreed on this internally. The word
"waiver" was to signify that we
want an in vivo
study for everything that is in solid, so
the title
was very carefully chosen to reflect
that.
Anyway, it's waiver for in vivo
bioequivalence studies is recommended for
a solid
39
oral test product that exhibit rapid and
similar in
vitro dissolution under specified
conditions to an
approved reference product when the
following
conditions are satisfied: products are
pharmaceutically equivalent, drug
substance is
highly soluble and highly permeable and
is not
considered to have a narrow therapeutic
range and
excipients used are not likely to affect
drug
absorption.
The class membership, the
boundaries that
you see, which are rigid, high
solubility, the
highest dose strength is soluble in less
than or
equal to 250 ml of aqueous buffers over
the pH
range that we had 1 to 6.5 or so,
whatever that
thing is I forgot.
The reason for 250 ml is the
glass of
water that we take when we do a
bioequivalence
study.
High permeability, the extent of absorption
in humans is determined to be greater
than 90
percent.
Rapid dissolution is 85 percent
dissolves
within 30 minutes in three different
conditions,
40
HCL, pH 4.5 and 6.8 buffers using
traditional
settings of dissolution apparatus.
Now, clearly, I had approached
this as a
risk to bio-in-equivalence because since
we started
with the premise that you needed
bioequivalence
trials for approval of changes, and so
forth, so
the risk factor for me was the proposal
the
recommendations should not result in
bio-in-equivalence.
The risk factors that we had in
mind were
clearly manufacturing changes, poor
process
capability, high between and within batch
variability, but the thing we focused on,
reliance
on in vitro dissolution tests and how
reliable that
is, single point specification, sampling,
predictability were the issues.
Clearly, the other factors were
there,
deficiencies in BE study design, Type II
errors,
and so forth.
Now, assessment of risk, what
is the risk
of bio-in-equivalence between two
pharmaceutically
equivalent products when in vitro
dissolution test
41
comparisons are used for regulatory decisions?
That was the question we asked.
What is the likelihood of
occurrence and
the severity of the consequences?
Severity was not meeting the
bioequivalence criteria was unacceptable,
but what
was the likelihood, so we needed some
information
on that.
Regulatory decision, whether or
not the
risks are such that the project can be
pursued with
or without additional arrangements to
mitigate the
risk, and clearly, acceptability of the
decision,
is the decision acceptable to
society? This took
four years.
We started working on this in
'96, and if
you think I was busy with the PAT
presentations
around the globe, that is exactly had to
do the
same thing for this one, too, because the
mind-set,
the paradigm was so entrenched in the old
system.
Professor Gordon Amidon spent
some time
with us, he and I. I had the luxury of having the
biopharm document room right outside my
office in
42
the Parklawn Building, so we went through
a number
of applications, about 160 applications
at that
point, to get a sense of what is
happening.
Roughly, what we found was on
the new drug
side only, because we have failed studies
or we
have all the studies submitted on the
generic side,
we couldn't use that database because you
just have
the passing studies in there.
So, we looked at the new drug
side and
said when does dissolution signal
bio-in-equivalence or does not signal
bio-in-equivalence. What we found there was
generally, you see big differences in
dissolution,
no difference in blood levels.
But, on the other hand, there
were signals
that dissolution fails to signal
bio-in-equivalence
about 30 percent of the time, and we
wanted to ask
why.
So, minimizing risk of
bio-in-equivalence,
does in vitro dissolution process emulate
in vivo
dissolution process in vitro and in
vivo? Dosage
form disintegration, dissolution, and
stability
43
were the concern.
The gastrointestinal fluid
volume,
composition, and hydrodynamic conditions
were the
concern, and clearly, I think one thing
which was
pivotal for the oral discriminating part
was the
surface tension, and that could have been
picked
up.
Residence time in the stomach
and small
intestine were an issue, so we did a lot
of
analysis actually of gastric emptying and
what
factors affect gastric emptying, and so
forth.
Impact of excipient differences
on GI
physiology and drug bioavailability were
the
questions.
The key question was how well
this
emulates in vivo, because this is our
standard
dissolution test.
This was a cartoon that I
prepared and to
take a look at typical physiologic
parameters in a
single dose fasting BE study. We had fairly good
estimates of the gastric fluid plus the 8
ounces of
water.
We knew what the gastric pH range is
44
generally in the normal subject.
We had the information on the
gastric
emptying time, which is highly variable,
but
approximately T50 is 15 percent. The permeability
is low, and that was an advantage in the
stomach
compared to small intestine, the surface
tension is
lower, and clearly, volumes in the small
intestine
were uncertain, and pH, and so forth, and
the
permeability was high. Hydrodynamics was a big
question in our minds.
Lawrence summarized to you the
debates
that we have had for dissolution for the
last 30
years, and that dissolution tests are
over
discriminating, on one hand, and in the
USP, the
statement that products that dissolve
about 70
percent in 45 minutes have no medically
relevant
bioequivalence problems, what was the
basis of
that.
Dissolution tests are not
sufficient to
assure bioequivalence, and demonstration
of IVIVC
is necessary, but when you do that,
product
specific, so those are two sides of the
debate.
I showed you this slide of the
problems
with the dissolution tests of false
positives and
false negatives, but then we also looked
at things
45
that we made decisions on.
Here is a product. The generic product
was Product B. We actually withdrew this product
from the market after approval. This is a pre-62
drugs, it was approved on the basis of
dissolution,
meeting the USP specification criteria.
This was a pre-62 drug, one of
the older
drugs, and we had a challenge from the
innovator,
which is Product A, that the generic is
not
bioequivalent, and that was the basis at
which we
had withdrawn this product, Product B,
from the
market.
The Cmax, you can see is
clearly high, but
in many ways, Product B was more
reliable, less
variable, and it was more modern
technology, but
the constraints on us is you have to be
equal, if
not better.
Here are examples of where
there were real
dissolution impacts on in vivo
absorption. Here is
46
a weak acid where the initial formulation
for
clinical was capsule. They went to
wet-granulation, and the to-be-marketed
was a
direction compression with dicalcium
phosphate, and
the dissolution in this case was Q17 30
minutes in
simulated intestinal fluid.
That's the criss-cross you see
if you do
acid in alkaline conditions, you don't
distinguish
that, and this had to be
reformulated. But this
was
I think in my mind a signal that we probably
are designing our products for
dissolution rather
than the intended use.
I wanted to walk through this
with you,
and that was one of the reasons for the
quality-by-design thinking.
Here is a Drug X. This is actually a
clinical study, 100 mg dose, so it's a
highly
soluble drug by all definition. It's a weak base
exhibits a sharp decline in solubility
with
increasing pH above 3.
Now, the clinical trial
material in this
case was wet granulation, drug particle
size of D50
47
of 80 microns, and this was a concern,
because our
particle size specification was very
crude. I mean
what does D50 percent give me. We had lactose,
microcrystalline cellulose, and so
forth. You see
that formulation there.
But the point to focus there is
the
dissolution 0.1 normal HCL was 65 percent
in 15
minutes and 100 percent in 20 minutes.
Disintegration time was 10 minutes.
The way I had presented this,
the
to-be-marketed was the formulation of
direct
compression, but actually the wet
granulation in
this case was a U.S. formulation, a
formulation
using U.S. clinical trials, and the
European
clinical trials were done with the
to-be-marketed,
and we had to bridge those together.
The to-be-marketed formulation,
you can
see what happened here. Direction compression,
drug particle size of 300 microns,
dicalcium
phosphate, and so forth, and the
dissolution is
more rapid now, 0.1 normal HCL - 85
percent in 15
minutes, about 95 percent in 20 minutes,
so the
48
initial dissolution burst is very rapid,
disintegration time is 1 minute.
Clinical product exhibits poor
dissolution
at 7.4. Can you imagine, I mean this is a
BCS Class
I drug.
The Cmax or the rate or the exposure of
this in terms of p concentration for the
to-be-marketed formulation in this case
was half,
so you see half the blood levels in terms
of
height.
So, it simply was signal that if you don't
get the physicochemical properties of
drug
understood, you will have these problems.
So, in vitro and in vivo dissolution,
dissolution methods evolved over the last
30 years.
The year 2000, I said there were
reproducible test
methods for lot-to-lot quality assurance,
so you
can imagine my surprise of the
calibration, which I
was not aware of at that time.
The dissolution media volume
and
composition selected to maintain
"sink" conditions.
In vivo dissolution is a complex process,
and you
have to consider pH profile, bile
concentration,
motility patterns, and so forth.
In vivo, the "sink"
condition is created
due to intestinal permeability, and this
was a
contention, which Lawrence and others, we
recently
49
published to show how permeability
actually impacts
in vivo dissolution, so we have published
on this
now already.
I will talk to you about in
vitro-in vivo
correlation. The formulation specificity of IVIVC
has been known since 1997. This is drug
spironolactone from a publication in J.
Pharm
Science in '97.
So, you can see a change in
particle size.
You may have a correlation, but a change
in
particle size could be outside that. So, a
correlation itself why this formulation
specific
has to be really brought into context.
So, reliance on current
dissolution
practice can pose an unacceptable level
of risk
from bio-in-equivalence perspective. Compared to
high solubility drugs, risk is higher for
low
solubility drugs.
Products with slow or extended
dissolution
50
profiles pose a higher risk. The dissolution is
rate limiting.
So, in a sense, we wanted to
use
dissolution test only to rule out that
dissolution
is not rate limiting. So, that was the basis for
our thought process. So, we constructed a rapid
dissolution criteria for that
purpose. We did not
want to use dissolution tests for
bioavailable
decisions if there was a hint that
dissolution is
rate limiting.
Potential for significant
differences
between in vivo and in vitro
"sink" conditions
higher for low permeability drugs, which
we had to
prove later on with a simulation study
that
Lawrence did.
Now, to establish a boundary
for rapid
dissolution, we simply postulated that
since
gastric mucosa does not have high
permeability to
drugs, you have a 15-minute time, so you
can take
advantage of that.
So, if the dissolution is rapid,
then,
much of it is complete before it empties
into the
51
small intestine where you have high
permeability.
So, in a sense, a very rapidly dissolving
drug will
behave essentially like a solution, and
it does.
So, here is a snapshot of
dissolution
versus AUC and Cmax ratios and the
bioequivalence
goalpost of a drug metoprolol. The reason I did
not take the name off here, because this
is already
an ACPS presentation, it is already on
the website.
So, you can see a solution
versus all the
other formulations that we have approved,
generic
and innovator, plus there are research
formulations, which we deliberately made
to be very
slowly dissolving.
You see that essentially, for
the most
part, the slope is zero. We then did extensive
simulation work to establish that if in
vivo
dissolution is rapid, as a function of
different
gastric emptying as a function of mean
intestinal
transit time, you are not likely to see a
difference between solution and a tablet,
and that
was the basis for our 85 percent and 30
minute in
vitro criteria for rapid dissolution, but
we did
52
not apply that to low permeability drugs
because of
the risk factors that we felt were coming
from
excipients.
The question we asked was is
the current
approach for evaluating excipients for
decisions
related to biowaiver for oral solutions
sufficient.
That is the database I have.
There were hints that the
excipient
effects were not fully appreciated. For example,
there was a study by Ian Wyling's group
where you
could show mannitol, 2.3 grams of
mannitol clearly
had a big impact on bioavailability of
cimetidine,
a low permeability drug, and on the other
hand,
Fassihi had shown that a high
permeability drug had
minimal impact of sorbitol, even 10 grams
of
sorbitol.
So, that was a hint, and we
actually
conducted a study at the University of
Tennessee,
and we have now completed that study,
even getting
to a mechanistic basis for generalizing
the
permeability effect to other excipients,
is to test
this out.
Metoprolol was our boundary drug
for high
permeability, so we did a study with
ranitidine and
metoprolol, and we did a crossover study
in
53
replicate design to get an estimate of
subject, the
formulation interaction also.
So, it is a very simple
formulation. You
have your drug. You have sucrose or sorbitol, and
you have 15 ml of water. That is the simplest
study.
What we found--I will just show
you a
picture--just a confirmation for a low
permeability
drug like ranitidine, a dramatic effect.
Now we have completed the study
of the
dose response, the amount of sorbitol
that triggers
this is about 1.2 grams. For metoprolol, the Cmax
was affected, but not to the same
extent. AUC was
not.
In addition, there were a
tremendous
amount of information coming out of other
excipient
effects on transporters, and so
forth. So, this
was an evolving issue at that time, and
it
continues to be evolving issue, and
methodologies
54
were being proposed of in vitro
evaluation of this.
I won't get into that.
But we also did an extensive
evaluation of
excipients and what we found was I think
in most
cases, excipients that are used in solid
dosage
form really do not have a significant
impact, but
the way we had to evaluate that was
comparing the
differences in formulation that we have
approved,
like, for example, verapamil, and so
forth.
But the risk factor was
excipients. Is
the current approach for evaluating
excipients for
decisions related to biowaiver of oral
solutions
sufficient? Well, I think we left the question
there.
For BCS-based biowaivers, a
higher
standard was adopted by limiting
biowaivers to
highly permeable drugs. Excipients used
in solid
oral products are less likely to impact
drug
absorption compared to liquid oral
products,
because it was simply the volume and
amount in
there.
For example, we had products on
the market
55
that contains 23 grams of sorbitol in one
dose, so
you can see cross interaction possibly.
High permeability attribute
reduces the
risk of bio-in-equivalence, decreased
small
intestinal residence time by osmotic
pressure,
because low permeability generally have a
tendency
to be absorbed in small segments of the
intestine.
Clearly, on the other hand, the
boundary
that we chose for high permeability to be
90,
because there are other surfactants, and
so forth,
that could increase permeability, so if
you set
your boundary at 90, there is no risk of
failing.
There were other examples. There were so
many examples that we had not really paid
attention
to.
Here is a submission--not a submission--this
is a graph that a student of mine sent me
from a
company, and they have seen such effect.
Here is a drug, a tablet and a
solution.
The solution has almost half the
bioavailability of
a tablet, so you can see that, with
sorbitol or
mannitol for a low permeability drug, it
can have
lower bioavailability.
So, that was the basis that we
came up
with the recommendations and the
boundaries for the
BCS classification system that gave the
basis for
56
waiver for new drug applications.
So, Class I drug, you have
jejunal
permeability. This was our research that
we
classified the number of drugs, and the
volume of
water required to dissolve the dose on
the x axis.
Class I dissolution in vivo is not likely
to be
rate limiting, and well characterized
excipients.
So, dissolution itself is likely to be
rapid
inherently, and then we can rely on in
vitro
dissolution for that purpose.
Class II dissolution is likely
to be rate
determining and complex in vivo
dissolution, and
solubilization process, so no, not going
there.
Class III was where the debate
was. Some
hesitation with the use of current
dissolution
test, because the site specific
absorption was a
concern, and excipients.
Class IV was generally problem
drugs with
in vitro dissolution may not be reliable.
So, that was the basis for our
recommendations.
So, wrapping up, in terms of
quality
design thinking, what can we do now? If I
summarize my concerns, one major concern
was if we
went towards a dissolution-based method,
people
57
will design products for dissolution
rather than
the intended use was a concern, and that
example
sort of illustrates that, the one
to-be-marketed
difference, that was a concern.
So, I wanted to feel
comfortable having
some formulation assessment as part of
this
extension. Clearly, I think excipients and the
transporters, all were evolving issues at
that
time.
There is a lot more information available
now than we had.
So, in quality-by-design
thinking, you
really have focus on what are the
critical
variables that affect dissolution, and
these are
easily identifiable especially for
immediate
release dosage form.
You easily can start thinking
about
58
excipients and what their impact might be
on
solubilization, and so forth, and
Lawrence himself
has done some work in this area, and so
forth.
So, with that in mind, what my
thoughts
are, in addition to thinking about
evaluating the
boundaries themselves, I would like to recommend
to
the group that, first of all, BCS should
be, and
probably will be, a key, too, in
quality-by-design
decision trees that we talked about.
I mean solubility, permeability
characterization has to be a starting
point for the
formulation, so clearly, I think we need
to build
these concepts in the decision trees we
talked to
you about yesterday, but also
quality-by-design and
design space with respect to pre- and
post-approval
by
bridging studies. Waivers for in vivo
studies
based on design space concept, sort of is
that
connection to extension concept.
The challenge I think is from a
generic
industry perspective, there is a lot of
hesitation
to seek for approval, the first time
approval, a
biowaiver based on that, concerned with
59
permeability assessment, and so forth.
That concern probably will remain.
It is not a scientific concern,
it is a
perceptional concern, it's a regulatory
concern,
and so forth, but that doesn't say that
you cannot
classify a drug for a generic product
after
approval.
The rest of the post-approval changes,
they could be based on that, and that
could be
quality by design.
I think those are the key
connections that
if the Technical Committee sort of starts
building
in, their efforts really get connected to
the PAT
and the quality-by-design thinking, so
you see the
connections sort of evolved.
Clearly, they have already
started
developing in FDA's knowledge base, a
knowledge
base.
Drug-excipient interaction, I think is an
increasing issue from chemistry and
clinical
pharmacology aspect, and I think you need
to start
connecting those dots.
At the same time, drug
substance and
formulation variables and clinical
performance that
60
Mehul alluded to the variability, but
with what is
happening on the clinical side now, with
focus on
biomarkers, focus on surrogate markers,
and so
forth, I think we need to proactively
keep an eye
on that.
I mean this is an evolving
issue, but seek
out some connectivity between quality and
clinical,
and be available to what is happening at
least, and
that is the point I made also to Jurgen
yesterday
when he gave his report.
So, with that, let me stop and
open it for
discussion.
DR. COONEY: Thank you, Ajaz.
Comments and questions from the
Committee?
DR. MEYER: While I am formulating my
question, I will ask another one, so I
will give
you some time to think.
How confident are you that our
knowledge
base on excipients allows a reviewer to
sit back
and say, well, it has X, Y, and Z, and
therefore,
there is no problem?
DR. HUSSAIN: Well, I think the
61
traditional excipients for immediate
release dosage
forms that we use as formulation aids for
process
ability, and so forth, I am fairly
confident that
there are very little concern there.
There are other excipients that
are
necessary to aid in the dissolution
process, such
as surfactants and other aspect. I think a close
grouping of those would be
necessary. I think if
we collect this information, it will
start making
the case, but if you have properties,
such as high
solubility, and so forth, you probably
would not
need those anyway.
So, I think you can carve out
excipients
that we know are not an issue.
DR. COONEY: If I can just pick up on
Marvin's point for a moment, your initial question
was about knowledge base of the
excipients per se,
but it is really the relationship of the
excipients
to the drug substance, to the API, that
seems to be
the area of uncertainty, and that
knowledge, it
seems to me, is much less clear.
DR. HUSSAIN: If I amy sort of put that in
62
the context, traditional screening
experiments that
are done for drug excipient
compatibility, may
provide not only information that will be
useful
for stability, failure modes of the
product, but
also hints about the interactions among
excipients
and drugs, how they might have a bearing
on
dissolution.
DR. COONEY: Ken.
DR. MORRIS: The point you just raised is
the source of my question, as well, since
drug-excipient interactions are typically
for
chemical stability.
Is it like particularly for
something like
BCS Class III, is it more of the concern
that the
interaction with the drug is changing
absorption,
or that the interaction of the excipient
with the
mucosa or the sites of absorption?
DR. HUSSAIN: I think they are both
concerns in the sense, but the concerns
we had when
we were working on this were more on the
impact on
the GI membrane, transporters, and so
forth, the
concerns with excipient-drug interactions
that
63
might be physicochemical were less of a
concern,
because we did not really focus on that
aspect.
DR. MORRIS: That is sort of where I would
assume it, but I just don't know enough
biopharm.
DR. HUSSAIN: The aspect I think is this.
I think the draft guidance that we have
issued on
polymorphism, for example, I think is a
concentration there, in the sense what we
have said
is you could have a different polymorph,
but if you
can design your product well and if it
meets the
criteria, it's fine.
So, I think that is the
flexibility that
already sort of comes through that, is
that ability
to demonstrate that, you can be
different, but yet
meet the intended use.
DR. COONEY: Art, then Marvin.
DR. KIBBE: This is more complex than we
can handle in one or two days. The number of
excipients you use exponentially
increases the
possibility that one excipient is
reacting with
another excipient, that is reacting with
the API.
On top of that, the processing
of the
64
product changes things. I mean we know all sorts
of problems with mag. stearate and
overblending,
but we know certain issues. The question
that
always sits in the back of my mind is we
have been
discovering these issues on a regular
basis over
the last 20 years, have we discovered
them all, and
how can I be naive enough to think I have
discovered them all, and I don't think I
have.
So, that gives me a basic
uncomfort level
with just waiving stuff when I really
want a part
that works in my patients. So, I am uncomfortable
with that.
I have a question, a substantive
question.
If I make a soft gelatin capsule which
contains a
solution, is it a solution or is it a
capsule?
DR. HUSSAIN: Capsule.
That's the way it
is.
DR. KIBBE: On your basic I guess third
slide, I could argue it's solution.
DR. HUSSAIN: Yes.
That's the aspect, I
think now we can start thinking about
those aspects
if you have not done so in the past.
But let me go back to the
concern you
raised in the sense, impact of magnesium
stearate,
and on dissolution, it is clearly
documented.
65
Impact of magnesium stearate on in vivo
absorption
has not been done yet.
All the studies we have done,
we had no
impact of magnesium stearate on immediate
release,
and so forth, on in vivo absorption. I could not
find a single paper that conclusively
tells me that
what we see in vitro, the big difference
is
translating in vivo differences.
There are two reasons for
that. One, is
that old study that was published in
1967, J. Pharm
Science, by Professor Newton from the
University of
London, where he demonstrated for lithium
carbonate
that if you include a very, very small
amount, 0.01
percent or 0.001 percent of sodium
sulfate in your
formulation, you negate the effect of
magnesium
stearate that you see in the solution.
So, that was a hint to me that
suggested
that the surface tension differences that
we see
between in vivo fluids and in vitro
fluids probably
66
are the reason, because all the studies
we did at
the University of Maryland, we actually
probed this
for a low solubility drug--I am
forgetting the name
of the drug--we didn't see in vivo
relevance of
that.
So, now that is the reason we have
to
start thinking about is risk-based
decision to
really understand the behavior of things
in vitro,
because one of the concerns that we had
earlier was
you see big differences in vitro, how do
you know
this will or will not translate.
If quality-by-design, we are
thinking, why
is this assessment, then, that provides a
basis to
think about it.
DR. KIBBE: But that argument, I think
would logically lead us to the conclusion
that we
have to go to a bioavailability study, we
have to
go to a clinical trial. We can't rely on any of
the standard tests that we do that are
surrogates,
because they don't work out, because they
either
show a problem that isn't real, or they
ignore a
problem that is real.
DR. HUSSAIN: Right.
That second bullet,
that is what I am really thinking
about. If you
have to qualify your design space, your
67
bioavailability studies, if you are a new
drug
applicant, that becomes your test of
hypothesis is
to say that we have looked at these are
the big
differences we see that has an impact.
So, one category of BCS-based
biowaivers
would be SUPAC related where you have
demonstrated
this in vivo, and that becomes the basis
for that,
and not just rely on in vitro testing and
lack of
that information.
So, waiver is an extension of
SUPAC in
terms of design space is a bigger
opportunity
probably in the quality-by-design
thinking.
DR. COONEY: Marvin.
DR. MEYER: Ajaz, I think I asked this
question yesterday, and I think you said
you were
going to address it and maybe you did and
I missed
it, the rigid fixing of the--
DR. HUSSAIN: Boundaries.
DR. MEYER:
--boundaries. I really don't
68
have any problem with the rigid
definition of high
solubility, high permeability, I mean we
have
pretty well nailed that down, but then
you have, of
course, if it's soluble in greater or
less than or
equal to 250, well, if it's only soluble
in 300, is
that really poor solubility, and if it's
only 89
percent absorbed, is that really low
permeability,
and, if so, does it fall in that 30
percent
probability of failing a product?
How do you deal with--you have
to draw the
line, but on the other hand, you draw the
line, it
becomes somewhat arbitrary and capricious.
DR. HUSSAIN: Very good point. This is I
think an important point because the
objective of
this guidance was to make the
decision. This is
the decision. You meet this, there is no issue.
If you don't meet, you always have an
option to
explain, but nobody uses that option.
So, this, in my opinion, is an
approach
that we had before. In the new paradigm, the
decision trees that we developed opens
the door in
a sense.
Here, the decision is pre-made, but
69
instead of premaking that decision, how
can you
allow your science to drive a decision
process that
can justify the recommendations that
come, but that
then becomes specific to a company. It is not a
general guidance. It is a decision tree to arrive
at a proper decision.
So, that would be an extension
concept for
BCS, not a general decision
recommendation, which
is what we have been trying to
achieve. It has
changed the boundaries, and so
forth. But to
incorporate that as a decision process,
it becomes
demonstrate this, and the decision can be
yours
sort of a thing.
DR. MEYER: So, it's sort of a work in
progress, so to speak.
DR. HUSSAIN: It's not.
I mean I think
the group has been busy with a number of
things,
but this isn't a thing that they could
start
thinking about, we have not done so.
DR. COONEY: Ajaz, if I can get clarity on
that point. I think the point you just made is
that the decisions on class membership
will be
70
integrated into the thinking about the
decision
trees.
DR. HUSSAIN: Yes.
DR. COONEY: Is that correct?
DR. HUSSAIN: Definitely.
If you are a
Class I drug and you exhibit the rapid
dissolution
with the conditions we have outlined, the
decision
is okay.
Anything else, the guidance does not
recommend a waiver. That's how it is.
Based on what Marvin just
suggested, and
what I am formulating that as, this is a
decision
for every sponsor right now. Their design and
process understanding would vary from one
end to
the other end, but one way of extending
this
concept is not a general decision that
this is
where you get the waiver, but to define a
decision
tree and how you demonstrate to the
degree of
confidence that we need, that waiver
would be you
have demonstrated an understanding that
the waiver
will be granted.
That will be Class I, that will
be Class
II, that will be Class III, so you have
different
71
levels of complexity in those, but the
signs and
the level of understanding could drive
you to that,
but that probably will become a
post-approval as
part of the design space.
DR. COONEY: Tom.
DR. LAYLOFF: I think I am not confused,
but
I don't understand some things like when a drug
goes into the intestinal space, it is
bound, not by
water, but probably proteins and various
other
things that are present in the medium,
and then it
is absorbed through different sites
depending on
how it is wrapped in with the rest of the
medium,
and that is a drug-specific property,
which then
can be affected by an excipient, which
might change
the transport site, it may change the
structure of
the solution characteristics, is that
correct?
DR. HUSSAIN: No, I think the basic
premise is this, yes, you can have
binding, you can
have a number of other complexation
reactions, and
so forth, that occur. Many of those are ionic and
loose, so you establish equilibrium.
For some drugs, you have
complexation that
72
really are almost very tight like with
calcium and
tetracycline, and so forth, there are a
few such
examples, but in this scenario, what we
are talking
about are equivalent behavior of the same
drug
molecule in two different formulations.
So, if there are intrinsic
properties of
the drug molecule itself that will
contribute, but
that molecule is the same, that we are
dealing with
two formulations. Now, how do formulations act
with that behavior is a concern.
I will sort of extend that
concern to a
paper that we had, a poster that we had,
is that of
precipitation. A weak basis will dissolve very
rapidly in acid conditions, but when they
get
emptied, there is a potential for
precipitation,
and so forth, and that could be a very
complex
process, and the size of the particles,
not
precipitation, crystallization may differ
based on
the excipients you have and the
conditions you
have.
There is a potential that
excipients could
impact that. So, that is generally Class II drugs,
73
that's the boundary for Class I for high
solubility
was intended to prevent some of those
things from
occurring, too.
DR. LAYLOFF: Do you think the
complexation and coordination around the
drug
substance would actually affect the
transport site,
change the site of transport, would change
the
properties of the system?
DR. HUSSAIN: Yes, it is clearly possible,
but unlikely for an immediate release
dosage form
with the type of excipients we use.
DR. MORRIS: You know when I think about,
it sort of makes my head hurt, but when I
think
about--
DR. HUSSAIN: It's complex.
DR. MORRIS: --the amount of time we spent
working on developing design spaces for
the
processing end of things, which as Jerry
says, may
be a way off, but still in comparison
relatively
simple to the larger problem, is there an
opportunity in the context of using
development
data to somehow leverage tox studies to
be able to
74
get early reads on, not the tox itself,
but in
terms of some of the dynamics that are
going on
with the dosage forms?
DR. HUSSAIN: I have a decision tree,
which I did not present yesterday, but it
was part
of the handout. That decision tree came out of our
AAPS workshop on how to leverage
that. The paper
is published, Diane Burgess [ph], Eric
Duffy from
FDA is on it, so it is there in your
handout. I
don't have it in this one. Take a look at it.
That leverage is every bit of
information
coming from Pharm Tox, and so forth, to
start
building that case for that.
DR. MORRIS: For the design of the dosage
form?
DR. HUSSAIN: Yes, for particle size
dissolution and bioavailability
concentration.
DR. COONEY: Marvin.
DR. MEYER: Ajaz, when a generic company
sends in their ANDA, it was my
understanding that
the generic group does not go back to the
NDA to
review the contents of the NDA, so they
don't look
75
at the excipients and see which
excipients are now
different in the ANDA than were in the
NDA product?
DR. HUSSAIN: I will let Lawrence answer
that, but we do have a process of
inactive
ingredient guide that we consult, and so
forth. I
put him on the spot here.
DR. YU: I guess this morning we talk
about excipients, which emphasize how
complex the
process is. Yes, with advances in molecular
biology, we discovered I even don't know
how many
transporters going on. As far as the PGP, at least
32 and 64 is transporters, however, I
want to
emphasize that how those transporters
impact
absorption we rarely see in clinical
settings.
In other words, we very see
excipients
impact on absorption of Drug A, B, C, D,
but in
vivo setting, we have very, very few, two
or three
publications out there compared to tens
of
thousands of publications to show that
excipients
impact in vitro.
So, I have to say that we still
want to
see more evidence to show the impact of
excipients
76
on absorption of drugs in general.
Secondly, while we see the impact exceeds
absorption, we very open to see the
unique of some
of the products out there. The reality for, say,
70 or 60 percent of immediate release
products,
people espouse the intensity, use very
limited
number of excipients, I would say 10,
within 10.
For example, Avacel almost uses the
majority of
products.
All those excipients impact, and have
not seen in vitro, as well as in vivo.
Certain, because of those
common used
excipients, since we have a sufficient
knowledge to
judge whether they are going to impact
absorption
or not, will generate and not see the
formulations,
however, in very few cases, some cases,
we suspect
potential impact of excipients
absorption, we will
look into it further before we make any
scientific
decisions about approvability of any
NDAs.
I hope that answers his
question.
DR. HUSSAIN: The other aspect, just to
build on what Lawrence said,
traditionally, the
composition, especially for immediate
release, it
77
is hardly any different than the quality.
DR. MEYER: My real question was do you go
back and look at the NDA to see if Pfizer
used
Avacel, and Teva used who knows what, do
you make
that comparison, say, well, wait a
minute, they are
putting in two things instead of Pfizer's
one
thing.
Can that potentially make a
difference?
Do you review the NDA product
composition?
DR. YU: Well, certainly, we will review
any scientific literature out there and
information
available to us to make the best
decisions.
DR. MEYER: But do you review the NDA?
DR. HUSSAIN: Marvin, often we don't have
to, because it's in the label.
DR. MEYER: Well, that's true. It didn't
used to be.
DR. HUSSAIN: But definitely, the criteria
there is to look at what has been
approved and what
has been used in dosage forms and
inactive
ingredient guide, and so forth.
DR. YU: I guess the answer is as long as
78
are trying to build in the science base
or any ANDA
decisions,
we will use any information which is
available,
whether scientific literature or not, to
us.
DR. COONEY: Are there any other questions
at the moment? Thank you, Ajaz.
We are running a bit ahead of
schedule. I
think this would an appropriate time to
take a
break for 15 minutes. We will reconvene at 8 past
10:00 and then begin immediately with
Lawrence Yu's
presentation.
[Break.]
DR. COONEY: I appreciate everyone's
diligence to staying on time. It has worked very
well.
Lawrence Yu will proceed with a
presentation on Using Product Development
Information to Address the Challenge of
Highly
Variable Drugs.
Lawrence.
Using Product Development
Information to Address
the Challenge of Highly
Variable Drugs
DR. YU: The assignment to me today, this
morning, is for me to discuss how to use
pharmaceutical development information to
address
79
or potentially address the bioequivalence
issues of
highly variable drugs.
Before I go on and talk about
how to use
or potentially use the pharmaceutical
development
information to highly variable drugs by
equivalency
issues, I want to give you a very brief
overview or
update what has been happening before.
For highly variable drugs, this
is not the
first time, it's the second time we
present it to
you.
In the first presentation on April 14th of
2004, we discussed the challenges and the
opportunities for bioequivalence of
highly variable
drugs.
At this meeting, the objective
was to
explore and define bioequivalence issues
of highly
variable drugs, for example, what is
called highly
variable drugs and discuss potential
solutions to
deal with the bioequivalence of highly
variable
drugs.
We invited a number of speakers
from
industry, academia to address issues
related to
bioequivalence including why the
bioequivalence of
highly variable drugs is an issue, highly
variable
drugs a source of variability by Gordon
Amidon from
the University of Michigan, and the
clinical
80
implications of highly variable drugs by
Leslie
Benet, and from bioequivalence method include
the
skin method by Laszlo, as well as
bioequivalence of
highly variable drugs, we had a good
discussion at
this meeting.
I want to highlight some of the
things
which have been discussed at this
meeting,
particularly the slides by Professor
Leslie Benet
from the USCSF. His talk with implications of
highly variable drugs, the argument was
why highly
variable drugs are safer.
Specifically, he said for wide
therapeutic
index highly variable drugs, we should
not have to
study the excessive number of patients to
confirm,
to demonstrate that two equivalent
products meet
the preset statistical criteria or by
equivalent
81
standards.
This is because, by definition,
highly
variable approved drugs must have a wide
therapeutic index, otherwise, there have
been
significant safety issues and lack of
efficacy
during Phase III.
Highly variable narrow
therapeutic index
drugs are dropped in Phase II since it is
impossible to prove either efficacy or
safety.
Now, for the benefit of some
new members
for this committee, I have two slides to
briefly
review why this issue, why the
one-size-fits-all,
what we are using today.
In order to determine
bioequivalence, we
normally define as a rate of bioavailability,
defined as a rate and extent of drug
absorption.
Bioequivalence is defined as absence of
significant
difference in the rate and extent
absorption.
In practice, when we give the
drugs
orally, for example, to a healthy
volunteer, we
will draw the blood. We got the plasma
concentration profile. We are certainly not able
82
to get exactly how much and how fast drug
gets
absorbed, therefore, in practice, we use
AUC, area
under the curve, to represent extent of
absorption.
We use Cmax as a surrogate for
the rate of
absorption, certainly in some cases we
also look at
Tmax, because indeed, if you look at Tmax
and Cmax
here, it represents the rate of
absorption.
So, from that, we will define
what the
bioequivalence study is passing or not
passing.
Basically, the bioequivalence criteria,
either
statistical criteria here is 80 to 125
percent.
At this date, that is the
one-size-fits-all regardless drug, drug
product,
regardless of therapeutic class,
regardless for
anything, that bioequivalence study, you have
to
use preset, so-called bioequivalence
criteria,
which is 80 to 125 percent.
Now, let's look and explain why
the highly
variable drug is an issue. Let's look at the red
one.
If you use a highly variable or intersubject
variability is high. Statistical confidence
interval, if you use the same number of
subjects,
83
when variability goes higher, the
confidence is
going wider.
When confidence gets wider, it
becomes more and more difficult pass the
confidence
interval or bioequivalence interval if 80
to 125
percent.
So, that explains when the
variability
goes higher, it gets more and more
difficult to
pass a study.
On the other side, in order to
narrow the
confidence interval, for example, here it
is fair
to demonstrate bioequivalence for super
red one
here in order to make confidence interval
narrower,
you have to use a large number of
subjects, because
the higher the variability, the higher
the
confidence interval, the higher the
number of
subjects in general, the narrower the
confidence
interval.
Therefore, for highly variable
drugs, you
will have to use higher number of
subjects. Just
to give you example here, for example,
normally, we
have a 20 percent or 30 percent
intersubject
variability. You maybe use 18, 24, even sometimes
84
for good product or good drugs, you only
need to
use 12, actually, they can pass the
bioequivalence
confidence interval.
But this is not always true, because
when
the variability goes higher, now, this
variability
could be because of a drug, or it could
be because
of a product, so think about if
variability goes
100 percent--some of you think 100
percent, that is
unrealistic, but we do have a drug, we do
have
examples--think about with 100 percent
variability,
assume test and the reference, there is 5
percent
difference, you end up it could be 500 or
more
subjects, or 300 subjects, so this is
certainly a
large number of subjects in order to pass
the
bioequivalence study.
So, Leslie argued at the
previous meeting,
from the clinical perspective, this is
not
necessary. To give you a real example, these are
slides from Leslie Benet. Now, you would argue,
you may ask how do we get intersubject
variability.
Certainly, you could get this
number from
literature or sometimes company conduct a
pilot
85
study, get some kind of estimate how many
subjects
need to be used to pass the
bioequivalence study.
Of course, in this case, based
on
intersubject variability, you need to use
300, now
this is the drug.
So, at the previous meeting,
when we
present the issue to you, and also we
present some
of the possible potential solutions
including
widening the confidence interval. Now, that is
very straightforward. You said by confidence 80 to
125 is too narrow for highly variable
drugs, and
your intuitive thinking is just widening
the
confidence interval, that is one of the
potential
solutions.
Another solution is a scaling
approach, in
other words, based on the variability of
reference
list product, reference list drugs, and
calculate,
use statistical approaches to calculate
the
confidence interval, then, to determine
whether the
study is passing or not.
Obviously, I have to say
this. The active
approach because the confidence interval
too wide
86
in order for the study to pass, so let's
widening
the standards.
You came in and asked to do
that, that
certainly the scaling approach, we ought
to
carefully look into, the Committee suggested--a
quote here--"the need to
understanding where the
variability originated. The members added that
prior knowledge of all biostudies may
help set more
appropriate specifications or criteria to
make
decisions.
So, you suggest that we have to
understand
the origin of the variability. Now, to look at the
mechanistic understanding of variability
for drug
substance obviously is the same,
reference list
product and the generic product, or any
other
product, but the potential difference
could be
formulation. Certainly, the generic products could
be narrower or could be wider, the
variability.
We believe at this point, in
order to
understand the origin of the variability,
that
pharmaceutical development report, or
pharmaceutical development information
can help us
87
understand the source of variability, can
help us
make rigid scientific evaluation.
Now, in order to see the
utility of
pharmaceutical development report to
evaluation or
reviews of NDAs, let me go back and
review some of
the basic fundamentals or the premises
for ANDA
approvals.
Ajaz has mentioned about
therapeutic
equivalence. Basically, the products are
considered
to be therapeutic equivalents only if
they are
approved as safe and effective, they are
pharmaceutically equivalent, they are
bioequivalent, adequately labeled, and
manufactured
according to cGMP.
Now, here, I want to emphasize
the
pharmaceutical equivalence. When we define
pharmaceutical equivalence, we basically
have the
same active ingredients, obvious. I know we are
managing about pharmaceutical solid
polymorphism,
which was presented to you two years ago,
has a
drugs guidance out there and published by
FDA in
December of 2004.
You have to be same dosage
form, same
route of administration, and identical in
strength
and concentration, and may differ the
other
88
characteristics, such as shape,
excipients,
packaging, and so on, and so forth.
Now, under the same dosage
form, I think
what the complexity of dosage form is
particularly.
Yes, I would say several decades ago,
that dosage
form is reasonably simple and in most
cases I would
say the immediate release product or
solutions.
Certainly, with advances of
pharmaceutic
industry and the pharmaceutic
technologies,
so-called dosage form gets more and more
complex,
and we now have the soft gel capsules, we
have
ricin [?] product, we have inhersion [?]
product,
presents additional challenge to us in
terms to
make scientific decisions, in terms of make
scientific evaluations.
We therefore would believe a
pharmaceutical development report,
quality-by-design, designed to be
equivalent,
become more and more significant in this
regard.
Why does pharmaceutical
equivalence
matter?
Because of user experience and
expectations. Then, bioequivalence test is
normally conducted in healthy
subjects. Certainly,
we have assumption that equivalence in
healthy
subjects equals equivalence in
patients. Now, we
89
have many, many generic products out
there which
are safe, which is a high quality, which
are
effective, which is the equivalent to the
reference
list product.
So, certainly, we have
tremendous
experience with that, and certainly the
pharmaceutical equivalence presents more
and more,
become because you want to make sure the
data from
the healthy volunteer does the equivalent
in
patient, and against novel drug delivery
systems
presents a challenge.
That is why we want to use more
and more
pharmaceutical development approach to
make a
judgment, pharmaceutical development
information to
make a scientific judgment.
Highly variable drugs very
often have, as
90
I mentioned, a wide therapeutic index,
and the
clinical trials of reference list product
have
established the acceptable level of
variability,
because I said otherwise, these highly
variable
drugs, a big window index, they will be
dropped in
Phase II.
So, under an ideal situation, you will
think about variabilities very high, so
you will
think it should be easier to pass, easier
to design
equivalent product simply because they
are so wide,
the target is wide, so it is easier for
you to
pass.
Obviously, as I said before, if
you use
the preset 80 to 125 bioequivalence
confidence
interval, it is not the case. While we explore our
tentative approaches to deal with the
bioequivalency issues, certainly, the design issues
come out.
So, now, how do we deal with
pharmaceutical development for highly
variable
drugs?
Obviously, sponsor need to understand what
are reference products supposed to do
with origin
91
of variability, and the purpose of design
can be
equivalent, and to evaluate and to verify
the
design and hopefully, in the future, use
the
bioequivalent study design for highly
variable
drugs.
So, we put more emphasis on
design in this
regard to establish pharmaceutical
equivalence, in
order to establish therapeutic
equivalence, which
will be more appropriate.
While we are looking for shared
information for generics with us, there
is a reason
for doing that, not only for evaluation
for highly
variable drugs, certainly for
pharmaceutical
development is required. It's one of the CTD
format.
It is also outlined in ICH Q8, although
they do not apply to us, but I think some
principles should apply to generic
industry also.
Also, more significantly, OGD
question
based on review. Now, this is still a work in
progress, but I want to share some
questions, I
think it is important to ask to share.
What is the formulation
intended to do?
92
What mechanism does it use to accomplish
this?
Were any other formulation alternatives
investigated and how did they
perform? Is the
formulation design consistent with the
dosage form
classification in the label?
So, those questions will help
us get
information about a pharmaceutical
product, the
report will help us, pharmaceutical
product design
and development, make more sound and
appropriate
scientific determination or evaluation.
The question often comes up,
why do we
need to provide those things to the
FDA? That
again is a quality-by-design paradigm,
and
pharmaceutical development report is
where you
demonstrate the drug is highly variable.
Now, this demonstrate not
necessarily to
study, but you certainly use any source
available
to show why this drug or drug product is
highly
variable, and may use a different criteria
other
than 80 to 125 percent confidence
interval.
Also, the pharmaceutical
development is
where you justify equivalence of design,
why do you
93
think the product which you designed is
equivalent
to the reference list product.
During the discussion, the
members ask
whether it is drug or drug product. Now, for
example, Product A, the variability is
the active
ingredient into exceptions, so
formulation design
could be rapid release, so demonstrated
by
dissolution comparison under
physiologically
relevant conditions, if this is BCS Class
I drug,
which is highly soluble, highly
permeable, even
though they are highly variable, you may
still
require biowaiver, otherwise, you will
have to
conduct some bioequivalence studies to
demonstrate
that they are bioequivalent.
Certainly, the approaches to
deal with
highly variable drugs, to deal with the
bioequivalence of highly variable drugs
are still
in discussion and still in
investigation. I am
hoping in the near future we share with
you some
proposal or recommendation we have with
respect to
bioequivalence of highly variable drugs.
Another drug could be drug
product, the
94
drug product could be highly variable,
even drug
substance is I would say low variability,
and
certainly design for equivalence begins
with the
characterization of the reference list
product, and
generic product should target the mean,
and the
current system again would have no reward
for
narrow or less variability of generic
products.
That is why we need to explore the
alternative
approaches or more appropriate approaches
to deal
with highly variable drug products.
I just want to give you some examples of
what we talk about here. This is real data. This
is single subject replicate design, in
other words,
you give the same product to the same
patient
twice.
Here is the plasma level, obviously, I am
sure that out of 80 to 125 percent
confidence
interval, by any standards, it probably
does not
need a statistician to figure this out.
You can see here, this is the
first period
or this is the second period. It is not in your
handout or printout because this is in
color. If
you look carefully, these two curves are
95
significantly different, probably
different by I
even don't know how many folders.
This is a single-dose study
twice,
replicate study design. Sorry, I should do a
better job next time, use red, so you can
see it.
DR. KIBBE: I am just looking at the curve
and wondering why we got the hump at the
back end
and whether the product is intended to
have a
second release.
DR. YU: No, it's simply by design, for
whatever reason this peak has come
out. Obviously,
a second dose, this peak is no longer
there. So,
it's not purpose designed, it's simply
because of
physiology involved.
This is happening because
enteric coated,
this is coated to release at the target
pH, so when
the physiological pH in the
gastrointestinal tract
may fluctuate, and those curves will
change.
Think about, for example, if we
have a
product designed will release a pH 7, so
then in
the terminal ileum, at one point is pH
6.8, you
will not see the release. But a second day,
96
because of food or because of other
reasons,
terminal ileum pH becomes 7 or 7.2, you
do not see
the release. Otherwise, you will not see it.
So, simply pH effect or
significant impact
the absorption.
DR. KIBBE: The product had gotten on the
market because it worked clinically?
DR. YU:
Yes. Even though we see the
significant variation in
pharmacokinetics, but we
have no reason to believe this variation
will
impact safety and efficacy.
So, in order to do more
appropriate
pharmacokinetic studies, we also look
into what
additional information, for example,
develop
information will help support those cases
or
bioequivalence cases, because you can see
the
bioequivalence obviously is very
difficult to
conduct variability probably up to 2 or 100
percent, and the number of subjects very
high.
So, we want to see can we use
any
additional pharmaceutical development
information
to help us to make more proper scientific
97
decisions.
Again, for example, when we are
looking,
in many cases, we do get very consistent,
the in
vitro dissolution actually out to say the
majority
of cases, those help us out to make a
more proper
scientific decision or rational
scientific decision
when we recommend any method to
demonstrate
bioequivalence, but occasionally, we do
get very
strange results, and actually, the
variability is
extremely high and does not help you.
I just want to show you another
case here
when we conduct the dissolution under
physiological
relevant pH condition, and you get
dissolution all
over the place.
Now, this is a 6 tablet, same
lots, same
bottle, put in 6 vessels, you get a
distortion
curve.
So, the next question we ask,
this is a
large variability because of the operator
or
because of other reasons. I think the answer is we
are almost certain those difference is
because of
product, not because of other factors.
So, what I can present to you
today is we
have challenges to deal with bioequivalence
of
highly variable drugs. We use the clinical
98
evaluation and sometimes we are also
facing
challenges when we are trying to use in
vitro
information to help us make decisions.
DR. SINGPURWALLA: Lawrence, what is the
difference between each curve, different
vessels?
DR. YU: Yes, six vessels.
DR. SINGPURWALLA: Six vessels, so it
could be that the vessels are different.
DR. YU: I think I stated that the
variability because other reasons, for
example,
vessel difference, media difference,
degassing
difference, operator difference, assay
difference.
We
do not believe all these reasons can explain.
DR. HUSSAIN: Yesterday, this same figure,
Cindy actually showed you the reason for
this
difference was the coating thickness, and
so forth,
so this is the same slide.
DR. MORRIS: You wouldn't get 2 1/2 hours
difference in dissolution time from
different
99
vessels.
That is not the magnitude you would
expect.
DR. SINGPURWALLA: How am I
supposed to
believe that?
DR. YU: You have to believe in me. You
don't have any other options.
[Laughter.]
DR. SINGPURWALLA: I don't believe in
anyone.
DR. KIBBE: This is a constant pH
throughout, right, we haven't shifted pH
during the
process or anything, right?
DR. YU: Correct.
DR. HUSSAIN: The reason to believe that
is
I think it was done by Cindy, and with our
stringent mechanical calibration.
DR. LAYLOFF: He demonstrated it with
variable coating. It's variable coating on enteric
coating material, so if there is a crack
in the
coating, it disintegrates much more
rapidly.
DR. SINGPURWALLA: I think I believe Tom.
DR. YU: Thank you very much.
So, the objective, the case we
presented
to you is certainly difficult, I just
want to say,
variability issue, whether from clinical
evaluation
100
or sometimes for in vitro conditions, in
vitro
testing, target main performance
question. I am
sure you will ask where is the main
performance.
I just want to show you that
these are the
challenges which we are facing, and
certainly we
are open to any suggestions or input from
you.
So, in summary, we believe
pharmaceutical
development information will help. I quoted here,
that's the conclusion made by you April
14th of
2004.
Understanding what the problem is, as well
as the real fundamentals, for example,
physical and
chemical parameters, and make coherent
and
scientific science-based decision based
on
pharmaceutical development information, I
think I
present to you the cases to see hopefully
how we
use pharmaceutical development
information to help
us in most cases, but in some cases, we
still have
challenges and we have opportunities for
us to move
forward.
Thank you and any comments are
welcome.
Thank you very much.
DR. COONEY: Thank you, Lawrence.
We now have time for questions
from the
Committee.
DR. SINGPURWALLA: Lawrence, I have two
101
kinds of questions. Question No. 1. Is it the
purpose of this presentation of yours to
ask the
manufacturers, namely, the industry, to
provide
more information to you because there is
so much
variability and you are trying to get to
the source
of the variability, is that the
objective?
DR. YU: Yes, very precise, certainly much
better than I said.
DR. SINGPURWALLA: That is the political
question. The scientific question, and I
have heard
this before, what does T/R percent mean
in your
Slide No. 8?
DR. MEYER: Test over reference.
DR. SINGPURWALLA: Test over reference.
DR. YU: Yes.
DR. SINGPURWALLA: How was this 80 percent
102
and 125 percent figure arrived at?
DR. YU: Slide 9.
I am trying to get
Slide 9.
DR. SINGPURWALLA: That's it, the picture.
So, 80 percent and 125.
DR. YU: T is the test.
DR. SINGPURWALLA: No, forget that. How
did you get 80 and 125?
DR. YU: That's an excellent question, and
we have been asked many times.
DR. SINGPURWALLA: It can't be excellent.
DR. YU: It's back to it was published
when I was in high school, I would say,
20 years
ago, or even more than 20 years ago, when
the
pharmacokinetics, the discipline was
developed, and
FDA developed the criteria. Actually, this
evolving process and trying to develop
what kind of
standards or criteria can we use to judge
a
bioequivalence study is okay or is not
okay.
I think at that time, the physicians
get
together, as we do today, and the
physicians
together made the determination that the
20
103
percent, the difference between product
would not
be considered clinically significant,
because the
20 percent will not be considered
significant
difference, therefore, when translated
into in vivo
setting, you have 80 percent.
So, you would think from 80 to
120 instead
of 25. Now, in the normal processing of
pharmacokinetic data, they used log
normal to be
much better to describe the
distribution. So, when
you use log normal, 80 is still 80. When
you have
the 1 over 80 or 1 divided by 0.80,
equals 1.25.
That is why you see 80 to 125.
Now, at the beginning, I would
think 20
percent instead of 19 percent or 21
percent, which
is 20 percent, it was decided. Then, the question
come back to us now can we change 20
percent to 25
to 15, 10, 5 percent, and I guess we have
to use,
say, over the 20 or 25 years, we approved
product,
they are all safe, they are all
equivalent, they
are all high quality, because of those
experience
or prior knowledge, determining 80 to 125
percent
works fine.
Now, this does not necessarily
mean we
cannot change it, but the criteria we
have is very
stringent criteria, we feel confident
with that.
104
Now, with a statistical
interplay--
DR. HUSSAIN: Lawrence, if I may.
DR. YU: Yes, please.
DR. HUSSAIN: It's a "feel good" criteria,
we felt good about it.
DR. SINGPURWALLA: I got the answer. I
think I got the answer.
[Laughter.]
DR. SINGPURWALLA: The answer is
tradition.
DR. HUSSAIN: No, it's rational science.
DR. YU: It is rational science. I think
I proved it.
DR. SINGPURWALLA: Let me make a
suggestion.
DR. YU: Yes, please.
DR. SINGPURWALLA: That tradition with
some dose of rationality was good 20
years ago when
you were in high school. Times have changed.
105
These kind of decisions to either prove
equivalence
or prove in-equivalence should be based
on risk
considerations and should be based on
appropriate
utilities.
So, I think it is time to
change, and I
think I said that April 14th, 2004. Has there been
any progress made towards changing?
DR. YU: The answer is yes.
DR. SINGPURWALLA: Oh, good.
What?
DR. YU: Certainly, you said you want
suggestion of change, and I think under
the
leadership of Gary Buehler, that we are
exploring
the confidence interval, for example, the
window
index drugs, and also we are exploring
confidence
interval for highly variable drugs. In other
words, in the future, I am hoping
someday, with
your support and agreement, we will have
different
criteria other than 80 to 125 to
different class of
drug in consideration of the risk
interplay.
Obviously, to make any changes,
six months
or one year is not enough.
DR. COONEY: Marvin, then Ken, then Paul.
DR. MEYER: Your talk I believe tried to
marry the quality-by-design to the highly
variable
drug and show that you could, in part,
solve the
106
problem by quality-by-design, that's the
objective.
DR. YU: Yes.
DR. MEYER: Personally, I think if you
have a competent company, then, your
highly
variable drug is biological problem which
the
company can't solve. You have to speak directly to
a higher power to get rid of that
variability.
So, I think, yes, there is
cases where,
for example, I could cite failure by
design if you
want to put an enteric coating on
something,
because that is, in my view, not a good
dosage form
because it is so dependent on gastric pH
and
emptying, and all of that, so you are
setting
yourself up for failure.
Now, you can say, well, I dealt
with
quality by design by not using enteric
coated, I
kind of took the reverse of that. A competent
company looking at Slide 24, the 6-vessel
graph,
would never go to a biostudy with a
product that
107
showed dissolution characteristics like
that.
So, indeed, some quality built
in that
says whoa, let's not spend $100,000 on a
biostudy
when our drug is all over the map in
dissolution.
So, I think you can deal with some
variability, but
that is fairly straightforward I think
for a
company.
So, the issue that really faces
us is the
physiological variability and do we
extend the
confidence limits, do we have point
estimate
restrictions or just do we do 600-subject
studies.
DR. HUSSAIN: Marv, may I just sort of put
that in context a bit? In some ways, what we are
seeing here is this. Since we are comparing two
formulations of the same drug, the drug
is the
same, the variability, the physiologic,
the
variability that is coming is the same
for the drug
substance.
If we can compare formulations
and say
that all the conditions that are critical
to
exposure are well controlled, and so
forth, and get
confidence, what will give us the confidence
to say
108
that the inherent variability is the
physiologic
variability, not the quality variability,
then, we
can move forward. I think that is the hope that we
hope.
DR. MEYER: Do you think practically, you
can look at the restrictions and the
SOPs--
DR. HUSSAIN: No.
DR. MEYER: --and just see how a company
is formulating and designing and
developing a
product?
DR. HUSSAIN: Not with the traditional
work we do about formulations, putting
things
together, and so forth, no, it has to be
a
structured design approach that goes
through
identifying the sources of variability in
your
materials, and so forth, and putting a
convincing
case together to say based on the
assessment, in
this case it's a generic product, and
based on
characterization of reference material
and your
test product, you can make the case that
the
variability that you are seeing in your
product is
no more different than of the best
argument.
That gives you a leverage to
now make a
rational decision with respect to what
sort of a
biostudy criteria would be necessary.
109
You can build flexibility, and
not go
rigid with, say, the Japanese approach,
which was
in
your background packet, was to say do we really
need confidence interval criteria
here. We just
want to confirm the mean values. It's a
confirmation rather than a complete
full-fledged
study.
One option could be that.
DR. YU: I think the message we
are trying
to convey is when we explore alternative
approach,
which could be a wide confidence
interval, or your
scaling approach to show or to
demonstrate the
bioequivalence is demonstrated with the
additional
information, which is pharmaceutical
development
information, will help us to make
scientific
coherent decisions.
Right now we don't, we don't
have those
informations. In other words, we are not able to
see how dissolution variability here may
change it,
for example, in this case, if we change
the pH,
110
dissolution is very beautiful, so that is
the data
we got.
We have now seen this data I showed you on
the screen. Thank you.
DR. COONEY: Ken.
DR. MORRIS: A couple of points. One is I
agree with Marvin in the sense that you
wouldn't
expect a company to release dissolution, I
mean
going to a biostate with dissolution like
that, but
I think those studies were done under
different
conditions. These were done here, so they wouldn't
have seen that under normal dissolution
conditions.
My more general question is--
DR. YU: You are correct, yes, in normal
conditions, especially, for example, USP
dissolution, maybe you are not able to
see.
Actually, dissolutions are beautiful.
DR. MORRIS: Right, so that comes back to
sort of our discussions yesterday in a
sense. The
question I have is to what level or to
what extent
do the ICH initiatives, I mean including
the CTD
and Q8, impact on the ANDA, I mean is
there an
intent that they follow suit with NDAs?
DR. YU: Obviously, the basic principles
from ICH and CTD, the CTD cure document
for drug
substance and drug products, it is not just
for NDA
111
only, for both NDAs and ANDAs. ICH Q8 is, in
principle, a part into NDAs, certainly
the basic
principle also apply to ANDAs.
The way I actively look into
this to
document and to see what information will
help us
to make scientific decisions. Certainly, as I said
before, we are not looking for
information which is
nice to know, we are looking for
information which
is essential to know.
DR. MORRIS: I guess to that end, because
this is something, of course, we have
been
discussing for several years, but the
idea that
rather than having checklists of what the
companies
have to do, if they can make scientific
decisions
based on the intended dosage forms and
the
properties of the API, which should be a
lower
hurdle, I mean that should be known more
by the
time you get to the generic.
DR. YU: Yes.
DR. MORRIS: Instead of having to do a lot
of the other testing that might normally
be done,
if they can focus on the identification
of the
critical to quality attributes of the
product and
capture that in a development report, it seems like
that is a reasonable way forward.
112
DR. YU: That is correct. In fact,
industry is coming forward and they share
some of
the pharmaceutical development report
with us, we
are actively looking into this to develop
some kind
of review templates which will
incorporate
pharmaceutical development information
into our
review process.
Again, I said we are looking
for
information which is essential to know,
not nice to
know.
DR. MORRIS: Maybe this is for Paul, is
that a reasonable stance as far as how
you look at
generic development?
DR. FACKLER: I am not sure exactly what
you are asking.
DR. MORRIS: I can clarify if you want,
113
but basically, if you could, instead of
having to
do sort of checkbox testing, if you could
do
testing that was largely prescribed by
your need to
establish certain scientific issues,
rather than
having to do as many, let's say, sort
of--what is
the
word--statutory testing, if you will, is that a
reasonable stance for you guys?
DR. FACKLER: I don't see a problem with
that.
What I didn't hear here was that there are
any different statutory requirements for
highly
variable drugs.
If a generic company still
needs to pass a
bioequivalence study, and we are going to
assume
that the pharmaceutical equivalence is
simple, I
don't understand what the generic company
understanding the origin of the innovator's
variability has to do with the
approvability of a
lot of material that is shown to be
pharmaceutically equivalent and
therapeutically
equivalent through a bioequivalence
study.
I guess that is the piece I am
missing.
Why is the burden on the generic company
to
114
understand the variability of the
reference listed
drug, and what value does that have if
really all
the generic company needs to do still is
demonstrate a bioequivalent product?
DR. MORRIS: You are talking about BE
variability now, not pharmaceutical?
DR. FACKLER: Yes.
DR. YU: Paul, if we use
one-size-fits-all, which is 80 to 125
percent to
some of drugs, you may have difficulty to
pass the
confidence interval. So, when we are exploring the
alternative approach including the
scaling
approach, you will have to demonstrate
this product
is highly variable or not highly
variable.
You have to know that because
otherwise,
suppose someday in the future, if the
scientific is
mature enough, we have a scaling
approach, for
example, for highly variable drugs, your
submitted
application did not show these are highly
variable
drugs, how would we know these are highly
variable
drugs.
So, you have to show, in your
development
115
report, that is a highly variable drug
before we
move forward.
DR. FACKLER: Agreed, but wouldn't a
replicate design bioequivalence study
inherently
capture the variability of the reference
listed
drug?
DR. YU: Yes, if you choose to do so, use
replicate design, certainly, you are able
to
demonstrate that reference list product is
highly
variable or not.
DR. FACKLER: But that is already part of
an ANDA application is my point.
DR. YU: I guess, Paul, we have not
reached a consensus or we have not made a
determination you have to use replicate
design.
DR. MORRIS: Is part of that the fact that
you are still struggling with the
concepts that are
entailed in that dissolution plot where
you can't
factor into the pharmaceutical variability,
factor
the pharmaceutical variability from the
clinical?
DR. YU: I guess the struggle we have here
is, look, Lawrence, in order for you to
get this
116
direct for pass, whether you use scaling approach
or you use widen the confidence interval,
you
simply widen the confidence interval, let
them to
pass.
You need to explain why. You need
to
explain why you think that is a feasible
approach,
you think that is scientifically sound.
So, when you say explain why
the
pharmaceutical development report can
help us
provide additional information to explain
why.
DR. FACKLER: I agree that certainly you
need to understand the variability of the
reference
listed drug especially if a generic
applicant is
claiming that the variability is an issue
for this
particular product.
DR. YU: Correct.
DR. FACKLER: I am not sure what value the
steps that were taken has to that
determination of
variability. Variability sometimes is listed in
the label for a reference listed drug;
other times
applicants do replicate design studies or
run
reference versus reference to measure
that inherent
variability, but that would all be part
of an
117
application already, as I understand it.
DR. YU: Yes, in many cases actually
lately for some of complex dosage
forms. Dosage
form, we very often sent many, many
deficiency
letters.
Actually, company provide information
during the cycles, and as I said, at the
GPA Chair
meeting, we have four or five or six
cycles,
provide additional information to us, and
eventually, the product get
approval. I am not
saying you not provide that information.
What I am trying to say is with
the arena
of pharmaceutical development report in
the ICHQ
paradigm, can you provide that
information in the
application instead of for us to send
many
deficiency letters.
When we see the OGD list
receive 25
percent or more of the applications every
year,
where do you want to put resource into
those
reviews.
Suppose you provide those additional
information, which I believe will help us
in our
reviews, and they reduce the cycles, I
see it's a
win/win situation for you and for us.
DR. COONEY: Ajaz.
DR. HUSSAIN: I think look at it from this
perspective in the sense the whole aspect
is you
118
are trying to make a decision and you are
trying to
choose the right measurement system here.
Now, the Code of Federal
Regulations
essentially has a hierarchy of methods
that you
choose for bioequivalence. Our current criteria is
a PK crossover, PK-based,
pharmacokinetic-based
study is the most discriminating one.
So, you are looking at, you are
trying to
now judge approvability of a generic
drug, and for
that you need to establish its
pharmaceutical
equivalence and its bioequivalence. The
bioequivalence measurement system that we
have has
inherent variability, and much of that
variability
is coming from the measurement system,
and may not
be coming from the test samples that you
are doing.
So, is this measurement system
the ideal
measurement system right now or not? That is
really the question.
The dilemma that we have is the in
vitro
119
characterization and in vitro testing
with
dissolution often is not reliable enough
by itself
to make that call. If it was, you would not be in
this dilemma.
So, if you really then look at
it, what
are we saying, is we have information
generally
that even if I give this drug
intravenously or as a
solution, and so forth, the variability
is coming
from the subjects, it is coming from
physiology,
which is inherently variable. If I sleep on my
lefthand side or righthand side, it will
make a
difference, I mean it literally happens.
So, that is the measurement
system, but
then you are putting your product into
that system
and trying to see is there a difference
of 20
percent or not, and to meet that
confidence
interval criteria, you need 600 subjects
or 300
subjects, and so forth.
Can we utilize the signs of
design to say,
to confirm, not necessarily to have a
confidence
interval, a confirmation that the new
formulation
actually is not contributing to that
variability,
120
is there sufficient science to do that or
not.
If it is, then it opens the
door for
saying that the bioequivalence assessment
then
could be tailored based on that
understanding.
DR. COONEY: Before we go on to some other
questions, I would like to see if your
question,
Paul, has been addressed.
I think the question was--well,
first,
Lawrence is proposing that there be a
pharmaceutical development report added
to the
information that is part of the
application, and
you are asking what will be the
implications of
providing that additional information and
facilitating the next step, which is
approval of a
bioequivalence.
DR. FACKLER: That is part of the
question.
The other part was what would be in a
pharmaceutical development report that
isn't
already part of an ANDA. That is really what I am
trying to understand, and, of course,
then, what
value would that provide.
DR. COONEY: Is there clarity to that
121
question?
So, that is back to Lawrence, to Paul's
question.
What would be in that pharmaceutical
development report that is not already
part of the
application?
DR. YU: I thought that was a topic of our
next advisory committee meeting.
DR. HUSSAIN: Let me put it this way.
There is nothing there right now. There is nothing
there to even gauge the aspects of. So, what we do
is our decisions are made based on one
batch test
results and the biostudy. That is what it is.
DR. MORRIS: Can I just weigh in? I think
part of this is that a lot of what would
go in the
development report is stuff that people
are already
doing, but doesn't just get included in a
summary
fashion, much like we have discussed
earlier, that
there is development studies you do, but
you don't
put together.
That is what we were talking
about
yesterday, is that, as a reviewer, if you
have to
try to piece together a development
rationale from
data here and there, you end up with sort
of a
122
development rationale that the person
filing really
wouldn't want to be there displayed to
the world,
you know, sort of a Frankenstein
development
report.
So, if the company does it,
then, they can
see the logic that you use. Whether they agree or
not is a different question. So, in my sort of
concept of this, which may be flawed, of
course, if
the company, let's say, had used
Cynthia's
dissolution method, because they said
this is what
has really mattered, and they got those
curves to
overlay, then, that is a big step forward
to say
that the variability that may come out of
the BE
studies are not due to our change.
So, if you see the variability
of the BE
studies and you have demonstrated that it
is not
due to the lack of adherence to a design
space, for
lack of a better word, then, that has got
to be as
good as the innovator. That is my concept. This
may be down the road, as Jerry said.
DR. YU:
I want to make comments that when
we say the pharmaceutical development
information,
123
I think I emphasize those information
that is
essential to know, not just for nice to
know.
We are looking into this, what
additional
information will help us in making
decisions, and I
think we are happy to share with you in
the future,
but at this point, we cannot say that for
every
single ANDA or for every single product,
you need
the pharmaceutical developed, because you
have a
prior knowledge, some of the information
already
there, so this need clarification when
you are
understanding what additional information
is
provided.
I think we need to discuss and work it
out.
DR. FACKLER: I understand.
To Ken's
point, you start over here and the
bioequivalent
product is over here, and sometimes you
take a
direct approach to it and sometimes you
don't. You
are right, oftentimes it is over here and
then you
realize you need to be over here, and
then finally,
you get where you need to be.
But I am not sure I understand
the value
or what it matters what path you took as
long as
124
you end up in the right place. All this
information does exist, of course, and
the field
inspectors have access to it, and we are
just
reluctant to expand the content of an
ANDA in the
fear that it will slow down an already
overburdened
review process.
So, where the information is
critical to
understanding whether a product is
pharmaceutically
or therapeutically equivalent, of course,
it ought
to be submitted, but where it is not
essential for
that evaluation, I just question whether
or not it
ought to be added to the burden of the
reviewers.
DR. COONEY: Art, then Marvin.
DR. KIBBE: Let's get back to what we are
trying to determine, and that is whether
or not a
clinician who prescribes this medication
for its
effect has got a reasonable expectation
of a
therapeutically similar outcome when he
uses the
innovator or when he uses the
generic. That is
where we are.
If a product is inherently
variable, as
manufactured by the innovator, then, we
ought to
125
know that early on, and as Les correctly
points
out, if that was the case during
development and
prior to approval, it wouldn't make it on
the
market if it wasn't that that breath of
variability
was allowable for clinical outcome,
because if the
clinical outcomes wouldn't--there were
times when
there were failures and times when they
were
toxicities apart, never gets on the
market. which
means that we have already historically
established
large variability is okay, because we
have that
product on the market.
Now, if I am a generic company,
all I want
to do is say that I am going to be no
more than, or
perhaps less variable, and I am going to
get to the
same therapeutic outcome.
If I can test a replicate
design that
shows that my level of variability is
lower than or
equal to the variability of the
innovator, and my
means are on target, then, I can with
reasonable
assurance argue that my product used in
the
marketplace on patients is going to have
the same
efficacy and failure rate as the
innovator.
The second thing is we already
have agreed
that dissolution is a hammer when we need
a
surgical scalpel to figure out what is
going on,
126
and if you make a shift in a dissolution
criteria
and all of a sudden you can differentiate
tablets
from the same batch, but that batch used
in people
isn't differentiatable, then, you are
making a
differentiation which is of no value to
anyone
except if you want to go back and process
improve.
In fact, that is what it should
be used
for.
The companies ought to be investing time and
energy in process improvement by looking
for better
differentiators for their own internal
consistency,
and perhaps they could narrow the
variability if
they found them.
I think the justification for
going to the
study that you said that if they used the
USP
numbers, they would all pass, and going
to your
numbers, we have this high variability,
but that
high variability doesn't relate to
clinical
outcomes.
Now, I am coming on the market
as a
127
generic.
If I can establish that I am not more
variable than they are, and my means are
the same
as they are in a biostudy, how much more
information does the agency need? I don't think it
needs much more.
DR. HUSSAIN: Art, you are missing the
point in the sense to demonstrate that
your
variability is acceptable, you actually
have to do
more now through a bioequivalence or
replicate
design, and so forth.
What we are saying is in the
sense, there
are ways or there should be ways to sort
of the
justification that goes into a
formulation that you
move forward, could then become a basis
to say you
don't have to go through extraordinary
means to say
the variability is unacceptable.
So, if we know a drug substance
is highly
variable, you mostly have that
information that
says you sort of at least definitely will
when you
approve the product, then, the signs of
formulation
design could provide you a basis for
saying there
is no reason your particle sizes, which
are
128
critical for your dissolution, your
coating
thickness, which are your release
mechanism, are
essentially being controlled, and so
forth.
So, why should a generic form
then have to
do a large study with replicate or with
whatever?
Isn't there an option available for
something--
DR. KIBBE: So, what you are really
talking about is a waiver of what we
would say
would be a standard replicate design to
get around
variability.
DR. HUSSAIN: Exactly, so that is what we
are suggesting.
DR. KIBBE: So, the company then would
come with its own development data and
show that a
broad range of dissolution numbers are
not highly
variable or something.
DR. HUSSAIN: Yes, the way I would think
about that is in a sense if it's a
tablet, I will
go to the basic mechanisms of what the
dissolution
will be affected, and here is my
assessment of my
particle size, here is my control
strategy, here is
the prior knowledge of similar dosage
forms. There
129
is no apparent reason for this to be
variable from
that perspective.
So, that becomes a basis for a decision
criteria saying that why would we expose
normal
healthy subject volunteers, a large
number of them,
to simply get our numbers within the
confidence
interval criteria, which is somewhat
arbitrary.
That is the crux of this.
DR. YU: I don't know if I can clarify,
the point we are trying to make is that
if you can
conduct bioequivalence study now to best
pass the
confidence interval, this is good
enough. I am not
saying this is not good enough. We are not asking
additional information.
The problem which we are facing
is you
will not have difficulty, it is not
impossible if
you have recruited 1,000 or 2,000
subjects, it is
almost impossible to do by a current
study, and
this is scenario that pharmaceutical
variability
information may come into play and to
help us out.
That is what we are trying to
convey. Thank you.
DR. MEYER: I think part of my problem is
130
that I believe what you are putting forth
is a
concept without any data, which obviously
you can't
have yet, because the concept hasn't even
been
implemented, it is just a concept.
I think certainly from my
perspective, if
you have some ideas that might streamline
the whole
system, I would say go for it and then
let's see
the
meat once the skeleton is exhumed, so to speak.
That is the bottom line, but I
think there
are some other ideas in there that are
perhaps
easier for me to understand, characterize
the
reference listed drug and then
presumably, if you
have done that, FDA will take that into
consideration to explain why you have
confidence
limits that aren't up to par perhaps.
For example, a simple example,
the RLD has
an overage in it of 10 percent. They claim that
isn't released ever, so they just have it
in there
because their release mechanism doesn't
allow for
except 100 percent.
You have some evidence that
says well, in
fact, it is released 110 percent
sometimes, so the
131
poor generic company is already 10
percent in the
hole when it comes to AUC. If that can be
demonstrated in some reasonable scientific
fashion,
that ought to maybe taken into account.
A better example maybe is with
the osmotic
pump.
We have done studies where you can harvest
the ghost out of the feces, and sometimes
it has 50
percent drug in it, sometimes it has 10
percent,
sometimes it has no drug in it. It seems
to be a
direct function of intestinal transit
time.
Well, if you are a generic
trying to match
without using an osmotic pump, you don't
have a
snowball's chance in hell of coming
across and
matching a product that sometimes is 50,
sometimes
is 100, sometimes is 10 percent.
So, I think as long as you hit
the means,
and you bring that kind of data to FDA,
they ought
to have the latitude of saying yeah, we
know that's
a problem with the RLD, and we can
therefore adjust
our thinking when it comes to the
generic.
Obviously, that is going to
take a fair
amount of work, but I think that these
things need
132
to be thought of, as well as more
statistically
based ways of dealing with high
variability. That
is kind of a short-term fix which
ultimately once
the statisticians get done fighting,
then, the rest
of us can agree, but the other is
certainly a
concept worth pursuing, I think.
DR. SINGPURWALLA: I would like to respond
to that.
DR. HUSSAIN: If I may, there is
an aspect
what Marv just said in the sense a
practice that
all of us know exists is when you have
variability,
then, you pick and choose what your
comparator is.
I mean it bothers me in a sense to say
that, you
know, you can pick and choose what lot
you will
compare to, and so forth.
Why do we have to sort of have
those type
of decisions where, you know, I think we
can be
better than that, so I think just to
build on what
Marv says, to say that I think we can
really be
confident in what we are doing, and not
to feel a
bit guilty that we are picking and
choosing what we
test, and so forth.
DR. MEYER: As you well know I am sure,
there are a number of countries. You do your
dissolution on three lots of the RLD and
then you
133
pick the one in the middle, not the one
that is
closest to what your product happens to
be.
DR. YU: I want to make comments about
Marvin's comments. Yes, in the case here, what you
present, actually, those information is
not in the
original ANDA submission, but those
information
eventually is shared with us.
So, go through many cycles,
many, many
months, or even several years to get us
that
information. What we are seeing is that we think
if those information, which you
eventually shared,
only a couple that go through the five or
six or
seven cycles, shared in first place will
help us to
make decisions, will help us to reduce
cycles, will
help us actually use the resource wisely. That is
what we are trying to say. Thank you.
DR. COONEY: Nozer.
DR. SINGPURWALLA: General comments.
First thing, Ajaz, don't use the word
confidence
134
limits for those two boundaries. Call them control
limits.
Confidence limits are completely
different.
The second thing is you are
fighting, at
least there is a lot of discussion
because there is
a lot of variability. What you seem to have done
is taken reactive approach, have said
variability
is there, what shall we do about it.
Well, yesterday, you talked
about 6 sigma
in one of your slides. Well, I think wherever you
have these high variability issues,
whether they be
in industry or whether they be within
your own
system, I would encourage you to put into
practice
what you were preaching yesterday about 6
sigma.
I would say, you know, has
anybody thought
about that, because 6 sigma came about in
industry
because there was a lot of variability,
and they
said how do we control it. Well, you just don't
control it by doing statistical
methods. You
control it by proper management and
proper
procedures, and I would say that you
should try to
bring that into the arena.
DR. COONEY: Paul.
DR. FACKLER: The generic industry is just
as interested in minimizing the number of
6 and 7
135
cycle reviews on products. Clearly, we have the
same goal in mind.
I guess what I would suggest is
that for
highly variable drugs, for instance, it
would be
useful for the agency to tell industry
the kind of
information that is generally lacking,
but with 500
applications a year, or 800, whatever the
numbers
might be these days, coming into the agency, I
don't think it is wise to require this
information
on all of the applications.
I would suggest maybe we
clarify the
additional information that is often
being left out
of
submissions for highly variable products, and
presumably, generic companies in the
interest of
having a minimum number of review cycles
will
submit it the first time rather than an
iterative
process to give you all the information
that you
need to make a fair decision.
DR. COONEY: Gary.
DR. BUEHLER: For the development reports
in general, I thank you for not wanting
to
overburden us with additional
information. We do
have a lot to look at. If we do get additional
information, we will look at it for sure.
I know that we get some amount
of this
136
information sprinkled through the ANDAs
and I would
think Ajaz was a bit draconian when he
said all we
get is the batch record and
whatever. I mean there
are explanations. We do demand explanations when
there aren't any deviations from what we
normally
see, that is in ANDAs and we do look at
that.
Lawrence and a group is working
on a
question-based review for the Office of
Generic
Drugs.
It is a very detailed project. He
is
working with experienced reviewers in our
office,
and he is developing this in a very
stepwise
manner, both first by involving both the
supervisors and reviewers in our own
office, and
then at a certain point we want to sort
of unveil
it to industry.
We want to make sure that when
we do bring
137
this new review method and these new
requirements
or whatever you want to call them with
respect to
pharmaceutical development reports, the
industry is
very aware of what we want and why we
want it, so
that they will feel good about giving us
this
information, and like Lawrence said, it
will
hopefully reduce the number of cycles we
have, it
will not overburden the reviewers, but,
in fact,
reduce the burden on the reviewers,
because they
won't have to see the same applications
four, five,
or six times, and they will understand
why we need
this information.
It is also a risk-based system,
so that
there are some applications that you
won't have to
provide this type of information, because
there are
some applications obviously that are
easier than
other applications, and the applications
for
complex dosage forms and unique dosage
forms
obviously, we are going to ask for more
information
than for the vary standard solid orals
that are
fairly easy to manufacture.
But we are doing this over a two-year
138
period and hopefully, sometime toward the
end of
this year, we will be able to begin to
tell
industry what we hope to expect in the
future
applications and industry will be
comfortable with
it.
DR. MORRIS: I just have a quick question
for Gary.
I am assuming that development reports,
as you say, depending upon the complexity
of the
dosage form, I mean they can be
relatively brief if
it's a very simplistic or simple dosage
form, so I
am not so sure that it's the burden if
the payback
is fewer review cycles or less clinical
studies.
Clinical studies are a lot more expensive
than
writing a development report and doing a
few more
development studies.
Is that more or less the case,
Gary?
DR. BUEHLER: I am not sure it is going to
be able to be submitted in lieu of a
study or
whatever.
DR. MORRIS: No, I meant the extensiveness
of a development report.
DR. BUEHLER: Some development reports
139
will say we wanted to develop a
bioequivalent
formulation, and, you know, here it is,
and it
could be a page or two. I mean clearly, it won't
be very long for a generic, because the
goal of a
generic is pretty evident, but other
development
reports will be more extensive, so yeah,
you know.
DR. COONEY: It sounds like there is a
need for clarity on what will be
requested and
expected, and also for clarity on what
the
implications of that will be. It sounds like that
will be forthcoming.
Ajax, what I would like to do
is move on
to the next presentation.
DR. HUSSAIN: Just go back to the original
intent.
Our initial thoughts that we wanted to get
the discussion started, so we never
intended this
to make a proposal, so these are initial
thoughts
and we are moving forward with this.
If industry wants to be
proactive, they
had better start thinking about it and
how they can
use this opportunity instead of asking us
what do
we want.
I think it is equally burdensome on
140
industry to think about how to develop
the products
for the intended use, and make the case,
and grab
that opportunity.
If not, the system as it stays,
we are
perfectly happy with it.
DR. COONEY: So, there is an opportunity
here for dialogue and there is no doubt
from the
last 45 minutes that there will be
dialogue.
I would like to ask Robert
Lionberger to
proceed with the next presentation.
Using Product Development Information
to Support
Establishing Therapeutic
Equivalence of
Topical Products
DR. LIONBERGER: Today, I am going to be
discussing how to apply the concepts of
pharmaceutical equivalence to topical
dosage forms
and look at how this is related to
quality by
design.
Here, I am going to focus on
topical
dosage forms that are in the local
delivery, so not
products such as transdermal products
that are
trying to deliver drugs systemically.
In the Office of Generic Drugs,
as you
have heard several times before this
morning, our
mission is to provide therapeutically
equivalent
141
products to the public. When someone uses a
generic drug, they should expect the same
clinical
effect and safety profile as the branded
reference
product.
Just to summarize some things
that Ajaz
talked about in his introductions, the
preface to
the Orange Book explains how we do
that. Products
must be pharmaceutically equivalent and
bioequivalent. But I want to dig a little bit
deeper into this and ask why do we
actually require
both, why isn't bioequivalence by itself
enough to
determine that the products are the same.
One aspect of that is that
consumers have
some expectation about product
behavior. If the
reference product is a capsule, you don't
want to
replace that with a solution. So, there is some
user experience and expectation.
So, pharmaceutical equivalence
encapsulates concepts related to like the
user
142
interface of the product, but then there
is another
aspect to it, and I have tried to express
it here,
is that pharmaceutical equivalence
supports the
determination of therapeutic equivalence
based on
bioequivalence study.
We don't say that just because
two
products pass a bioequivalence study,
they are
therapeutically equivalent products. An example
might be an oral solution and a
tablet. There can
be many products for which those two
dosage forms
would be bioequivalent, but we wouldn't
say that
they are therapeutically equivalent
products.
One aspect of that is that our
current
determination of bioequivalence is really
very
strongly based on in vivo testing. So, again,
there are limitations to testing. We test these
products in a small population and then we
extrapolate that conclusion to all people
who are
going to use the products from all
batches in the
future.
So, to sort of back up that
extrapolation,
there is some other information. Right now that's
143
the pharmaceutical equivalence between
the products
that supports that.
In the occasions when we do
equivalence
studies in patients, there are other
differences.
Sometimes the clinical endpoints aren't
very
sensitive to small differences, bringing
in
examples from topical products, you can
imagine
there are cases where, say, a cream and
an ointment
formulation might have the same
therapeutic effect,
but they wouldn't be considered
pharmaceutically
equivalent products or therapeutically
equivalent
products even though the clinical
endpoint study
might show equivalent efficacy.
Again, from the sort of
pharmacokinetic
studies for one of the challenges that is
often
made to some of our bioequivalent studies
for
topical products is since the skin is a
barrier,
you say, well, healthy subjects have
healthy skin
barriers.
There is a question. Sometimes
people
will claim in patients, the skin might be
diseased
or damaged, so that is a common
concern. There is
a common challenge to some of our
bioequivalence
144
determinations here.
So, inside of the
pharmaceutical
equivalence concept, there is some idea
of other
things we want to know about the products
to sort
of generalize this idea of equivalence.
If you think about this and want to sort
of tie this to quality by design, one way
that
might be useful for you to think about
this is that
our current definition of pharmaceutical
equivalence might be considered a first
step toward
a quality by design.
If you were going to design
equivalent
products, the first things you would
start with
were some of the concepts that are in our
current
definition of pharmaceutical
equivalence. You
would want to have the same active
ingredient. You
would want to have the same strength, the
same
dosage form.
So, if we look at sort of a
different way
of looking at our paradigm, maybe instead
of a
regulatory framework, a more scientific
framework,
what we are doing when we review a
generic product,
145
is we are looking to see is the product
designed to
be equivalent, and then does it
demonstrate
bioequivalence in an in vivo study.
So, you can see sort of this
combination
sort of parallels our current sort of
regulatory
framework of pharmaceutical equivalence
and
bioequivalence leading to a determination
of
therapeutic equivalence, where we might
say that on
sort of a scientific level, what we might
want to
be doing in the future might be to say
look at the
quality by design, look at the generic
product that
is designed to be equivalent to a
reference
product, and then based on this design,
choose the
appropriate either in vitro or in vivo
bioequivalence testing for this product
to complete
the determination of therapeutic
equivalence.
So, I want to bring this sort
of
conceptual framework and bring it into
this sort of
particular example for topical
products. Sort of
to motivate that, I just want to outline
some of
the complex issues that we deal with that
are
related to pharmaceutical equivalence for
topical
146
products.
Again, we have a lot more
experience with
immediate release, oral dosage forms in
effective
excipients, what excipients you can
change, what
excipients you can't change. For topical products,
a lot of times the excipients may or may
not affect
the barrier properties of the skin and
drug
delivery.
We don't have as much
experience about
that, so a lot of times we are worried
about what
differences in formulation are
appropriate for
comparing a test in a reference product -
is a
change in solvent appropriate, what if
the base of
the formulation in ointment or cream has
changed
from being hydrophilic to lipophilic, how
much
water content should there be in the
product. You
might affect evaporation, the feel of the
product.
A lot of these sort of
differences in
formulation get wrapped up into the
question of are
two products the same dosage form. I will talk a
little bit more in detail about that in
the rest of
the products.
We also have questions, when we
don't have
good bioequivalence methods for use for
topical
products, what indications should be used
for the
147
clinical equivalence studies. Perhaps the product
has multiple indications, which one is
the most
appropriate one to use.
These are the kinds of issues
that we deal
with in generic topical products. Some of the
implications of these for the ANDA
sponsors are
that the approval times for these
products can be
longer.
If there are these issues that we don't
have a good understanding internally, we
have to
schedule meetings with the appropriate
people, have
to have internal discussions.
When the sort of standards
aren't clear,
this is an opportunity for the reference
listed
drug sponsors to challenge correspondence
to OGD or
through the citizen petition process that
we have
to address the scientific issues there
that aren't
sort of clearly defined.
A lot of times, at the end of
these
discussions, we will end up going back to
the
148
sponsors and asking them for more
information to
help us resolve these issues, and then
usually that
is done through deficiency letters to
them, and it
ends up with sort of multiple review
cycles.
So, as we heard in Lawrence's
talk, there
is the question of more product
development
information in the ANDA itself may help
OGD deal
with these issues more efficiently.
This is sort of very similar to
some of
the things that Lawrence talked about,
that there
are harmonization efforts underway that
describe a
product development report, but I think
it is clear
that these are mainly aimed at new drug
applications, so it is not sort of
obvious or clear
how these should apply to ANDA sponsors.
I think the theme of this talk
to see this
as an opportunity, these development
reports, as an
opportunity to provide information that
will help
the agency set rational specifications
for products
that are complex, for immediate release
oral dosage
forms we have various standard systems
set in
place, but for topical products, where we
have less
149
experience, the more information that is
provided
about, say, why was an excipient changed,
and why
do you know that it is not going to have
any effect
could be very helpful to us in making
efficient
decisions.
Again, the product development
reports are
the place in the application to emphasize
the
quality by design, that the product is
designed to
be equivalent. That will help us set the right
requirements for the bioequivalence
testing for
particular products.
This is just a few examples of
what some
of these harmonization documents say
about a
pharmaceutical development report.
In this case, again, the key
part here
might be to establish that the dosage
form and the
formulation are appropriate for the
purpose
specified in the application, or in the
Q8
document, it talks about an opportunity
to present
the knowledge gained through the
application of
scientific approaches.
Here, it is talking
specifically about
150
sort of formulation and development for
the topical
products, that there is information that
the
company that is developing the generic
product
knows about why they made certain choices
in the
formulation. It would be very helpful to us in
deciding that that is acceptable, where
the agency
itself has less experience with
particular dosage
forms.
I have emphasized this concept
of quality
by design or, in the case of the generic
products,
quality by design means you are designing the
product to be equivalent to the reference
product.
So, I want to try to be a
little bit more
specific about what that means. There are two
cases.
One, the mechanism of release.
Clearly,
the mechanism of release between a
generic product
and the reference product can be
different, but the
intent of those different mechanisms
ought to be to
produce the same rate and extent of
absorption.
This is the bioequivalence criteria.
Again, we also recognize that
depending on
the particular product, that the release
rate from
151
the product might not be the rate
controlling step
at absorption. So, the determination of how close
release rates might have to match would
depend on
the absorption process involved and what
is the
rate-limiting step in the absorption
process.
Again, between generic products and
reference products, the excipients can be
different. Again, it is a good thing to understand
the differences between the excipients.
The IIG limits are a starting
point. They
tell you that this excipient has been
used in this
dosage form up to a certain amount, and
that really
addresses, specifically in the case of
topical
products, safety-related exposures, so
you know
that level of exposure.
The thing that complicates the
topical
products is when you change the
excipients, the
real question that we often deal with is
do the
changes in the excipients to the products
affect
the permeation of the drug through the
skin. I
think that is the sort of challenging
question
there for the topical products that we
occasionally
152
have to deal with.
Again, as I said, the purpose
of quality
by design is to design the equivalent
product. I
want to just give sort of three sort of
examples of
this process here.
The first is talking about Q1
and Q2
equivalent products for topical products,
and then
look at what happens when you make
changes to the
formulation, they become Q1 and Q2
different, and
then this leads into the discussion of
issues
related to the dosage form classification
and how
product development information might
help us make
a better decision or more scientific
based
decisions on dosage form classifications.
First, I want to start off with
the
definition of Q1, Q2, Q3. So, products that are Q1
have the same components, so both the
generic and
the reference product would have the same
components.
If products are Q2, they would
have the
same components, but they would also have
the same
amount of each ingredient.
The Q3 concept is same
components, same
concentration, but here I am saying same
arrangement of material or
microstructure, and this
153
is particularly important for topical
products that
are semisolid dosage forms, so
non-equilibrium
dosage forms, where you might have, say,
an
emulsion with exactly the same
components, exactly
the same concentrations, but say, for
example, the
droplet size might depend on how you have
manufactured that product.
So, there is potential
differences for
semisolid dosage forms depending on how
they are
produced even if overall the composition
is exactly
the same.
A contrary example would be a
solution.
If a solution is Q1 and Q2, because the
solution is
at thermodynamic equilibrium, you would
be able to
say we know that this product has exactly
the same
arrangement of material in the product.
The importance of the Q3
concept is when
you know that the products have the same
arrangement of material, you know that
they are
154
going to be bioequivalent, there is no
question
about that. An example of that is again a solution
where you know that the products are in
thermodynamic equilibrium if the compositions
are
the same, the structure and arrangement
of the
material is the same.
Unfortunately, for most topical
semisolid
dosage forms, they are not necessarily
equilibrium
arrangements of material, and so a direct
measurement of Q3 level equivalence is
challenging.
So, if we have the topical
products where
Q1 and Q2 are identical, again, the only
potential
differences are differences in this Q3
parameter,
which can come from differences in
manufacturing
processes, because they are not going to
be
manufactured by exactly the same process.
We know for particular
semisolid dosage
forms, such as emulsions, that rheology
and in
vitro release rates can be very sensitive
measurements of microstructure and are
related to
product performances.
So, the sort of idea that sort
of
155
advancing here from a scientific point of
view is
when the products are Q1 and Q2, that in
vitro
tests should be equivalent to ensure
bioequivalence
of the two products, because again here,
the issues
are detecting differences due to
differences in
manufacturing processes, and the argument
would be
that in vitro tests are the best
evaluation method
to detect whether any differences in
manufacturing
process have significant differences in
the product
formulation or performance.
Now, things get more complex
when a
generic product and a reference product
have
different compositions, and this connects
with the
dosage form classification, and these
differences
occasionally could be barriers to generic
competition.
A generic company might want to
formulate
products that are Q1/Q2 different because
the
innovator has formulation patterns, so
there might
be either legal reasons or perhaps
manufacturing
process reasons why you might want to
formulate a
product that is not exactly identical in
156
composition to the reference product.
One of the products, again, one
of the
members of the Committee mentioned the
sort of
economic effect of uncertainty on product
development if you don't know what dosage
form the
product is going to be classified
as. That adds
cost to the development process because
of
uncertainty of what is going to happen to
the
product.
In particular, if we think
about methods
by which we would classify the dosage
form of
topical products, here, I have generated
a list of
four possible ways that you could
approach this.
One is we would just use
whatever the
sponsor says their product is as long as
it is
consistent with some of the traditional
definitions
that are available in various sources,
and we will
look in sort of detail at some of those
traditional
definitions.
You might say, well, the
generic product
is the same dosage form if it feels the
same to me,
so I will just try it out and see if it
is the
157
same, if it passes. You know, if the look and feel
of the products are the same. That is
getting to
the
aspect of pharmaceutical equivalence, a sort of
patient experience rather than sort of
scientific
issues related to product performance.
Then, I am going to sort of
discuss recent
work that the FDA group led by Cindy has
done on
looking at a whole bunch of products and
coming up
with a quantitative decision tree to
classify
topical products.
Then, sort of the fourth aspect
of that is
looking at whether or not issues about
dosage form
classification for complex issues would
be
something that you would want to include
in a
product development report, so justifying
the
formulation development as being the same
as the
reference product. That sort of might be a more
scientific way to look at these issues.
First, if we look a some of the
traditional definitions. Here, I will just focus
on the difference between a cream and an
ointment.
One source is the CDER's data standards
158
definitions. These are sort of similar to USP
definitions of these products.
The cream is a semisolid dosage
form
containing one or more drug substances
dissolved in
a suitable base, and then it says more
recently the
term has been restricted to products
consisting of
oil-in-water emulsions. That is obvious what a
company should do - does a cream have to
be an
oil-in-water emulsion or not.
Then, it talks about products
that are
cosmetically and aesthetically
acceptable, is part
of the definition of the cream, so that
is not very
quantitative. It is hard to say is this
product
aesthetically acceptable. That is really
opinion
based.
An ointment is a semisolid
preparation
intended for external application. It seems to me
that a cream could be a semisolid preparation
and
fit under the ointment definition. So, it doesn't
seem that those two definitions are
really
exclusive.
In another FDA guidance, this
is the SUPAC
159
semisolid guidance. It has a glossary with
definitions of dosage forms, but these
aren't the
same as the previous ones. A cream is a semisolid
emulsion, and an ointment is an unctuous
semisolid
and typically based. So, typically based is not
sort of a definition, it doesn't have to
be based
on petrolatum.
This definition talks about an
ointment
being one phase, and not having
sufficient water.
Again, the USP definition is sort of
similar to the
one in the CDER data standards, but it is
not
word-for-word identical, and talks about
four
different classes of ointments.
So, again, the problem with the
traditional classifications is they are
not really
consistent, and not very
quantitative. So, a lot
of the sort of decision process would
depend on
what your opinion was of a particular
product, and
they might be overlapping, like you might
be able
to call--under a particular definition of
a
particular product, you might be able to
call it a
cream or an ointment.
So, the result of this Topical
Working
Group led by Cindy has been presented to
previous
advisory committee meetings, and they
recently
160
published a paper outlining this
classification
scheme.
What they did was they surveyed
existing
products and devised a classification
scheme, and I
just included the classification scheme
here just
for reference in the presentation.
These are just some slides from
their
previous presentations to give you the
general idea
of what they did. They measured
particular aspects
of products, say, creams and ointments,
they
measured viscosity.
They looked at the loss on
drying, and
then based on these products that were
either on
the market or manufactured for them, they
came up
with a classification scheme that sort of
put the
products in the right category based on
existing
products.
The real advantage of this is
it is
quantitative. If you take a product and
you go
161
through and you measure the things
outlined in
their decision tree, you will always end
up in the
same place, and it will always be
consistent.
In addition to that, this is a
very data
driven approach. They looked at the products and
then drew the lines. It wasn't said here is sort
of a mechanistic definition of what a
cream or an
ointment should do.
So, the question is, could this
be overly
restrictive. If you follow this classification
scheme, you would be restricting products
to
essentially what has been done before,
and then
there is a question.
They didn't survey every
product that is
on the market now, so there is a
question, if a
reference listed drug falls into a
different part
of this classification scheme, then, it's
labeling.
So, it might be labeled as a cream, but
by the
definition, it would be classified as an
ointment.
What should a sponsor do in that case?
So, the final sort of approach
to dosage
form classification might be to look at a
more
162
scientific view of the formulation
design. I just
want to point out that sort of the legal
aspects,
referring to topical use, sort of point
toward this
here from the CFR.
It talks about inactive
ingredient changes
for topical products. It says again that
abbreviated applications can use
different
ingredients if they identify and
characterize the
difference and provide information
demonstrating
that the differences do not affect the
safety or
efficacy of the proposed drug products.
So, a current way of looking at
is a
change in formulation acceptable, you
should check
the new excipients against the IIG. As I said
before, this looks at the safety of the
individual
excipients.
We also really consider that
passing
bioequivalence tests are evidence that
the
formulation change is acceptable. That is one
strong piece of evidence against
that. But again
the product development report is an
opportunity
for sponsors to characterize the
differences.
Again, this could be important,
you know,
if you are formulating a product and you
are on the
boundaries of these, we have this
empirical
163
decision tree, what happens if you are on
the
boundaries, how do you explain that this
product
should be considered the same as the
reference
product, you know, from a scientific
point of view
rather than empirical classification
scheme, of if
someone says, well, no, your product is
not really
an
ointment because it doesn't meet a particular
published definition.
So, again, the product
development report
is the opportunity for a sponsor to
characterize
the difference that is sort of requested
in the
statutes.
Again, also, in the statutes,
they list
reasons to reject ANDAs, and they talk
about drug
products for topical administration where
there is
a change in lipophilic properties of the
vehicle.
Again, in this case, a product development
report is an opportunity for sponsors to
explain
why the changes, Q1 and Q2 differences
are
164
appropriate for this particular product.
If this issue comes up, a lot
of times we
will actually have to go from the review
process,
you will have to go back and ask sponsors
for more
information about these particular
issues. So, the
development report is sort of an up-front
way to
explain the reasons for doing that.
Just to sort of conclude the
discussion
here, the first concept is the importance
of Q1,
Q2, Q3 classification to identify
appropriate
bioequivalent studies for the level of difference
in the product design. If a few products have
exactly the same active and inactive
ingredients,
you might want to request different in
vivo
bioequivalence studies than for a product
where
there has been a change in inactive
ingredient that
may affect the absorption of the drug
product.
So, here again, we are looking
at the
second concept, we are looking at the
evolution of
the concept of pharmaceutical equivalence
where we
have these traditional dosage form
definitions,
maybe now backed up by empirical decision
trees,
165
but in the future, looking for a
quality-by-design
aspect where the determination of whether
a product
should be considered equivalent would
depend on the
mechanistic understanding and the
formulation
design rather than some traditional
definitions,
and
that the ideal state would be that this
understanding would reduce the need or
allow us to
set the appropriate in vitro testing for
a
particular product, and also to expand
sort of the
formulation design space beyond past
experience.
If you want to formulate a
product that
goes beyond, say, an empirical dosage
form
classification, this is the sort of way
that you
would approach it, by providing the
scientific
information to show that the formulation
you have
chosen gives equivalent performance in
the key
attributes as the reference product.
With that, I will conclude my
presentation.
DR. COONEY: Thank you.
I believe the
purpose of your presentation today is to
bring us
up to date on the current thinking where
you are
166
and where you are going as opposed to
requesting a
specific action on our part, is that
correct?
DR. LIONBERGER: Yes, that's right.
DR. COONEY: I would like to invite
questions and comments from the
Committee. Yes,
Cynthia.
DR. SELASSIE: This is a very general
question.
With all these product development
reports that you get, obviously, there is
going to
be a lot of information that is
extraneous and
won't be useful for that particular
application,
but will you all retain this information
like in a
database, so that it could have use down
the line?
DR. LIONBERGER: I don't know if we would
retain it in a database, but I would say
that like
as Lawrence said, we are looking at our
review
process, and in that, had the opportunity
to read
several product development reports.
I find that they are a very
useful way to
get an overview of what is going on with
a
particular product. You know, an hour of reading
the development report, it seems like a
very good
167
way to start the review of the
application in more
detail, so I think it can be very
valuable.
We don't have much experience
with using
them yet, so in that sense, it could be
valuable,
but we don't know how we would use that
information
or store that information in the future.
DR. HUSSAIN: If you are suggesting that
there is a need to capture and create
databases, I
think we do want to move in that
direction, and we
tried to do that. Currently, our systems does
capture some of the key aspects. The
inactive
ingredient guide is a process that we
capture every
inactive ingredient that comes, but
developing a
formal knowledge base would really be
helpful, and
I think we have been thinking about it.
I tried to do that with immediate
release
dosage forms and actually did some
modeling with
that data that we have, and so forth, so
we will
look into that.
DR. COONEY: Are there any other questions
from the Committee? Marv.
DR. MEYER:
Just a quick comment. You
168
have my sympathies. I thought it was difficult to
determine how to do the BE studies on
topicals, and
now I have been reinforced, you don't
even know
what slot to put them in the Orange Book
if they
are bioequivalent, so you have a big job
ahead of
you.
DR. COONEY: If there are no further
comments, Robert, thank you very much.
There have been no requests for
participation in the open public hearing
at 1
o'clock, so we will proceed with the
continuation
of the discussion on quality by design
precisely at
1 o'clock when we come back from lunch.
We will begin that by a
presentation of a
summary of the plan by Ajaz, and then we
will
continue the discussion that we began
earlier this
morning.
So, enjoy lunch and we will see
you back
at
1 o'clock.
[Whereupon, at 11:59 a.m., the
proceedings
were recessed, to be resumed at 1:00
p.m.]
169
A F T E R N O O N P R O C E E D I N G S
[1:00 p.m.]
DR. COONEY: I would like to welcome
everyone back from lunch.
We will proceed with the
afternoon
schedule.
The first topic this afternoon will be
Ajaz Hussain, who will provide a summary
description of the plan to go forward.
Quality-by-Design and
Pharmaceutical
Equivalence (Continued)
Summary of Plan
DR. HUSSAIN: I am going to go back to the
slides I used in the morning instead of
the ones I
had for this session. That was based on the
discussion that occurred.
Just on reflection, I just want
to make a
couple of points. Yesterday, in a sense, as part
of the tactical plan to start our journey
towards
the desired state, in a sense what we
have done at
this meeting is to take a look back last
10 years
or so to see how our policies have
evolved and how
they could evolve with two tools that we
have
170
introduced, the PAT guidance and ICH Q8.
Tom Layloff reminded me that in
many ways,
some of the topics we have discussed, we
have been
discussing for 30 years, and we keep
discussing
those topics again and again, and the
difference
that we have tried, at the training
session that
some of you attended, I am clearly
cognizant of the
fact that we are discussing topics that
we have
been discussing for 30 years, and the
quote I had
was the thing that if you tried to
approach the
problem with the same tools and the same
approach
again, we are bound to find the same
solutions, so
we need something new.
What is new at the issue of
this problem
is the science of formulation design, of
science of
product design. The key aspect, much of that
has
always been considered as an art, and as
the
complexity of products is increasing,
that art will
not be sufficient to really achieve the
performance
we are trying to achieve.
So, it is a reflection back of
saying all
right, 30 years of pharmaceutical
sciences in
171
particular pharmaceutics, industry,
pharmacy, and
so forth, what have we learned and what
we need to
learn more to do things differently.
In some sense, that is the
heart of the
debate.
I also sort of mentioned to you, and this
is my original starting point in the
thought
process was that you really need at FDA
more people
with that background to really make that
happen. I
changed my thoughts over the last several
years.
What we have at FDA is
scientists from
many, many different disciplines who sort
of work
together.
The reason I changed my mind was I think
looking at some of the practices and
formulation
development, and so forth, you really
need a
multidisciplinary approach to challenge
some of the
inherent assumptions which are in the system.
Therefore, I think what we have
is
non-pharmaceutics people evaluating this
is an
advantage, not a disadvantage, but then
the key is
you have to put this in a scientific
terminology
that can become negated across different
scientific
disciplines. That is a significant challenge.
So, with that in mind, we want
to make
this a scientific process. The review assessment
is a scientific process. Therefore, it has to be
172
essentially a scientific format offer
hypothesis
tested.
So, with that in mind, if I
look back at
the SUPAC guideline, what we have done
there is the
guideline was a first step in moving towards this
direction, and in a sense we tried to
identify in
that guideline changes that can be
classified as
minor, moderate, and major changes.
How did we accomplish that? We
accomplished that through expert
solicitation is a
very real thing, not just where we had
some
workshops, and where we collected the
wisdom of
people in this area to say what are the
changes
which are minor, major, and so forth.
Then, we took those
recommendations and
actually challenged those recommendations
through
experiments and studies that we did at
University
of Maryland to design experiments, and so
forth.
So, those are pretty much the
recommendations in
173
the guidance were very conservative. So, that was
the starting point.
Now, quality-by-design thinking
forces and
challenges the industry to do this instead of FDA
doing this, and it says simply that if
you could
understand your formulations and your
manufacturing
process to such an extent that you can
start
predicting the behavior of those things,
then, you
will start getting process understanding,
and that
information can allow you to document and
justify
what is critical, what is not critical
for your
given formulations instead of having a
blanket peer
guidance to say what is critical or what is
not.
So, that introduces the concept
of needing
to prove that hypothesis of your design
space.
With that in mind, what would
that
hypothesis be in the sense there are two
aspects of
the hypothesis that one could look at?
One is proving that you have
understood
your formulation and manufacturing
process to an
extent that you can predict the behavior
or its
performance in terms of your shelf life,
in terms
174
of your bioavailability.
So, these experiments that you
conduct,
you conduct them, you have to conduct
them anyway.
Instead of sort of approaching them as testing for
the sake of testing, if you test those or
you
conduct those experiments as a
hypothesis, then,
you have a means to document your
understanding and
a means to, in a regulatory sense, prove
your
hypothesis through a hypothesis testing
mode.
So, when you think about it
that way, the
tests that you do today are no different
except you
are approaching those tests differently
as
hypothesis testing.
What that does is that creates
a
flexibility for changing based on your
understanding, based on what is critical
to your
formulation, and so forth.
There were several challenges
to that.
One of the challenges was in terms of
trying to
prove your hypothesis, trying to do
testing in more
robust way, you do need to have estimates
of
variability and bring variability into
discussion.
So, yesterday, our discussion
then focused
on was a dissolution test procedure,
which is a
pivotal test procedure, which is a tool
that is
175
essential in product development. The implications
and the concerns FDA had in how are we
setting
specification, we saw a disconnect there.
The variability in the
dissolution test
method may itself not be large, but the
disconnect
there was simply the suitability criteria
opened a
wider door than what our specifications
are, and so
forth.
So, a stringent approach, a
stringent
mechanical calibration provides you a
better handle
on your target value or your mean values,
and doing
assessment of sensitivity of your
formulations in
that test system gives you an
understanding and
gives you a handle on the variability for
your
given formulation.
So, that gives you a better
handle on your
variability, and that helps you start
setting up
your system to prove a hypothesis, and
your
hypothesis could be that my understanding
of my
176
formulations is such that I know what
will happen
to my shelf life if I change this or what
will
happen to the bioavailability if I change
this.
So, your stability program,
your
bioavailability studies that you do essentially
are
a confirmation of that. So, if we repeat
that and
use that as a decision criteria, you have
become
proactive. So, that sets up the regulatory
flexibility that is needed in the concept
of design
space.
Similarly, I think bioequivalence is a
hypothesis test. Instead of approaching it just to
document bioequivalence for the sake of
documenting
bioequivalence, you turn that around and
say that
is my test of hypothesis, I have
understood my
formulation, I have understood my
manufacturing
process, and I have also understood the
product
that I am duplicating or I am sort of
reproducing
to be equivalent, and therefore, my
bioequivalence
test now is the test of my hypothesis of
how well I
have understood, how well I have
designed, and that
opens a door for that test becoming a
hypothesis
177
test, confirming your knowledge base, and
so forth.
So, that combination opens the
door for a
scenario that Lawrence talked about, in a
sense
dealing with variability, which
measurement system
do we use to ask the right question.
Clinical variability clearly is
wider, and
the drugs are approved on the basis of
clinical
trials.
The variability and quality has to be
narrower by virtue of the system, and
that is what
Janet talked about in the sense
variability and
quality, or bioequivalence, we consider
that as a
quality test, not a clinical test,
because it is
not a clinical study, it's in healthy
subject, is a
confirmation that your variability is
acceptable.
With the question that we proposed
with
highly variable drugs is trying to
understand what
is the source of variability. We know that many
drugs are inherently variable because of
the
pharmacokinetic characteristics,
metabolism, and so
forth, that have nothing to do with the
quality of
the product.
So, if you have understood your
sources of
178
variability in your manufacturing
process, and your
manufacturing process and your
formulation
strategies is consistent with the
principles of
formulation design that you have used
previously
and have documented lower variability,
that gives
us
a handle to say that variability in this product
is not expected to come from the
product. It is
going to be inherent from the drug
itself.
Then, your biostudy becomes a
test of
hypothesis. Now, what is the hypothesis
that we
might want to test there? The hypothesis could be
test of means, an analysis of means
rather than
analysis of variance, because we have
addressed the
issue of variance in terms of being
comfortable
that the variance is coming from the drug
substance, and we have enough confidence
to say the
variance for product is not expected to
be
different.
So, instead of analysis of
variance,
analysis of means could be one option to
consider
there, instead of trying to do replicate
design,
tend to do large subject, and so forth.
These are some of the initial
thoughts
that we have, and these are clearly not
proposals
at this time, and the intent of this
discussion was
179
to simply initiate discussion dialogue,
to have the
Pharmaceutical Committee get engaged in
the
discussion to see what opportunities we
have.
Highly variable drugs, topical
products,
we have been debating these issues for
decades, and
if we propose the same solutions, we will
be
debating those for the next couple of
decades.
So, I think it is an
opportunity to think
differently. Similarly, I think some of the
biopharm classification system in the
context of
design space, I think the biopharm
classification
system becomes a pivotal tool for your
decision
criteria that drives your decision to
certain
aspect based on the drug's property and
what you
are trying to achieve, and the biostudies
that you
do again become a confirmation of your
hypothesis.
So, one extension of BCS
clearly is in the
post-approval world, more so than the
approval of a
brand-new product, is the extension of
SUPAC in
180
application of design space. So, that is the point
that we tried to make.
The aspect I think which is
very difficult
is industry often relies on us to tell
them what to
do, and it is very easy for them to have
a check
box.
FDA said this, let's do it, end of story,
because the goal is to get the products
approved.
Well, that's one way of doing
business,
but in terms of I think FDA's role is to
clearly
ask the right questions. As I again said at the
training session, I think the decision
system that
we have for pharmaceutical quality is
owned by the
societies, not owned by the regulators or
by the
industry.
The decision is that of the society, and
all of us are simply caretakers of that
decision
system.
Unless we ask the right
question, because
of the scenario of the market failure,
where the
patient or the clinician cannot tell the
difference
between good quality and bad quality, the
system
may have inefficiencies built in, and
even may not
be asking the right question. So, I think that is
181
one of the things that we are trying to
address.
For the last four years, when we started
the discussion on PAT, and so forth,
clearly, the
focus was on manufacturing, and
relatively, I mean
that was not an easy task, but
relatively, that was
easier to grasp for many because you
already have a
revolution of manufacturing that had
occurred
outside the pharmaceutical sector for the
last 30
years, and we are probably 30 years
behind that
revolution.
Now, the most difficult part of
the
discussion, the journey starts now, is
tackling the
issue of science of design, and the
reason I use
the term "science of design" is
that is a National
Science Foundation terminology, which
they have
started a major funding program for
focusing on
science of design, because you cannot
test quality
in, and the infrastructure for U.S. in
terms of
design is so weak, especially in the
software area,
that is where the funding starts.
Science of design provides you the
scientific framework to say the
empiricism that we
182
have really, when structured, can provide
you the
fundamentals that you can start moving
towards
hypothesis-based decisions rather than
just testing
after the fact.
So, I think that is the
journey, and that
is the first step in trying to think
about it
publicly.
For the last three, four years, or three
years at least, our focus has been
discussing only
the first three bullets to a large
degree. It is
focusing on supplements, focusing on
deviations,
focusing on testing and real-time
release, and so
forth.
With ICH Q8, we started
discussing the
last two bullets, multiple CMC review
cycles. Why
do we get into multiple CMC review
cycles? Because
our reviewers are searching, trying to
put the
story together to see what are the issues
as they
try to approve this.
Often, who gets blamed for the
delay is
the reviewers. They are just trying to find the
answers that they see to be comfortable
in
approving drug product. If you get into multiple
183
cycles, the reason is they don't have all
the
answers together.
In Office of New Drug
Chemistry, we are
trying to move towards a quality oral
summary as a
starting point for this analysis. Similarly, in
OGD, we are moving towards a
question-based review
that will help sort of formulate the key
question.
But you have to keep in mind
one aspect.
That is, FDA does not develop or
manufacture drugs.
We are here to assess whether the quality
is
sufficient based on the standards that we
have.
Expecting FDA to give you the
answers of
how to develop and how to innovate and
how to sort
of make the case for science of design is
expecting
too much.
That is the reason why I think we wanted
to sort of get the entire pharmaceutical
community
engaged to find and seek answers together
rather
than saying this is what we expect.
So, that is the fundamental
premise on
which our discussions have been focused
on, and
clearly, I think industry has always
argued for the
last four years that it will increase the
review
184
cycle.
It will increase the delay over approval.
We don't know how we will use it.
One aspect of that argument
simply says
either they don't know what they are
doing, they
are afraid to hide that, or the concern
is real.
So, clearly, I think we understand that
the
concerns could be real, and that is the
reason why
I think we position the peer review
process, but
moving towards a quality system for
review
assessment, and so forth.
But at the same time, I really
think
having the diverse disciplinary
background that we
have in the reviewer is an asset, not a
liability.
The challenge then is to construct the
submission
as a scientific submission hypothesis
based.
The key to that is without
increasing the
burden, utilizing the existing
evaluations that we
do, bioequivalence, stability, and others
as part
of hypothesis testing. Suppose the hypothesis
testing is your science that says I
understood
this, I expect this to happen, and here
is the
proof a priori providing that information.
So, I think you have to think
about that
as a basis for discussion, particularly
this
morning's discussion, where we presented
to you
185
three examples, and the three examples
essentially
try to address the paradox that we run
into, is
trying to ascertain what is an acceptable
variability, and trying to resolve the
issue of
whether our test procedures, whether our
questions
that we are asking are really reducing
that
uncertainty to get to an acceptable
variability.
Variability in the clinical, we
are not
touching, but that is what really we want
to be
lower or smaller than the clinical
variability.
So, our test procedures, and so forth,
quote,
unquote, I think gives us comfort that
they are
more discriminating, but the
discriminating aspect
of those test procedures is clearly an
experience
rather than science driven.
So, how do you overcome the
challenge, I
think is the key issue. So, in terms of
formulation development, I really was
fortunate in
terms of getting trained in
pharmacokinetics, as
186
well as formulation and physical
sciences, so that
was my benefit.
I can go across that and try to
see both
sides of it, and from my experience, I
can see
easy--not easy--approaches to sort of
connecting
those dots and aligning the current work
that we do
into a scientific structure.
The challenge, the concern, a
personal
concern seems that is always with me is I
think
people who can connect all these dots are
very few,
and unless we build a team approach to
this, we
will be missing a lot of things, and much
of the
challenge today organizationally are the
turf
issues between different parts of the
organization.
We saw this very clearly with
the biopharm
classification system. For Jack Cook to get the
first submission in, he had to connect
the PK
Department, the Formulation Department,
and so
forth, and that was not easy, because
each
department is set in their own ways of
doing
business, their own test procedures, and
the
interfaces are difficult to manage, and
much of the
187
challenge today we have are dealing with
the
interfaces.
So, the challenge is
variability, what is
an acceptable variability? At the same time, the
other challenge that we have is that of
what is
minimal expectation and what is optional
expectation. That is the definition, and that is
the provision provided in ICH Q8.
In some ways, this table, in my
opinion,
seems to give us a direction for trying
to tease
out what is the minimal expectation, what
is an
optional expectation. Now, if you are a company
with a generic or innovator, you will be
making a
tablet for the sake of argument.
How much information does FDA
really need
to assess that quality was by design, and
so forth?
Actually, depending on how simple the
dosage form
is, things could be different.
So, in the case of a
conventional dosage
form, what is the primary focus
understanding the
materials especially the new material
that you are
putting in existing materials, that is
the drug
188
substance into existing excipients, how
well can
you characterize that and how well can
you predict
the behavior in a set of mixtures of
excipients
which we have been using for about 150
years or so.
We have been manufacturing
hundreds of
different formulations in the
manufacturing
process.
How can we capture that knowledge base
and bring that? So, if you bring that
predictability and are able to do that,
that amount
of information that will be needed would
be very
minimal, and nothing probably more than what we
have, but presented differently, that
provides a
way forward.
But then you move towards more
complex
dosage form, I think where we don't have
that, then
even there, a science of design concept
where you
are testing hypothesis in a structured
manner,
leads you to a decision criteria.
So, in this case, for example,
I think our
pharmaceutical quality characteristics of
pharmaceutical equivalence, clearly, I
think the
minimal requirements are listed in this
table, same
189
active, identical amounts, same dosage
form, route
of administration.
Same active, I think again how
well can
you characterize from simple to complex,
there is
an issue, identical amount, hopefully,
that is not
a challenge.
Same dosage form raises many
issues, and
this is the nomenclature issue that we
run into
because we are dealing with nomenclature
that
started from Egypt--no, Egyptian based,
no--our
nomenclature, we have a lot of work to do
in the
nomenclature, because the description of
our dosage
form, and the performance and
expectations, really
have a lot of challenges built into that,
and that
is the source of constant legal issues
that come
about.
That is the challenge to the pharmacy
community, and just publishing the paper
that Cindy
published, the initial reactions from the
reviewers, I was not surprised, but
didn't see why
it was important, so the pharmaceutical
science
community is ignorant of some of those
issues.
It is unfortunate because these
things
wrap us up in legal battles, and so
forth.
So, if you really look at this
table, the
190
acceptable variability that we have built
into our
system are our materials, our methods,
and so
forth.
That's the common cause variability that is
part of the system, and simply the design
aspect is
how well you manage that and how well you
make sure
you don't introduce special causes.
In terms of measurement system
for
bioequivalence, the key question is what
is an
appropriate measurement system and how
you balance
that with that of your sign that drives
you to the
right measurement system is the key and
the
goalpost for that.
So, I think with that in mind,
I think the
premise that we had in putting this
session
together was the quality-by-design
approach by
pharmaceutical development can
potentially provide
an excellent means to address a number of
challenges previously discussed and have
been
previously discussing for years.
The topics of highly variable
drugs, I did
not see the discussion that occurred,
that focused
or was able to pinpoint a solution to
that, and we
didn't expect that. That was not the purpose of
it.
The purpose of the discussion was to get
started.
191
If you go back to the same old
solutions,
we will have the same old results. So, how can we
leverage this? Is analysis of means, which the
Japanese seems to have moved forward
towards, a
means to go forward?
Again, it's a point of view
right now that
needs to be discussed, debated, and so
forth, and
how do we make a case. Keep in mind, the way I
look at bioequivalence, the way I look at
stability
studies that documents the shelf life, is
a
wonderful, final conclusion of a
development
report, which is a hypothesis test.
In the regulatory setting, you
need that
level of clarity to make a decision, so
what the
pharmaceutical development does is
provides you a
means to come to that clarity, at that
same time
192
provide the right test procedures to create
your
hypothesis.
So, that was the premise, and
our hope was
to engage you to start the journey
together to see
whether we are on the right track in our
thought
process, and the proposals or the
discussion that
we presented, clearly, is simply an
initial thought
of how should we proceed in even thinking
about
this.
With that in mind, I will sort
of pose the
three questions to you.
Help us structure our thought
processes to
discuss this in a structured way, to seek
solutions
that have eluded us for the last 10 or 15
years.
DR. COONEY: Thank you, Ajaz.
Questions and comments from the
Committee?
Committee Discussion and
Recommendations
DR. SINGPURWALLA: Yes, Ajaz.
There were
several things you said, and I started
making
notes.
I think you were trying to say that
hypothesis testing should be a basis for
all forms
of approval and all forms of activity, is
that
193
correct?
DR. HUSSAIN: I think it gives the
structure--
DR. SINGPURWALLA: No, answer yes or no.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: No, I mean--
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: Good.
A simple
question to you. How many statisticians do you
have in your division, in your group?
DR. HUSSAIN: We don't have any.
DR. SINGPURWALLA: Well, the first
suggestion is go hire one, because what
you are
really looking for is somebody who knows
the art of
testing hypothesis, and that is what
statisticians
do.
So, I would strongly suggest
that if
that's the way you want to move, you
should at
least have some in-house experience.
DR. HUSSAIN: We have a whole department
of biostatisticians.
DR. SINGPURWALLA: I know, but, you know,
194
you ought to have your own lawyer and
your own
doctor, too.
Now, you also said industry
looks up to
the FDA as to what to do. Well, as a lay person,
not connected with the pharmaceutical
industry in
any form, my sense is that the industry
would
rather wish you go away, but given that
you are an
approving organization, industry comes to
you to
make sure that their chances of getting
approval
succeed.
DR. HUSSAIN: True.
DR. SINGPURWALLA: That is just a general
comment, but as far as your three bullets
are
concerned, I am very sympathetic to the
presentation made by Lawrence demanding
more
information, and I heard the cross fire
from my
colleague, Paul Fackler, who was
concerned, I
quickly understand. I fully support your thesis.
How can more information hurt you?
The question is how are you
going to use
that information judiciously. Otherwise, you know,
you will be loaded with eight volumes
instead of
195
the seven.
As far as your second bullet is
concerned,
my suggestion is that is the whole
premise of
Bayesian inference, how to use data that
is not
directly observable on a certain
phenomenon, but is
auxiliary, to be able to make your tests
of
hypothesis.
So, I can answer the second
bullet by
saying that pharmaceutical development
information
should be used and should be incorporated
in
whatever decisionmaking procedures you
use through
this particular inferential mechanism.
That's all.
DR. HUSSAIN: Thank you.
DR. COONEY: Ken.
DR. MORRIS: One point that I wanted to
bring up was that in talking to
companies, to
generic companies, there will be
acknowledgment of
the sort of cycle of questions. When you talk to a
lot of the innovator companies, they all
say that
they don't go through multiple CMC review
cycles.
DR. HUSSAIN: Uh-huh.
DR. MORRIS: So, in that sense, the
question that is often raised is so what
do we get
for this.
I know you have heard this, too.
I
196
guess in partly response to Nozer's
observation,
which I think is spot on, is that they--"they"
being the industry at large--wants FDA to
disappear, in a sense, but not in
reality.
But what they do rely on, I
guess, is FDA
as a consultant as opposed to adopting
the attitude
that you would adopt if you were writing
a
scientific paper, which is here is my
thesis, if
you will, and here is my defense of
it. Now, you
can judge whether my defense is
sufficient.
I think that is the mentality
that has to
shift, is that the industry has to say,
now, look,
I am not looking for FDA to tell me how
to do this,
I am going to do what I think is
appropriate to
make the case and defend the case
scientifically,
and then, having done this in a way that
makes it
hopefully more obvious to the reviewers,
have them
comment on the sufficiency of the
application.
I don't know if that is a
comment or a
197
question, but it's an observation in part.
DR. COONEY: Paul.
DR. FACKLER: I guess I should put on the
record that we are not looking for FDA to
disappear.
[Laughter.]
DR. FACKLER: That's my hypothesis. We
will have to discuss working on that.
Of course, I don't think we are
looking to
FDA to help us develop drugs. 7,000 drugs
approved, somebody had on a slide over
the past
many years.
I think a large experience with those
7,000 products to suggest that they are
generally
safe and efficacious. I am certain there are
exceptions to that, not a lot I don't
believe.
There is a handful of products
for which
we know how to develop what we consider
to be
bioequivalent and pharmaceutically
equivalent
products for which there doesn't seem to
be a
mechanism to get FDA to approve them, and
those are
the ones that I think we are really
looking to FDA
for guidance on, not how to develop them
mind you,
198
how to document appropriately that they
are
bioequivalent and pharmaceutically
equivalent.
We have obviously, records on
all the
pharmaceutical development
activities. They exist,
so it is not as if we need to do more
work to give
those to you, and they are available for
the field
inspectors that come to our sites to do
the
preapproval inspections, and they often
go through
them.
Really, the question in our
mind is how
will it help you here at the Center
evaluate our
applications, and how will you use those
to help us
demonstrate bioequivalence for this small
fraction
of products for which the standard
analysis and
treatment methods don't work.
So, highly variable drugs is
one of those
classes. Topical products, we know how to
get those
approved, we know how to develop what are
bioequivalent formulations. I think the testing is
a bit onerous, and revisiting it I think
is a great
idea.
So, just some thoughts and I
guess I will
199
leave it at that.
DR. COONEY: Marv.
DR. MEYER: In sense, and in response to
Nozer, I think that, in a sense, the FDA
is almost
like the group I have to deal with, the
IRB. I
think the FDA is kind of they put the
blessing on
something, and now you have a shared
marketing
responsibility, a sharing of the guilt,
if there is
any to be shared.
The IRB would ask
questions. They would
reject protocols or they would accept
protocols.
You didn't like it when they were
rejected, but
sooner or later, you would get it
approved.
So, I think the industry
probably enjoys
having the partnership of FDA as long as
the
products ultimately get approved.
I might rephrase your first
bullet. How
can pharmaceutical development
information help? I
would be more inclined to say what kind
of
information is needed to help extend the
application, be it manufacturing, be it
in vitro
permeability or oral water partition
coefficient,
200
or whatever, some physiological,
some--just don't
restrict it to pharmaceutical
development, because
I think there are some other things we
could put
into play as a measurement and extend
that waiver
perhaps.
Bullet No. 2, how can
pharmaceutical
development information be utilized? I would say
to make sure we have the best possible
dosage form
that one could make within reason before
you even
go to the clinic. So, make sure that your--one
example--make sure you don't have the
six-vessel
dissolution example. Make sure that you understand
the solubility and the PKA, and all of
those
physicochemical parameters.
So, I think that kind of
information, the
idea being let's reduce the variability
on the
pre-body side, so that when we got on the
human,
all we have to do is worry about highly
variable
human beings.
No. 3, I am not real sure how
to tackle.
DR. COONEY: Pat.
DR. DeLUCA: I really commend your effort
201
on the quality-by-design approach. You know, this
is a systematic approach to research and
product
development, and it must be hypothesis
driven. I
think you are going to get that by
establishing the
decision tree, and this is going to be
the plan.
I think, you know, I try to encourage
my
students when they are going to do some
research,
is to map out what they are going to do
and what
they expect to get, and what they expect
they get,
they may get one thing they are expecting
and one
thing that they are not, and what are
they going to
do if they get that.
So, to spend a little bit of
time, even if
it's a couple of days, planning, so that
you have
got a pretty good idea what it is you are
trying to
do.
I think by your suggesting this
to the
industry, this quality by design, so you
are
expecting them to kind of carry it
out. So, I
think this quality-by-design approach is
a two-way
street.
I understand and appreciate
what Paul is
202
saying, but I think it's a two-way
street, and you
have got to be also available to be able
to
communicate to them what it is that you
expect,
knowing that they are carrying it out.
But I think you can't just say,
well, you
know, you are doing the development, go
ahead,
don't ask us what to do, I think they
have got to
be able to ask, and you ought to be able
to get
some response to this.
I think by carrying out the
quality by
design, and the decision tree, that,
first of all,
the variability in performance should not
be due to
the product. You have pointed that out. I think
by going through this process, you will
be able to
assess the acceptable variability.
You know, you have a highly
variable
product, maybe the limits can be
widened. Probably
with a low variability product, you might
be able
to even tighten them. So, those are the things.
The BCS system is a very good
tool. I
looked at that and I see it's a matter of
solubility here. That's all based on solubility.
203
You have II and IV that are low
solubility drugs,
and I think in your formulation efforts,
the goal
is to try to promote availability and
bioequivalence.
With the I and III, the high
solubility,
the goal is not to hinder availability or
maybe to
prevent bio-in-equivalence.
So, I think the goal, the
formulation
strategy is going to be different where
those drugs
are in that classification, and I don't
think you
can get away, for all but the Class I,
with an in
vivo test. I don't see how you can waive that for
any of the other classes except I.
DR. COONEY: Art.
DR. KIBBE: This has been a fun couple of
days, it always is. Perspective.
To tell the
industry that you do a really good
scientific thing
and send it to us, and that will speed up
the
process, I think might fall on deaf ears.
The reason is that they have
had
experience sending stuff to the agency
that wasn't
exactly what the agency has been looking
for, and
204
it has taken iterations because part of
the process
of sending that kind of data is that you
have to
educate the people who are reading it to
the value
of it.
So, when you get off of a
guidance or a
document that fits exactly what the agency
has
asked for, when you get off of that, no
matter how
good the science is, you have guaranteed
yourself
one more round, because there is going to
be
questions, and it is not that the agency
is being
mean or pejorative, it's that the people
who are
looking at it are going oh, wow, this
looks really
good, and maybe it's good and maybe it is
really
good, maybe it's not so good, boy, I
would love to
get them in here and talk about this,
let's bring
them in and let's talk about why they did
that, and
let's see what some of the background
thinking is.
There is no company that can
put down all
of that and write a textbook for it, and
expect to
do it on one time. So, you are asking the
companies to come in and help you develop
what
would eventually be guidances, and they
are not
205
really going to leap in there.
I think this committee helps
get us there
in some ways, but you are going to end up
having to
write guidances for some of this stuff,
and
especially when you say give us
pharmaceutical
development information, because
depending on the
company, you are going to get different
kinds of
information.
Different companies have
divided their
research and development efforts in
different ways,
and
they will name it differently, and one company
will give you a bunch of one kind of data
and leave
out a little bit of something else, so
you really
are going to, after we leave, leave you
to your own
devices, you are really going to have to
come up
with something that is a little bit more
concrete.
DR. HUSSAIN: If I may, it is not exactly
the way. We are planning our decision
trees, and we
will be developing the decision trees,
and those
will be the questions that we, as
consumer
advocates, will be asking.
The rest of the job is through
the
206
industry, so we will provide a structure
to this.
DR. KIBBE: The next part of where I was
trying to go is that sometimes the
questions that
are asked are dependent on what kinds of
decisions
you are going to make. A company might have a
series of questions to ask if it wanted
to design
in quality.
An academician might look at it
and
decide, ooh, wouldn't it be nice to know
the
mechanism rather than just know how to
control it,
and regulation is really aimed at knowing
that
whatever you are controlling is going to
get me
consistent quality, and those are
different kinds
of questions, and all worth asking and
worth
knowing about.
I think we have another topic
to come up
with, which is the research end of it,
and that
kind of feeds into that. It would be really nice
to be able to have a collaborative
research effort
with academia and industry and the agency
on these
issues that is not going to necessarily
be the
answer, but a place to ask really good
questions.
Then, of course, the last thing
I wanted
to say is it is impossible to read
people's minds,
so you don't really know what they are
thinking
207
when they get to that point. You know, it's hard.
DR. COONEY: Tom.
DR. LAYLOFF: As we were visiting earlier,
I think that there is enough knowledge
base in the
industry and academia for formulation and
manufacturing to produce products which
dissolve
and which are uniform without failure.
I think what we see in all of
these,
especially No. 1 and 2, is wrestling with
an
unknown, and how do you evolve a waiver
around
things that are not well defined and
unknown.
Certainly, highly variable drugs belong
with drugs,
but they don't fit in the BCS, because
they are not
understood well enough.
The BCS takes a rough cut at
physical
properties of the substance, but not at
the
transport mechanisms or the metabolic
processes
that might control some of the properties
of the
drug.
So, I think that the waiver is
going to be
hard for broad-brush strokes, but maybe
narrow
categories can be trivialized to a few
physical
properties. The highly variable drugs are
startling, and I don't know where you go,
but I
think they are the class that sort of
makes you
208
uncertain about the waivers and the
BCS. They put
an uncertainty in there also.
The last one, therapeutic equivalence of
topical products, I don't know what to do
with
that.
DR. HUSSAIN: There is an aspect, Tom, I
think, if I may, the Class IV drug
inherently tends
to be more variable, so there is a
relationship
between variability and class, I
think. Hopefully,
when Raman's database is audited and
ready, I think
you might see a pattern there, because I
think
variability, physiologic variability--I
actually
was going to show a slide that we just
finished,
our analysis of a Class IV drug that
Raman sent me
over the weekend. You will shocked at the
variability that we see.
But there is a mechanism to
sort of start
identifying what is the source of variability with
the GI physiology, with its metabolism,
and so
forth, so you can actually start thinking
about a
structure to say what characteristics
make the drug
more variable.
So, in some ways, I think the BCS
classification, and this is a proposal of
Les
Benet, is to extend that. I mean he has simply
209
used that to extend and start predicting
the class
of metabolism of those things.
So, I think we could consider
sort of
characterizing the sources of variability
and see
if we can start.
DR. LAYLOFF: Have you ever tried to put
another column on the box, the BCS box,
like
polarizability of the molecule or
footprint of the
molecule, geometry?
DR. HUSSAIN: No.
What Lawrence actually
has done is actually went back to the
structure and
predicted the bioavailability, so there is an
element of that. We recently published a paper on
210
going back and actually predicting the
permeability
from the structure, so there is an
element of that.
Professor Les Benet has now
extended that
to actually a classification system to
include
metabolism. So, that is a recent proposal. To
there is lots of progress in that area.
DR. LAYLOFF: So, that will fit into the
possibility of going towards a waiver
business.
DR. HUSSAIN: I have not studied some of
the latest ones, so I just have seen the
papers,
but not studied them, so I can't say, but
I think
there are some positive signs there.
DR. COONEY: Ken.
DR. MORRIS: Tom made actually one of my
points better than I would have probably,
but to
that point, I think if you look at BCS-3,
clearly,
from the data we saw, I was a little
surprised that
that was the highest variability class,
as we
talked about earlier, but if you include
some of
the work that Les has been doing, was
that
editorial?
If you include some of the work
that Les
211
has been doing, so that you could
subdivide Class
III in particular into mechanistic
subcategories,
if you will, it certainly seems like
there ought to
be something in Class III, that is some
element or
some subcategory of Class III that should
be ripe
for waiver.
I mean if their premise is
valid, the
hypothesis is valid, then, there ought to
be a way
to do that.
The other thing with respect to
what a lot
of people have talked about, Jerry
before, and Paul
and Art to some extent, when I was in
industry,
which was admittedly a while ago, we used
to
generate what in my particular case we
called IDSC,
initial drug substance characterization
report.
As we were talking about
earlier, these
exist already in most places. The only question I
think, or only caveat I guess that needs
to be
added to that would be that once you are
to the
point of filing, in the light of what you
know post
this initial drug substance
characterization
report, you might truncate what you
provide only
212
based on what is or isn't necessary. It's not like
you want to just provide everything.
But in many instances, and I
have seen
this in consulting, these documents almost
exist in
place already, and it is just really a
question of
pulling the right things out or adding
what is
relevant in. I think that is relatively common.
DR. HUSSAIN: Again, I do know they exist,
and that was the reason for starting
this, because
I knew that was already there, but it was
bringing
those into making decisions, because I
think Moheb
mentioned we get volumes and volumes and
volumes of
things that we have to sort through,
which is not
value added.
We get supplements after
supplements,
which is not value added. So, the whole idea is to
utilize that and make the decision, and
then
without having to get all of those things
that we
have to sort through, and so forth. So, that is
one way of looking at it.
DR. COONEY: Michael.
DR. KORCZYNSKI: Just a few generalized
213
comments relative to communicating to the
industry.
As this unfolds and is described to
industry, I
think they ought to be reminded that I
see the
quality-by-design plan for pharmaceuticals
somewhat
analogous to the Center for Radiological
Health and
Devices' developmental design plan, and
it is sort
of a similar concept, and they ought to
be made
aware that indeed there is an analogous
situation
here.
The other thing is I think back
when we
talk about industry not knowing what the
FDA wants,
well, there was a climate back in the
1980s
relative to sterilization technology of
sterile
products, and a number of companies were
concerned
when they were making submissions and
were
receiving some rejections and questions,
gee, what
does the FDA want.
Well, the FDA went on to draft
a guideline
for sterilization technology information
when
submitted in NDAs, and actually went on
several
performances at different cities, about
four in
all, and that was discussed openly with
industry,
214
and
that became very effective and really did a lot
in terms of dispelling some
misunderstandings. So,
a similar approach could be undertaken
here at some
time.
DR. COONEY: Any additional comments from
the Committee?
The request here for this topic
comes,
well, as on the screen, these are our
initial
thoughts, are we on the right track. As you can
see, there are three questions that have
been
posed, I think somewhat rhetorical
questions in
that you are not looking for a vote on
these
particular issues.
I have tried to capture what I
think is
the consensus of what people have been
saying, and
if you will allow me to try and summarize
this
point, and the question I want to ask the
Committee
is does this--what I am going to
say--does this
capture what we collectively have said.
I am looking for omissions in
this summary
and I am also looking for things that
shouldn't be
there, so that is the input I am looking
from the
215
Committee, and then I will ask if we, in
general,
agree that this is a consensus.
The platform here is that there
is a need
for a better understanding of the science
of
formulation design will lead to improved
product
quality with reduced variability. In fact, this is
the foundation for quality by design.
That the implementation of
quality by
design will require additional
information on the
product development process. This is what has been
generally referred to as the product
development
report, and that the FDA wants to use this
information, this product development
report, which
is ill-defined at the moment, or loosely
defined at
the moment, to do three things, as you
have
outlined in your earlier slides:
To extend the BCS-based waiver
for
immediate release products, to facilitate
approval
of highly variable drugs, and to
facilitate the
establishment of pharmaceutical
equivalence of
topical products.
So, those are the three general goals, and
216
from this conversation, there is a need
that has
been discussed to work with both the
industry and
the reviewers, in other words, the system
needs to
be receptive to receive and use
effectively new
information, and that it is important to
add
clarity on what information is required,
as well as
how that information will be used, for
instance, to
establish a bioequivalence, and that the
general
consensus seems to be to recommend that
the FDA
continue down this path to address
quality by
design and define its use to facilitate
issues in
the regulatory approval of drug products.
DR. HUSSAIN: A point of clarification.
DR. COONEY: Please.
DR. HUSSAIN: One aspect also I think,
please consider this, the CTD Q B2
section has the
sections and everything defined. The ICH Q8
defines what information goes where, and
so forth.
So, in that sense, it is
already
structured, it is already part of the
guideline,
and one of the aspects, the timing of
this meeting
in relation to ICH also has to be
considered here,
217
because starting this Saturday/Sunday, we
are
moving towards putting together decision
trees for
the dosage forms in Q6A, so you will see
the train
leaving the station of how these decision
trees
will evolve, and the goal is to get to
Step 2 by
2006.
So, that process is beginning next week.
Now, this meeting, one of the
other
aspects is also is we focused this on the
generic
side for one reason, also was we often
have
hesitation as generics really do not have
the level
of involvement there, because there are
just
observers there.
So, I think is also a plea for
the
generics to keep engaged with that
process, because
that process is leaving, and Europe
already has
their decision trees for all of this, and
we are
not fully happy with that. We want to make sure
the decision trees that evolve the next
six, seven
months will be the science base.
DR. COONEY: I think that in the
presentation that you have made, Ajaz,
the role of
decision trees at multiple points in this
process
218
was clarified, so I believe that that is
clear.
I would ask the Committee, did
this
summary capture what you believe was the
essence of
the conversation from this morning and
this
afternoon?
DR. SINGPURWALLA: I think in terms of
proper vocabulary, I think the word
"hypothesis"
was constantly used by Ajaz.
DR. COONEY: I noticed that it was used.
DR. SINGPURWALLA: I also noticed that it
was eliminated from your summary, and so
I am just
trying to remind you whether you want to
endorse it
or not.
DR. COONEY: I did not leave it out by
design.
DR. SINGPURWALLA: It was because of
variability.
DR. COONEY: It was a bit of variability.
DR. SINGPURWALLA: I would try to give a
strengthening hand to Ajaz and Helen and
all in
terms of endorsing what they want to do
by
specifically including that in the
vocabulary, so
219
that it succinctly conveys the intention
of what
they want to do.
I wouldn't say anything about
the fact
they don't have any statisticians in
their group.
DR. COONEY: This will get written up in
minutes of the meeting, and I will see to
it that
it is appropriately worded and we will
check the
vocabulary and the grammar.
DR. SINGPURWALLA: Spelling.
DR. COONEY: Does everyone--so, the train
is leaving, you should be aboard the
train and
rolling down the tracks, and I believe it
is fair
to establish the expectation that
probably at our
next meeting, we will hear something more
definitive.
DR. HUSSAIN: At least on some aspects of
that.
DR. COONEY: Yes.
It would be nice to
have all the problems solved by the next
meeting.
I think this brings us to
closure of this
topic. We are going to go to another
topic which
deals with the research, and I would
suggest that
220
we take a five-minute stretch break and
reconvene
at approximately 7 minutes past 2:00.
[Break.]
DR. COONEY: I realize that a five-minute
stretch break is a very short period of time, but I
wanted to look around and see those who
didn't get
up and stretch, and that I would go wake
them up.
DR. KIBBE: Just so that we keep
everything on point, stretch breaks are
an
extremely highly variable process. If you say 5
percent in stretch breaks, that could
mean anywhere
from 10 to 40 minutes.
DR. COONEY: I said 5 minutes, and there
has already been a 2-minute variation on
that, so
your point is well made, Art. I will take that
into account in the future.
The next topic is a very
important one and
it revolves around the Criteria for
Establishing a
Working Group for Review and Assessment
of OPS
Research.
Criteria for Establishing a
Working Group for
Review and Assessment of OPS
Research Programs
DR. HUSSAIN: The topic is a request to
form a subcommittee and this advisory
committee to
have a peer review process for
research. We
221
already have a committee under CBER and
we need to
migrate that committee under this to have
a process
in place for Office of Biotechnology
Research
Program.
But also I think we want to
take this
opportunity to put in a place for a peer
review for
all of our research programs in one
umbrella. With
that in mind, all we seek today from you
is an
endorsement to form a subcommittee and
define the
scope and charter as the committee gets
formed, and
so forth.
But for you, we have just a
presentation
of the background of what the current
system is,
and then Keith will come back and ask the
questions.
DR. COONEY: The first presentation will
be by Kathleen.
CBER Peer Review Process for
Researchers/Reviewers
DR. CLOUSE: I have been asked to put
222
together a simple but concise summary of
how we do
peer review for the OBP Research Program.
Hopefully, you can follow along without
much
confusion.
I have divided this up into
four
discussion topics. The first is an outline of the
Researcher/Reviewer Model. Secondly, how
Researcher/Reviewer Program is
monitored. The
process for external scientific
review. Then, the
promotion and conversion evaluation or
PCE
Committee through which the
researcher/reviewers
are converted to permanent positions and
promoted
through the GS system.
The Researcher/Reviewer Model is something
that has existed at CBER for a
while. We do use it
in OBP.
We have individuals who do both research
and review, and we also have individuals
that do
full-time review. So, before I describe the
program, I would like to emphasize the
fact that
more than 75 to 80 percent of our
full-time
reviewers have come up through the
Researcher/Reviewer Program. So, this is also in
223
part a training program for our
reviewers.
The responsibility of a
researcher/reviewer, first of all, is to
conduct
research that is relevant to the FDA
mission, and
this research is generally dealing with
specific
products, and that can be for mechanism
of action,
for toxicity, or surrogate measures of
efficacy.
It can be related to product
classes,
specific diseases, or therapeutic modality,
and it
can also be associated with the
development of
methods and standards by which products
can be
prepared.
In addition to the research,
the
researcher/reviewer performs regulatory
review, and
this is at the level of investigational
new drug
applications, as well as biologic license
applications, and they also are involved
in
conducting inspections for specific BLAs.
They also contribute to policy
development
as
they become more senior in the structure.
The funding of OBP research,
the majority
of the funding is provided at the OBP
level from
224
our operating funds, and it is
distributed on a per
capita basis. A portion of the allocation is held
aside, and these additional funds are
distributed
by OBP based on research prioritization.
The research prioritization is
determined,
not just at the office level, but from
guidance at
the agency level and what the agency
deems to be a
priority for that given year.
We also have access to
competitive funding
through the CDER Review Science and
Research or RSR
program.
We have obtained competitive
funds through
the Office of Women's Health granting
program.
We also have access to
competitive funding
through the NIH Intramural Grant Program. These
are limited for the most part for
research dealing
with AIDS and, more recently, for
counterbioterrorism efforts.
We also have some funds that is
obtained
through CRADAs and inter-agency
agreements.
The program monitoring is done
at multiple
levels. The first tier of monitoring is
done by the
225
Lab Chief. Now, the Lab Chief generally has their
own research program and is responsible
for several
additional principal investigators.
The Lab Chief does not
determine the
research focus, however, they do assess
the
research productivity of the principal
investigators and offer some guidance if
they don't
appear to be productive enough, if they
are spread
too thin, and so on.
But more importantly, the Lab
Chief is
involved in the actual training of the
principal
investigators and any Staff Fellows
working under
them on the regulatory review process,
and the Lab
Chief evaluates the ability of the
individuals to
perform regulatory review.
The next tier for evaluation is
the
Division Director, and the Division
Director
discusses the scientific productivity and
regulatory abilities at least twice a
year, but
this is often done through the Lab Chief,
because
they have the first tier of evaluation.
The third level is at the Office
Director
226
and Associate Director for Research
level. Here,
the scientific productivity is assessed
via
publications. What is taken into consideration is
not just the number of publications, but
the type
of journals, the impact factor, and also
the
relevance to the FDA mission.
Finally, we also have External
Scientific
Review or site visits. The purpose of the External
Scientific Review is, first of all, to
determine
the relevance of the research program to
the FDA
mission; secondly, to evaluate research
productivity; third, to assess the
regulatory
contribution, and this is a portion of the External
Review, and also to provide input
regarding
resource allocations.
In general, the input is we
should get
more resources, but there is usually not
much the
agency can do about it.
The External Scientific Review
ideally
occurs every four years. Now, the research group
that is reviewed, generally, it is all
principal
investigators within a specific research
lab, in
227
other words, you have the Lab Chief and
whichever
principal investigator works in that
particular
lab.
On some occasions, we have
grouped site
visits based on expertise, so that the
site visit
reviewers don't have to be duplicated or
they can
overlap in their review process.
The Site Visit Committee, and
this is most
important and one reason that we need to
bring up
the issue with this advisory committee
today, the
Chair of the Site Visit Committee is
generally a
member of the parent advisory committee.
Previously, this was the
Biological
Response Modifier Advisory Committee,
however,
since our transfer from CBER to CDER,
they have
renamed the group and refocused the
emphasis of the
committee members. That is currently known as the
Cell, Tissue, and Gene Therapy Advisory
Committee.
So, what is happening is as individuals
with expertise in our area end their
term, they are
being replaced by individuals with more
of a focus
on cell and gene therapies.
In addition to the Chair, there
are one or
two external scientists with relevant
research
experience or expertise for each
principal
228
investigator under review. When possible, if there
is a member of the Advisory Committee
that has the
relevant expertise, they also will be
asked to
serve on the Site Visit Committee.
The format of the external
scientific
review, first of all, the committee is
assembled,
they are given the review package, and
they review
the scientific program in a formal
setting.
At the conclusion of the site
visit, a
summary is given to the Center and Office
Directors, so that they have a pretty
good idea of
how the site visit went.
Several weeks later, a
preliminary written
report is sent to the Center for review,
and then
that preliminary report is presented by
the Chair
of the Site Visit Committee to the Advisory
Committee, and the report is ratified by
the
Advisory Committee before it can be used
by any of
the scientists.
A copy of the official report
is then
provided to the Center and Office
Directors, and
individual reports are given to scientists
under
review.
The site visit report is used
in the
following manner. Within two years of the site
229
visit, a favorable report can be used for
tenure or
conversion of the principal investigator
to a
permanent position.
Within four years of the site
visit, if
the individual is already tenured, it can
be used
for promotion to a GS-14 or 15, and these
promotions are permanent. It can also be used as
supporting documentation for internal
grant
applications or external grant
applications when
applicable.
Now the Promotion and
Conversion
Evaluation or PCE Committee actually
makes the
decisions on the conversion and promotion
of
scientists. So, the purpose of the committee is
the conversion of Staff Fellows to
tenured Civil
Service research and regulatory
positions. They
230
also are involved in promoting tenured
Civil
Service research and regulatory
scientists to the
next grade level, as I mentioned before.
The composition of the
committee is as
follows.
There are two tenured principal
investigators from each of the Research
and Review
Offices, so we have our own two
representatives
from the Office of Biotechnology
Products. That is
myself and also Emily Shakter from the
Division of
Therapeutic Proteins.
In addition, there are members
from the
Office of Blood Research and Review, the
Office of
Cell, Tissue, and Gene Therapy, and the
Office of
Vaccines at CBER. Each of those respective offices
has one full-time ad hoc reviewer, so for
any one
situation, one of those ad hoc full-time
reviewers
also serves on the committee.
There is a representative
present from the
Office of Personnel Management to make
sure all the
procedures are followed, as needed, and
as legal,
and there is one representative from the
CBER
Office of the Center Director.
The guidances that are used by the PCE
Committee for Promotion and Conversion,
there is a
general CBER guide for the evaluation of
research
231
and regulatory scientists from GS-13 to
GS-15,
which is available on their website.
There is also a Research Grade
Evaluation
Guide, and this is from the General
Schedule
Position Classification Guide, which I
think is
from the Office of Personnel Management.
Generally, through the use of
these
guidances, there is a scoring system, and
the
scoring for promotion and conversion is
actually
documented by the Office of Personnel
Management,
and
that is maintained and brought back for
comparison for each subsequent promotion
opportunity.
There is additional information
that is
requested by the PCE Committee. This includes a
publication summary, as well as a
presentation
summary, and these can be scientific
presentations,
as well as regulatory presentations.
You have to include a summary
of your
232
regulatory work, as well as examples of your
regulatory reviews. You have to have a copy of
your external scientific review report,
and you
also need letters of recommendation from
experts
outside FDA that are familiar with the
investigator's research.
Now, the use of the site visit
and the PCE
Committee systems has advantages and
disadvantages,
and this is the slide I will end with.
The current advantages are that
scientific
and technical positions are evaluated by
scientists
who are actually familiar with the
activities
performed, and the scientific community
is expected
to have greater confidence in decisions
made by
peer scientists.
The current disadvantages to
the existing
system, first of all, is the cost to OBP,
OPS, and
CDER.
Each site visit costs us not just for
bringing the scientists in, but also
because the
administrative office overseeing the site
visit is
the CBER Division of Scientific Advisors
and
Consultants, so we also pay for their
time and the
233
coordination of the site visits.
It is also difficult to coordinate site
visits across the two Centers at this
point. As I
mentioned before, there is a change in
expertise of
the Advisory Committee. Members of the Advisory
Committee have been instrumental in
advising us
with regard to the scientific expertise
that is
needed to review the biologic therapeutic
applications. We really would be remiss if we
didn't have that input from the external
scientists.
There is also a difference in the
regulatory workload among the members of
the PCE
Committee, and this has to do with
different
structures of the offices. One of the offices has
a structure similar to ours, where the
product
reviewer does both research and
regulatory.
Two of the other offices
actually have a
structure where there is a separate
division that
does the majority of the review, and the
scientists
are viewed more as consultants, so the
workload
varies.
There is also a difference in
regulation
of BLAs versus INDs. Very often in the Office of
Vaccines and the Office of Cell, Tissue,
and Gene
234
Therapy, the majority of the applications
are under
IND, and they don't have the experience
of dealing
with as many biologic license
applications as we
do, so there is some disconnect with
evaluating the
actual amount of the work.
There are also differences--and
this is my
latter point--in the systems for
performing review,
and that has to do with whether the
researcher/reviewer has both the full
product
review or CMC review responsibilities and
inspections.
DR. COONEY: Thank you.
Some questions? Tom.
DR. LAYLOFF: How many people are involved
in the review side of this group?
DR. CLOUSE: I think it is split about
50-50.
Keith can answer that.
DR. WEBBER: Within the office, there is
about 14 full-time reviewers, and there
is about 36
235
or so who are research/reviewers, who are
supposed
to spend half their time doing review and
half-time
research, but I think they spend more
time review.
DR. LAYLOFF: The laboratory people, where
are
they located?
DR. WEBBER: They are all physically
located down in Building 29A and B of NIH
campus.
DR. LAYLOFF: And the full-time reviewers
are located?
DR. WEBBER: They are located in the same
place. They work together and share
meetings.
DR. LAYLOFF: So, there is 50 people
there.
There is 36 and 14.
DR. WEBBER: Right, plus there are support
staff and technicians who work in the
laboratories
for the research program.
DR. LAYLOFF: How many applications or
supplements do they review per year?
DR. WEBBER: Applications, we get
generally around four full field
applications per
year, and that varies. Sometimes we have gotten up
to nine.
We get about between 150 and 200
236
supplements per year, somewhere in that
range, and
then annual reports. INDs, we have approximately a
little over 400 products in IND.
DR. LAYLOFF: Thank you.
DR. SELASSIE: I have a couple of
questions. You said the majority of the funding is
provided at the OBP level. Could you tell me how
these funds are appropriated to each
department, is
it a peer review process, do they write
proposals,
how those decisions are made?
DR. CLOUSE: No, it is divided, as I
mentioned, on a per capita basis to each
of the
programs, a portion of the money, and
then there is
a portion that is held back for research
prioritization, which is awarded based on
productivity or the nature of the
research and how
it fits in with the current
prioritization for FDA.
DR. SELASSIE: I suppose scientific merit
comes in there someplace.
DR. CLOUSE: The scientific merit pretty
much comes in the site visit process and
the annual
review of productivity. So, yes it does. We
237
haven't had an instance that I can recall
where we
have had any lack of productivity. I mean
generally, the thought is the resources
would
diminish for someone who is not
productive, but we
haven't come across that in the years
that I have
been there.
DR. SELASSIE: I assume that most of the
Lab Chiefs basically supervise the labs,
and they
don't do any research, they supervise the
PIs under
them?
DR. CLOUSE: No, we do research.
DR. SELASSIE: They do research, too?
DR. CLOUSE: Yes.
DR. SELASSIE: So, how much of your time
is like spent during research and how
much on
review activities?
DR. CLOUSE: I was asked that question at
a presentation at NIH last week, and my
Staff
Fellow said 200 percent was
regulatory. I would
say more than 90 percent of my time right
now is
spent on regulatory, and what I do
researchwise is
done at home.
DR. SELASSIE: When you do this, the
reviews of your researchers/reviewers,
and I guess
go to the various steps, to the advisory
committee.
238
At some point, I guess eventually, the
reviewer
gets to see the individual report. At
some time can
they respond to issues that were raised
in those
reports before they go on file as, you
know, done?
DR. CLOUSE: Currently, that is a touchy
issue.
In general, what has happened in the past,
we get a draft report and if the report
is not
consistent with what happened at the
summary
meeting, at the level of the Center
Director, you
know, the individuals under review or
their
immediate supervisors are not allowed to
contact
the Advisory Committee members.
It is not considered
appropriate. But if
there is an issue, you know, potentially,
at the
level of the Center or Office Director,
they can
contact the Committee Chairperson, and
they would
deal with it at that level.
DR. WEBBER: Generally, an effort has been
made to try to maintain, since we have a
239
multi-tiered review process, to maintain
a site
visit as independent as possible, so that
there
isn't any--unless, as Kathleen said, if
there is a
serious issue, serious problem with the
review that
comes from the Site Visit Committee, that
they may
have been biased or something like that,
we
generally try to avoid getting involved
before the
report is made final.
But afterwards, certainly, if
there are
issues or concerns or additional
information, that
the
Site Visit Committee didn't have in hand at the
time, that can be added to the review
process.
DR. SELASSIE: One other question. In
choosing outside reviewers, does the
reviewer, the
person under consideration, do they have
a choice
or do they give you a list of outside
reviewers,
and can you pick from them?
DR. CLOUSE: Generally, the person from
the Scientific Advisers and Consultants
Division
asks for a list of names. This list of names
cannot be anyone that you have
collaborated with or
a friend.
That list of names is provided
to the
Chair, whoever has been identified as the
Chair of
the Site Visit Committee. They are not obligated
240
to choose anyone from those, however,
once they do
choose your reviewer, they do let you
know or
contact the individual principal
investigator and
ask if there is any conflict or problem
with who
has been chosen.
So, you have some say in the
process, but
you don't have the final decision.
DR. SELASSIE: One last thing. You talked
about the cost to OPB of bringing in
outside
reviewers. Have you ever thought of doing
videoconferencing? I know the EPA does that.
DR. CLOUSE: For site visits?
DR. SELASSIE: Yes.
DR. CLOUSE: We haven't pursued it at this
point, but then again, we are in the
process--
DR. WEBBER: It's something we can
consider, but oftentimes it's an all day
affair,
because you have a meeting in the morning
with
presentations from each of the people
under review,
241
and then there is discussions within the
committee,
and usually, it takes pretty much all
day.
We might save some money by
bringing
people in by video as opposed to in
person, but we
would probably lose a great deal in terms
of the
actual interaction.
DR. CLOUSE: It is pretty much like you
have with the interaction of the Advisory
Committee. You would lose a lot if everybody
teleconferenced in consistently. It is just a
little more fluid if you have the people
there.
The one thing I did forget to
emphasize,
and that is, for the researcher/reviewer,
when you
do get an application in, whether it's an
IND
original submission or biologic license
application, or supplement, that's a
priority, your
research stops.
So, very often when you look at
someone's
productivity--and this is one reason why
it's
difficult to assess productivity, let's
say,
annually, your productivity can go like
this
depending on what your regulatory
workload has been
242
for any given year.
DR. SELASSIE: Thank you.
DR. COONEY: Carol.
DR. GLOFF: Just a couple of quick
questions. So, there are 14 people who are
full-time reviewers, 36 who are half and
half,
which we know it's not really 50-50. Are there
people who just do research?
DR. CLOUSE: Only technical staff, and if
we have funding for postdoctoral fellows,
those
individuals do full-time research.
In the majority of cases, if
the
postdoctoral fellow is a citizen or has a
green
card, and expresses an interest in doing
the
regulatory, the next step for them is to
become a
staff fellow. Then, very often, lately, the
majority of our staff fellows have gone
on to
become full-time reviewers.
DR. GLOFF: Then, my other question is--I
know we are going to have a presentation
by Dr.
Collins--I am just curious. Setting aside the
Center for Biologics, and obviously your
group now,
243
but are there other review centers or
sections in
the other review centers that have a
process
similar to what you just described?
DR. CLOUSE: If I recall correctly, NCTR
is the other center that has a structure
similar to
ours.
DR. GLOFF: I guess I don't think of them
as being a review center, but I may have
that
wrong.
DR. WEBBER: I am not sure if CVM has a
research review program, I don't know
about that,
but that will be something to look into.
DR. HUSSAIN: I think CDRX, CFSAN, they
have research programs. They are not, as Keith
said, reviewers, and they do have aspects
of this,
but not in the form that exists under
CBER right
now.
DR. COONEY: Let's proceed on with Jerry
Collins and the next part of the
presentation.
Then, we will have a chance to come back
for more
questions.
CDER Peer Review
Research
DR. COLLINS: Good afternoon. The
background document that I prepared
focuses more on
the review of research programs than on
review of
244
individual scientists, but when I
realized that we
were going to be covering both topics, you
will see
the copies that you have of my slides, I
tried to
cover both.
In my time at FDA, in addition
to working
in CDER, I have been asked from time to
time to
help other centers evaluate their
research
scientists or their programs, so, in
general, I
would say that the systems for peer
review of
individuals in all centers have more
similarities
than they have differences.
One of the mentors, Bob Dedick,
used to
say that biologists are always looking
for
differences, and engineers are always
looking for
similarities, so this may just reflect my
engineering background.
Every employee at FDA has a
semiannual
management review, so that is the
baseline review.
Everything else is built upon that. Within the
245
Center for Drug Evaluation and Research,
non-laboratory scientists, the people do
full-time
review and policy work, have promotion
letters to
the 14 and 15 through things that we call
expert
reviewers or master reviewers.
Those committees are composed of
internal
FDA members and they are intended for
non-managers
to have a promotion letter. Those promotions,
unlike in our laboratory side, are
permanent, and
they are not periodically recertified.
We have a few additional
personnel system,
Title 42 and Title 38, that are used for
non-lab
personnel and at least until recently
they have not
been subject to committee review or
recertification.
Finally, Congress created the
Senior
Biomedical Research Service that I will
be talking
about that at FDA, is implemented to
cover both
non-laboratory and laboratory scientists.
Within CDER, to go back to
being a
biologist and to highlight the
differences between
the way the OBP Committee has been set up
through
246
the CBER system versus the CDER system,
we have
always had a requirement of a minimum of
50 percent
to the voting members of our committees
to be
scientists from outside our Center, not
outside our
research program, not outside our office,
but they
have to be outside CDER.
Most often, for convenience and
for
compliance with some of the nuances of
personnel
review regulations, we have used
individual
scientists from NIH and frequently from
other
centers, and our staff has also served on
the
review committees of other centers.
Their purview is the hiring or
promotion
of scientists to GS-14 or GS-15, and
effectively,
they are three-year renewable promotions,
they are
not permanent. A survey of the record indicates
that very few people are not renewed, but
occasionally, it has been a leverage to
use when a
person unexpectedly underperforms. We point out to
them that at their next review, this will
be noted.
The Senior Biomedical Research
Service is
an agency-wide program. We have an agency-wide
247
Credentials Committee supplemented by
external
consultants, and it covers promotions
from GS-15 to
essentially above the regular Civil Service
pay
scale, and it clearly has a
recertification
requirement, so it is either four or five
years
depending on the center that the people
come from.
That is a recertification with
teeth, and
I can't discuss individual cases, but
plenty of
discussions are made, and it has
provisions, for
example, for a one-year renewal instead
of a
four-year renewal to keep your feet to
the fire if
necessary.
Some laboratory scientists are
also
covered by Title 42, and as I said, for
the non-lab
folks, up until recently there have been
no
committees or recertification associated
with that.
Again, I think based on my
experience in
consulting for other centers, as well as
my
experience within CDER, I think there you
could
nitpick some of the differences across
the review
of individual scientists. I think generally, there
is a lot more similarities, and it is a
lot more
248
effective, understood by all parties, and
truly an
ongoing process.
But as I said in my
backgrounder, the peer
review of research programs themselves
has
considerable polarity, and so as we just
heard in
the discussion after the previous
speaker, CBER and
NCTR have lab research programs that are
much more
like the academic or the NIH model, site
visits
conducted by advisory committees.
We have five other
laboratory-based
research units at the FDA: Center for Devices and
Radiological Health, Center for Food
Safety and
Applied Nutrition, Center for Veterinary
Medicine,
the field organization in CDER, and for
lack of a
well-defined term, I call that a
corporate or a
management model, very similar to what a
pharmaceutical company does for its
research
programs.
The primary evaluation of
research
programs is internal by the program
management.
Within CDER, we have had
occasional
episodic external review. They are not formally
249
established, they are not regularly
conducted.
Sometimes they are conducted when a
problem is
noted by center management in their
semiannual
review.
Sometimes it's just we haven't done one
for
a while, let's do it again.
I think what we are looking for
today in
terms of advice from the committee is
whether that
is really the most effective model.
In terms of the ad hoc reviews
that we
have had, the FDA Science Board, which is
another
advisory committee like this one, usually
picks one
topic at a time, and might review the
program, for
example, in genetics or genomics across
all the
centers, rather than just a genomics or
genetics
program at CDER.
The predecessor of this
committee is
called the Generic Drug Advisory
Committee, and it
started the tradition of at least having
some site
visit-like character and certainly
information
briefings.
So, last October I was here in
front of
this committee talking about the OTR
research
250
programs.
I did that also back in March of 2003.
We have training sessions
periodically. I think
those are very valuable in helping to
orient you
folks and to prepare you to give advice
to us, and
we do get feedback, but that is not the
same in any
stretch of the imagination as a formally
organized
peer review process.
The ad hoc reviews from
external folks of
CDER programs usually are problem solving
exercises. At one time, we had another advisory
committee called the Antiviral Drug
Products
Advisory Committee, still have it, and
when we
created a laboratory program on antiviral
drug
products, we made it part of the charter
of that
committee to conduct periodic reviews of
that
laboratory.
Unfortunately, that laboratory
did not
flourish, and that laboratory no longer
exists and
has been abolished. So, our review
process does
have teeth, it is not just a friendly
pass among
colleagues.
We also had, in the Center for
Drug
251
Evaluation, support of a cardiovascular
pharmacology laboratory, and after an ad
hoc
external review, that laboratory was
decided to be
no longer funded.
So, again, reviews aren't as
frequent and
regular, and don't capture the benefit of
that, but
they do provide sort of a final chance to
prove
yourself when things are going bad.
Internal reviews. I mentioned a little
bit about this at a training session
earlier this
week.
There is a tradition of annual presentations
to the Center Director, the Deputy Center
Director.
A year might take longer than 12 months
to call it
an annual review, but that has been a
goal for a
long time.
I think we have had a number of
serious
efforts to have a Research Coordinating
Committee,
and it is always important when
evaluating Center
for Drug Evaluation and Research, is that
we are
not primarily about laboratory
programs. There is
at least as much, or perhaps more,
research that is
conducted outside the laboratory.
Things like reviewing files to find
common
class effects of drugs, things like
creating
databases to improve the review process,
thinking
252
about looking at new standards for either
safety or
efficacy.
So, all these programs in a
very large and
rambling center like ours is hard to keep
track of,
so the Research Coordinating Committee
currently,
in its current form, is chaired by the
Deputy
Center Director, is an attempt to try to
pull
together centerwide databases of research
and to
help center management in a pretty tough
decision
of resource allocation.
Now, I made a comment at the
training
session that the good news is we have
high level
visibility with the Deputy Center
Director as our
chair.
The bad news is because at that level, the
person is so busy, we get a lot of
cancellations.
Shortly after that, all our
Blackberries
went off and another meeting was
scheduled. I
don't think there is any connection, but
I am
nervous.
Within OPS, for example, one
example of
the kinds of non-laboratory research that
is
conducted by the Informatics and
Computational
Safety Analysis Staff, looking at
structure-activity relationships, and
spinning off
various databases in terms of different
elements of
253
safety, carcinogenesis, reproductive
genetox, and
the like.
Elsewhere, the Biostatistical
Biometrics
Office, the Office of Drug Safety, Office
of
Information Management, and Office of
Clinical
Pharmacology and Biopharmaceutics have
well-established research programs.
Funding has come up in the
question and
answer period. The primary sources of funding for
CDER research programs, as with the
tradition and
history of OBP when they were in CBER,
and now that
they are part of CDER, is primarily
determine by
office management.
Managers should be accountable
for the way
they spend all their dollars, whether it
is for
review, policy development, travel, or
research,
254
and that has been the policy in CDER as
long as I
have been here.
In addition, there is, as was mentioned
in
the OBP presentation, there is an
opportunity to
get funds from outside your individual
budget
through the Review Science and Research
program,
but those funding areas are limited to
certain
areas determined by CDER management.
There is an internal peer
review by CDER
scientists. Almost always those funds are not
intended for laboratory-based research,
but they
are intended to foster primarily
activities, such
as database generation within review
divisions. In
a sense, they are equivalent of a
laboratory.
Within the agency, we have a
number
offices, the Office of Health Science
Coordination
chaired by the Deputy Commissioner for
Science, and
the Office of Women's Health, have had a
certain
amount of money set aside every year over
the last
10 years, and competition agencywide for
these
funds is conducted. The priorities, again, the
categories that they are willing to fund
are set in
255
advance, so that is the management of the
funding
office.
Proposals are peer reviewed
both for
quality and for relevance to the
priorities that
have been set by the funding office. The peer
review is conducted only by internal FDA
staff, but
both lab and non-lab proposals are
accepted.
Within our Laboratory Research Program, we
do have CRADAs, cooperative research and
development agreements, which is a source
of
outside money. We also have had occasional
interagency agreements with other federal
agencies,
primarily NIH.
As you can imagine, those
sources of funds
come with strings attached to them. By law, they
can only be spent on the purpose defined
in the
CRADA or in the interagency agreement, so
there is
a
compromise between what might be your primary
mission and the mission of your partner
in those
agreements.
I would say, in summary, that I
grew up
scientifically, mostly within the NIH
system, so I
256
am used to a system of peer review, site
visits. I
see a lot of strength in that.
I am also a very strong
proponent as a
part-time manager, part-time scientist,
of holding
management accountable. I don't think it is
necessarily bad to make it a part of the
review of
management on how well or how poorly they
fund
research and how well or how poorly they
evaluate
it.
I am very strongly convinced of the nature
of applied research, relevant
research. I probably
have a reputation for pushing that angle
too hard.
Whenever I do, I try to remember my own
interview
when I was joining FDA, and I had a
chance to
interview with Commissioner Frank Young.
He took me in his office and he
said,
well, Jerry, I see you come from an
applied
background and I am glad to see that
because that
is what you should be doing in CDER. So,
I thought,
great, I can really depend on the
Commissioner to
support this, whenever anybody is off
doing blue
sky stuff, I will just tell them what the
257
Commissioner told me.
But he didn't finish his
sentence there.
He looked out his window and he said,
"You see that
sky.
I think your job description ought to include
an element that says you spend 20 percent
of your
time looking out the window or at least
doing blue
sky research."
So, I think applied research,
directed
regulatory relevance, is clearly doable,
a little
bit of flexibility in terms of pursuing
something
that may not quite be there from a
regulatory
relevance, but has at least some hope in
the
future, not 80 percent, but I will take
Commissioner's Young's 20 percent.
I was asked by some of the
other members
of the Office of Testing and Research to
mention
that we do occasionally very short-term
projects, a
little bit more of a testing flavor than
of
research.
They are given by Office of New Drug
Chemistry of Office of Generic Drugs, or
another
Office of Pediatrics, one of the other
offices
within CDER.
They have a very short
turnaround time,
and in a sense they are peer reviewed,
because the
offices are either pleased with our work
product or
258
they are not, and if they are not, they
don't come
to see us again.
That really is my view of how
the CDER
research operation has worked up until
the time
that the merger occurred and OBP joined
us.
Committee Discussion and
Recommendations
DR. COONEY: Thank you, Jerry.
Are there some questions from
the
Committee? Cynthia.
DR. SELASSIE: Just one question. You
mentioned that the funds for research are
usually
used for database generation at CDER?
DR. COLLINS: That is in the particular
category of review science and research,
so the
primary applicants, in fact, the
principal
investigator for all those things has to
be a
primary reviewer. Other people can be
co-investigators. So, by its nature, the funds
that are available there tend to be used
for
259
creating databases.
At the training session earlier
this week,
I talked about the project that we were
co-investigators on, looking at a review
of
neuropharmacology NDAs over the last 10
years.
That was an example of a project that was
funded by
the Review Science and Research program.
What does it do? In theory, it gives a
little bit of release time to the
reviewers. In
practice, they probably just do it on top
of their
regular job. It gives us some travel money. The
poster that came out of that meeting, it
was
presented at a meeting in Florida. The travel
funds came out of the RSR budget. Publication
expenses come out of that budget.
DR. SELASSIE: But could the Informatics
people help you all with that?
DR. COLLINS: The Informatics people are
sort of built into the process. If you are going
to make a database generally available at
FDA, you
have to start by talking to the people
who run
either the OIM or the OIT, the
Information
260
Management Information Technology. All databases
have to fit the new corporate model, so
that is
there.
If in that process, they find
out there is
some off-the-shelf software that is available
for
it, that's great. Our Neuropharm project has used
Microsoft Access, it wasn't one of these
mega-databases. The hard part was extracting the
data from paper documents that had come
in over the
last 10 to 25 years and putting them in
electronic
format.
MS. WINKLE: Let me make it clear, too,
these aren't large sums of money. They may be
$150,000 that are put aside, or may be up
to 250
depending on what the budget allows each
year, and
the amounts allotted are usually like in
small
amounts, 5- or $10,000 just to keep a
project
going.
It is not enough to do any real bench
research on.
DR. LAYLOFF: How many people are we
talking about, Jerry?
DR. COLLINS: The Office of Testing and
261
Research has about 70 laboratory-based
persons.
That includes a handful of support staff.
We don't
actually have a classification system
that permits
us to tease out the technical support
staff from
the principal investigators.
So, when we were talking about
the numbers
for OBP being 36 review-based scientists,
we
actually have, in all, 65 review-based
scientists
or something like that, but many of them
would be
classified as technical support under a
different
classification system. So, we just lump all our
folks together.
DR. LAYLOFF: You don't have a review
function corresponding?
DR. COLLINS: There are no line reviews
assigned. There are probably 10 of our
staff who
spend more than 25 percent of their time
doing
review and policy work. I chair several committees
that are related to the writing of
guidance
documents, the FDA-wide Imaging
Initiative, which
is primarily a non-lab operation.
Up until this year when these
other duties
262
took me away, I did a tertiary review of
every
single new molecular entity that was
submitted to
the Center for Drug Evaluation and
Research, an
average of about 30 a year.
Other scientists, like John
Strong, work
in the Drug Metabolism, Drug Interaction
area,
picked up the slack as I have moved into
other
areas.
On the Chemistry side, we have folks who
are consultants to that process, but we
don't have
signature authority on the review of any
product
from within--
DR. LAYLOFF: There is no growth concept
like people going from research and
moving into
doing some review, and then becoming
reviewers full
time?
DR. COLLINS: Well, Tom, we call that a
"stealing away" phenomenon, not
growth. Let's be
clear that Ajaz Hussain was the Director
of our
Division of Product Quality, and Moheb
Nasr was the
Director of our Division of
Pharmaceutical
Analysis, and on and on, like that, so it
is a
measure of quality and desirability, but
you have
263
to debate the idea that it's growth.
[Laughter.]
DR. COLLINS: Just kidding.
DR. COONEY: I think it is probably
appropriate as the next step, Keith, if
you would
pose the question that you would like to
Committee
to address.
DR. WEBBER: I think what we are looking
for here is not really a lot of
discussion about
setting a peer review program or a site
visit
program or the pluses or minuses of the
various
aspects of it, but really just to come to
the
Committee to look for an agreement to
support the
creation of a subcommittee that will help
us to
develop the criteria and the processes
within OPS
to evaluate the research programs, the
diverse
research programs that we have within the
office
now.
Certainly, you can ask
questions in that
regard, I think hopefully, we can come to
an
agreement that you would be interested in
that,
because we are interested in that.
DR. COONEY: I would like to open up this
question for discussion. Our charge this afternoon
is not to solve this problem, but rather
to ask if
264
we concur in making a recommendation
towards the
establishment of this committee.
Tom?
DR. LAYLOFF: So, you would basically
create a subcommittee, which would come
back and
report to ACPS on the activities?
DR. WEBBER: That would probably be one
avenue or one aspect of developing a
subcommittee,
and most subcommittees do come back to
report to
the Committee, so I would imagine that
would be how
it would work.
DR. LAYLOFF: So, the ACPS then would be
providing guidance to the subcommittee on
how to
proceed with this?
MS. WINKLE: Let me point out, too, if you
determine to create a subcommittee, you
would have
to have two members of the Advisory
Committee that
would serve on this subcommittee, so not
only would
you expect for the subcommittee to come
back and
265
report to the Committee, the Committee
would also
have input into the subcommittee through
those two
members.
DR. COONEY: Marv.
DR. MEYER: Well, I don't have any
fundamental objection to that
approach. I just
wonder why it is necessary. You have several
models out there in different groups in
FDA
already.
It would seem like you could
use some of
their expertise, as well as some of your own
people, to develop your own criteria for
promotion
and for funding and research, and not
have folks
like us sitting around the table and muck
it all up
for you.
DR. WEBBER: I don't know that we are
necessarily looking for that much in
terms of
mucking with the process.
[Laughter.]
DR. WEBBER: But I think that right now we
have a system within OBP's site review system,
which I think clearly needs to be
replaced, and we
266
have a system which is now with OTR in
the same
office, and I think if we can look at
both aspects
of both research programs, and try to
come up with
something that works for both, it doesn't
necessarily have to be the same, but has
to be
something that will be consistent within
the Office
of Pharmaceutical Science, and provide us
with some
external guidance on the research
programs that we
have, something that we have always
gotten from--or
at least with OBP, we have gotten that
from the
CBER system, but we need to move forward.
DR. COONEY: I would like to thank Marvin
for introducing technical terminology
into the
minutes.
Art.
DR. KIBBE: I think it's a wonderful idea
that you have a review of research
activities
within the agency, and if you need our
help, then,
we should stand ready to do that. So, you lay it
out and we will populate the committee
for you.
DR. DeLUCA: I agree.
I think you have
certainly given this some thought, and
you think it
267
is important. I certainly think you do need some
external input into this, into the
research that is
being performed and the caliber of it.
You do, I guess, derive some funding
from
NIH, too, right, for this?
DR. WEBBER: Funding from NIH to establish
a peer review? No.
DR. DeLUCA: No, no, for the research.
DR. WEBBER: For the research, no, we get
money from NIH for the research. We get money from
operating funds, we get money, as you
saw, from
other sources.
DR. DeLUCA: Maybe we ought to tap that
source.
DR. CLOUSE:
There is money from NIH, but
only through Intramural NIH grants, so
the money we
can apply for is limited. I mean we have a number
of investigators who have been funded
through the
Intramural AIDS programs, and received
AIDS grants.
We have received money for
equipment
through that program, and this year NIAID
has also
started an Intramural Grant program for
268
counterbioterrorism research, and we have
people
who have applied for that.
So, we have been
successful. That is
competitive with the other NIH
institutes, and we
have received funding.
DR. COONEY: I think the fact that there
are different models to look at, both
models that
exist within the system now as a
consequence of the
merger, as well as alternative models and
practices
from other organizations, it would very
interesting
and useful to look at.
Perhaps--not perhaps--I am sure
there are
best practices from alternative models,
and I would
hope that this working group would be
able to reach
outside and look at a number of alternatives
and
come up with recommendations towards a
system that
is most appropriate for the diverse
activities that
are present here.
DR. WEBBER: I agree with that completely.
I don't think we need to reinvent the
wheel
entirely, but to look at what other
systems are in
place, and take the best practices from
those.
DR. COONEY: I personally see this as an
important activity for a working group.
If there are no further
questions from the
269
Committee, what I would like to do is to
pose this
as a recommendation. I think it is appropriate for
us to vote on it, which I will go around
the table
and ask for votes in just a moment.
The alternative votings are
yes, no, or
abstention. What we are voting, this would be a
recommendation by this committee to the
FDA to form
a working group of the ACPS to address
the criteria
and processes for evaluating the OPS
research
programs.
We are now empowering the
creating of a
committee, but we are recommending that
they go
forward with the formation of a
subcommittee.
Marv?
DR. MEYER: A point of clarification. You
mean a subcommittee under ACPS with two
members
from this group, not members of this
group.
DR. COONEY: Yes, that is what I meant.
Thank you.
Since we began with Art
yesterday on the
previous vote, we will begin with Tom
today, and I
would like to go around and have a yes,
no, or
abstention.
Tom.
DR. LAYLOFF: Yes.
270
DR. COONEY: Cynthia?
DR. SELASSIE: Yes.
DR. SWADENER: Yes.
DR. COONEY: Mike.
DR. KORCZYNSKI: Yes.
DR. COONEY: I think I heard yes from
both.
Morris?
DR. MORRIS: Yes.
DR. COONEY: Pat?
DR. DeLUCA: Yes.
DR. COONEY: Carol?
DR. GLOFF: Yes.
DR. SINGPURWALLA: Yes.
DR. KIBBE: Yes.
DR. MEYER: Yes.
DR. COONEY: And yes for myself. We have
a unanimous 11 yes's, zero no's, zero
abstentions,
and 11 yes's total to 11 votes.
Thank you very much,
Keith. This brings
this topic to a close.
I would just like make two
further
comments before I believe we close for
this
session.
One, I appreciate very much the very
thoughtful contributions that each of the
271
presenters have made in a very nice
style. I like
the data-driven presentations, and the
fact that
they were very concise.
I would like to thank the
Committee
members for their very, very thoughtful
comments on
all of the topics that allowed us to move
I think
reasonably efficiently through what was a
very full
and very important agenda.
This is an important committee
to OPS as
it helps them as they go forward and
craft an
aggressive agenda being proactive and
changing some
of the paradigms with which they work.
I would certainly like to ask
the
272
question, if anyone on the committee has
thoughts
on things that we should be talking
about, should
be addressing that we haven't talked
about before,
this is an open-ended question. We can
deal with
thoughts that you might have now, but it
is meant
to be a permanent question on the table,
that as we
have things that we think should be addressed
by
this committee, I would hope that people
would be
very forthright in bringing them up, so
that we can
come back to them in an ongoing manner.
Does anyone have any thoughts
at the
present time?
Nozer.
DR. SINGPURWALLA: Not on the question you
asked, namely, but I would like to make
some
comments about the format of the
meeting. I would
like to suggest that the number of
presentations be
cut down and the length of each
presentation be cut
down, and there be more time for
discussion
instead.
This puts not only less burden
on the
committee, but it also puts less burden
on the
273
staff and yourselves. I know you work very, very
hard, and I know this is a stressful
thing for you
to do, and it is not as stressful for us,
but I
think cutting these down would be of some
value to
us.
DR. COONEY: Any other comments or
thoughts from the Committee?
If there are no objections, I
will call
the meeting to a close and thank you all
very
much--oh, I am sorry. Ajaz, Helen, please.
Conclusion and Summary
Remarks
DR. HUSSAIN: Let me quickly summarize.
Just wanted to sort of encapsulate some
highlights
that were, in my opinion, I think the key
directives and recommendations we heard
from the
Advisory Committee.
First, I think I would like to
acknowledge
and thank our colleagues from Health
Canada who
have attended this session and have
shared with us
their perspective as the meeting went
along, and
also shared their experience on the same
issues. I
think we share quite a bit in common and
we are
274
collaborating on many fronts.
The meeting started with a discussion on I
believe an important topic where the
tactical plan
that we proposed in some ways is a
paradigm shift,
and that is the reason we proposed a
tactical plan
instead of proposing putting forward a
proposal to
you, because this will allow the
community to go
back and debate and vigorously engage in
this
topic, so that when we come back with a
proposal,
we hope the entire community will connect
to that.
The accomplishments there were, in a
sense, nothing new from a quality sense
from
outside the pharma sector, but I think we
introduced some of the tools and
methodologies that
have been utilized and approaches that
have been
utilized successfully in other industries
to
attempt to move towards a more
probabilistic
approach to setting specifications that
allow us to
be risk based and science based, and
bring a high
level of ability to manage variability in
measurement systems in the case of
dissolution, but
more so I think start to focus on the
product of
275
interest and see how we can take that
information
and move towards a controlled philosophy
that
allows us to gauge the capability of a
process and
also the state of control.
I believe that will be
extremely important
for our CMC reviewers and GMP inspection
staff to
really connect, because establishment of
state of
control and ability to have confidence in
that is
the part of continuous improvement, and
that is one
way of reducing the need for supplements,
and so
forth.
So, that becomes a basis for
moving
forward, but at the same time,
dissolution is just
one of the physical performance
attributes of
interest.
This becomes a model for all other
specifications especially with respect to
physical
attributes.
The challenges are even greater
on the
other fronts including particle size, and
so forth.
So, I think the strong endorsement of the
Committee
really sends a strong signal and provides
the
support that we needed to really push
ahead with
276
this, and the timing of this could not
have been
better, because we start engaging with
our European
and Japanese colleagues on putting
decision trees
starting next week, and we needed this
leverage to
make the case of where we want to go and
hopefully,
bring them along with us, because all of
us are in
the same boat right now.
So, I think I really thank the
Committee
for the discussion, as well as the strong
support
they have given us on this front, and I
hope the
pharmaceutical community will really
engage and
debate this extensively, so that when we
have a
proposal to this committee next time, we
actually
can build consensus and move
forward. Otherwise,
this could be a long debate.
The topics for Day 2, today,
clearly, I
think show the challenge that we have
with respect
to move towards a tactical plan for the
type of
questions, the complexity of the
questions that you
saw, but in many ways, what we have done
is
addressed or attempted to frame a
question on
challenges that we have faced for the last
10, 15
277
years.
I am hopeful that bringing a
knowledge-based approach to tackling that
problem
might find a solution. It is not going to be easy,
and clearly, I think we tried to push the
agenda in
terms of seeking to tackle a problem like
topical
therapeutic equivalence, which will be
one of the
most significant challenges.
The challenge will not only be
technical,
but also educational, because we will
have to
communicate that to the clinicians, the
dermatologists, and the pharmaceutical
community in
general.
So, the challenges are not just
technical,
but also educational and consensus
building across
disciplines to the stakeholders.
With regard to I think highly
variable
drugs and the Japanese in many ways have
already
made that call. They are moving. They have
already applied what we were seeking to
apply.
A re-examination of their
decision
criteria and putting more rigor to our
approach
278
might find a way, not only to seek
harmonization
internationally, but also the challenge
has always
been that generics are not part of the
International Conference of
Harmonization, but
those do things do impact the general
decision
trees that we come up with ICH.
So, again, the reason for
bringing topics
more focused on generic drug approval was
also to
get the generic industry as part and
parcel of the
ICH process as much as we could in this
discussion.
The key aspect I think I was
hoping and
did get the general consensus on is to
focus on a
scientific hypothesis driven process, and
that is
important because in a regulatory decision
criteria, you need the comfort, as well
as the
rigor of a hypothesis testing concept to
make
clear-cut decisions.
In many ways, the
bioequivalence, although
the goalposts we can argue are arbitrary,
and so
forth, but it does give you a sense of
decision
which is less arbitrary than it could
have been,
and we have been through that transition.
So, in many ways, if you recast
the
current requirements that we have on the
regulatory
side, like stability testing,
bioequivalence, and
279
all of those requirements in the form of
a
hypothesis, and your prior knowledge
leading to
that hypothesis testing, that provides a way
forward.
I think we will try to
construct our
decision trees with that in mind, so as
not to add
more burden, but also be relevant in the
questions
we ask, and not direct the development
program.
So, I think that hopefully,
will provide a
common ground to lay out the decision
trees.
Our research programs, I think
are
critical and thank you for endorsing our
request to
have a subcommittee. I am hoping that the working
group or the subcommittee that we form
will find
the best practices to lay and create a
foundation
for our peer review.
At some point, I think we are
initiating
peer review on our review side, and Moheb has
already moved forward in instituting
that, that
280
each review of CMC will--not all--but I
think
selected reviews will be peer reviewed by
their
peers, and at some point I think he will
come back
and share with you his thoughts.
Peer review for review is not
new. In
fact, Jerry Collins, when I joined the
agency years
ago, we had established a peer review for
the
biopharm, and that biopharm day now has
really
become a nice model, so I thank Jerry for
initiating some of that thought process,
and I
think they are just trying to find the
best
practices.
With that, I will stop and
thank the
Committee for the valuable information
and feedback
that you have provided.
MS. WINKLE: It looks like every time we
meet, I am recognizing the same two members
of the
Advisory Committee, but I do have
beautiful plaques
today for Art and Marv for their services
as
members of this Advisory Committee.
Obviously, we have enjoyed
having them so
much that we haven't let them go away,
that we
281
continue to bring them back, because I
think they
contribute a whole lot to the
conversations and the
discussions we have had.
Anyway, I have some really pretty plaques
for you this time, so I appreciate
it. The last
were just certificates, but these are
plaques for
advisors and consultants.
I just have a few things I want
to say. I
have enjoyed listening to the conversations
and
discussions over the last two days. Both of these
topics are topics that I have wanted to
discuss for
a long period of time.
For several years now, Ajaz and
I have
both been discussing some of the issues over
dissolution, many of the issues over
pharmaceutical
equivalence in general, so I was really
happy when
we decided to bring these to the Advisory
Committee
this time, and to begin to open up our
thinking in
these areas.
As Ajaz said earlier when he
was talking,
we have actually been learning how to do
things for
the last 30 years, and now it is time to
apply some
282
of things we have learned, to changing
some of the
way we do things.
I think today's and yesterday's
conversations were our good step forward
in doing
that.
I started off by talking about the journey
that we were on here and changing the
paradigm. I
think that we took some really
significant steps.
They may have seemed small to some
people, but they
are very significant to us, I think, in
OPS as we
move forward along that pathway.
So, I want to thank you all for
your
input.
One of the things, too, I wanted to mention
that up-front, in my opening, I mentioned
the fact
that I thought that, in my mind, one of
the
initiatives that we have now been working
on, the
GMPs for the 21st Century, the Critical
Path
Initiative, and the PAT are all leading
to a shared
responsibility for product quality.
I think through the shared
responsibility,
we need to do more partnering. We need to partner
with industry, but we also need to
partner with
academia, and I think with working
through this
283
committee, it is a really good
opportunity to
partner and get input from many people
who know
things that are going to be beneficial to
us as we
do move along our pathway.
So, with that, I want to thank
Ajaz. Ajaz
spent a lot of time putting this together
along
with everyone else that gave
presentations. I know
Nozer felt many of them were long, but I
think
there were a lot of good points made in
these
presentations this time, and I think they
were very
worthwhile in helping us get a better
understanding
of some of the issues that we had to
tackle.
Also, I want to thank Bob King,
who herds
us all through this. It is just like herding cats,
believe me, and he really deserves a lot
of thanks
for that.
I appreciate, too, your input
on the
subcommittee. I think this is very going
to be very
valuable to OPS to take a look at the two
research
programs and see how we can better
coordinate and
set priorities, et cetera, so I
appreciate that.
With that, I will close and
turn it back
284
over to Charlie.
DR. COONEY: Thank you.
My apologies.
Art?
DR. KIBBE: Listening to the summary made
me think of one thing that I had written
down and
forgot to say. I think it would be well if the
agency could assure the industry that when they
provide drug product development
information, that
the reviewer who reviews it will have a
working
knowledge of drug product development and
some
hands-on experience with the equipment
and the
materials that are being used to do drug
product
development, so that the review is
worthwhile on
both ends of the thing.
Second, thanks for the
plaque. It has
really been fun irritating Ajaz all these
years,
and I continue to look forward to having
an
opportunity to continue to do that.
DR. COONEY: Thank you all very much and I
think I can now close the meeting without
creating
yet another faux pas. Thank you.
[Whereupon, at 3:30 p.m., the
meeting was
285
concluded.]
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