ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND
DRUG ADMINISTRATION
CENTER
FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ONCOLOGY SUBCOMMITTEE OF THE
ONCOLOGIC DRUGS ADVISORY COMMITTEE
Kennedy
Ballroom
Holiday
Inn
PARTICIPANTS
Victor M. Santana, M.D., Chair
Thomas H. Perez, M.P.H., Executive Secretary
SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (VOTING)
Peter
Adamson, M.D.
Jeffrey
Blumer, M.D.
James
Boyett, Ph.D.
Alice
Ettinger, R.N.
Jerry
Finklestein, M.D.
Ruth
Hoffman, Patient Representative
Patrick
C. Reynolds, M.D.
ONCOLOGIC DRUGS ADVISORY COMMITTEE MEMBERS (VOTING)
Steven
L. George, M.D. (by telephone)
Donna
Przepiorka, M.D., Ph.D.
FEDERAL EMPLOYEES (VOTING)
Don
Mattison, M.D. (a.m.)
Malcolm
Smith, M.D.
Anne
Zajicek
GUEST SPEAKERS (NON-VOTING)
Louis
Cooper, M.D.
Douglas
Flanagan, Ph.D.
Walter
Shaw, Ph.D.
FDA
Richard
Pazdur, M.D.
Patricia
Dinndorf, M.D.
Steven
Hirschfeld, M.D., Ph.D.
Rik
Lostrito, Ph.D. (p.m.)
Rosemary
Roberts, M.D., (a.m.)
C O N T E N T S
PAGE
MORNING SESSION
Off-Patent Oncology Drugs
for Which Pediatric Studies are Needed
Call to Order and Introduction:
Victor M.
Santana, M.D., Chair 5
Welcome:
Richard
Pazdur, M.D. 7
Conflict of Interest:
Thomas
Perez, M.P.H. 9
Labeling and Formulation: Challenges in
Pediatric Therapeutics:
Steven Hirschfeld, M.D., Ph.D. 10
BPCA: For Oncology Drugs:
Louis
I. Cooper, M.D. 23
BPCA: Role of NIH:
Anne
Zajicek, M.D., Pharm. D. 30
Off-Patent Drugs for Young Children with Cancer:
Gaps in Knowledge and Public Health Needs:
Malcolm
Smith, M.D., Ph.D. 37
Population Pharmacokinetics in
Childhood Cancer Drug Development:
Peter C.
Adamson, M.D., Ph.D. 52
Questions to Presenters 65
Open Public Hearing:
Gregory
H. Reaman, M.D. (by Dr. Santana) 102
Committee Discussion and Questions to Subcommittee 104
***
AFTERNOON
SESSION
Age-Appropriate Formulation Changes to
Facilitate
Dosing of products Used in the Pediatric
Oncology Setting
Open Public Hearing 176
C O N T E N T S (Continued)
PAGE
Lym-X-Sorb: A Revolution in Oral Drug Delivery:
Walter
A. Shaw, Ph.D. 177
Best Pharmaceuticals for Children:
Best Formulation for Children:
Douglas
R. Flanagan, Ph.D. 187
Drug Formulation in Pediatrics:
If It Tastes Bad, It Must Be Good For You:
Jeffrey
Blumer, Ph.D., M.D. 198
Questions to Presenters 216
Committee Discussion of Questions
to Subcommittee 258
P R O C E
E D I N G S
MORNING SESSION
Call to Order and
Introduction
DR. SANTANA: I
apologize to the committee and to the audience that I have a bad cold so I have
my radio voice on for today. I know that
I have another career. Maybe that will
be it.
Welcome everybody and good morning. This is a meeting of the Pediatric Oncology
Subcommittee of the Oncology Drugs Advisory Committee of the FDA. We have convened today to advise the agency
on two matters pertinent to pediatric oncology.
One is a discussion this morning of off-patent oncology drugs and then,
this afternoon, a discussion on age-appropriate formulations that would impact
oncology pediatric patients.
So, with that brief introduction, I will ask the committee
to introduce itself. Please state your
name and your affiliation for the record and make sure you turn on the mike
when you speak so it will be recorded appropriately.
Can we start with the gentleman on the left.
DR. SHAW: I am Walt
Shaw with Avanti Polar Lipids.
DR. FLANAGAN: I am
Douglas Flanagan with the
DR. SMITH: Malcolm
Smith, Cancer Therapy Evaluation Program, National Cancer Institute.
DR. ZAJICEK: Anne
Zajicek, NICHD, NIH.
MS. HOFFMAN: Ruth
Hoffman, Patient Advocate.
DR. STEWART:
DR. BLUMER: Jeff
Blumer,
DR. ADAMSON: Peter
Adamson, Children's
DR. REYNOLDS: Pat
Reynolds, Children's Hospital,
MR. PEREZ: Tom
Perez, Executive Secretary to this meeting.
DR. SANTANA: Victor
Santana, Pediatric Oncologist at St. Jude Children's
DR. PRZEPIORKA:
Donna Przepiorka, University of Tennessee Cancer Institute.
DR. FINKLESTEIN:
Jerry Finklestein, UCLA and the
MS. ETTINGER: Alice
Ettinger, Nurse Practitioner, St. Peter's
DR. BOYETT: James
Boyett, St. Jude Children's
DR. DINNDORF:
Patricia Dinndorf, FDA, Division of Therapeutic Biologic Oncologic
Products.
DR. HIRSCHFELD:
Steven Hirschfeld, FDA, Division of Oncology Drug Products, Division of
Pediatric Drug Development.
DR.
PAZDUR: Richard Pazdur, FDA.
DR. SANTANA:
Thanks to everybody for being here this morning. Then I will ask Richard if he wants to
address the to address the committee.
Welcome
DR. PAZDUR: Just a
few words. This, I believe, is our
eighth meeting of the Pediatric Oncology Subcommittee of the ODAC or the
Oncology Drug Advisory Committee. On
behalf of the entire FDA, I would like to thank all of the participants of this
panel as well as the public representation here.
Today, we have two important topics that we are going to
talk about, the first one stemming from the Best Pharmaceuticals or Children's
Act, and that is examining off-patent drugs for which pediatric drugs are
needed. And we really look forward to a
diverse input from the entire oncology community on this topic.
The second, afternoon, topic deals with, I think, a topic
that is of interest to pediatric oncologists and also an important issue in
oncology in general and that is age-appropriate formulation changes to
facilitate dosing of products used in the pediatric-oncology setting.
So, although we have two groups of people here, we would
like a really robust discussion of both of these and really look forward to
this. Again, on behalf of the division
as well as the FDA in general, we appreciate the participation of all of the
ODAC members as well as the special committee members here today.
Thank you.
DR. SANTANA: Thank
you, Richard.
Steven, do you want to say any words?
DR. HIRSCHFELD: I
believe I am scheduled for some prepared remarks.
DR. SANTANA: We have
to read the conflict of interest first, though.
Could you give us a minute to do that?
DR. HIRSCHFELD: Yes.
Conflict of Interest
MR. PEREZ: "The
following announcement addresses the issue of conflict of interest with respect
to this meeting and is made a part of the record to preclude even the
appearance of such at this meeting. The
topics to be discussed at today's meeting are issues of broad
applicability. Unlike issues in which a
particular firm's product is discussed, issues of broad applicability may
affect many sponsors and their products.
"All participants have been screened for their financial
interests as they may apply to the general topics at hand. Because they have reported interests in firms
that could be affected by today's discussions, the Food and Drug Administration
has granted waivers to the following special government employees which permits
them to participate in this meeting; Donna Przepiorka, Steven George, Victor
Santana, James Boyett, Alice Ettinger, Jerry Finklestein, C. Patrick Reynolds,
Peter Adamson, Jeffrey Blumer.
"A copy of the waiver statements may be obtained by
submitting a written request to the agency's Freedom of Information Office,
5600 Fishers Lane, HFI 35, Rockville, Maryland, 200857.
"Because general topics impact so many institutions,
it is not prudent to recite all potential conflicts of interest as they apply
to each participant and guest speaker.
FDA acknowledges that there may be potential conflicts of interest but,
because of the general nature of the discussion, these conflicts are
mitigated."
Thank you.
DR. SANTANA: Thanks,
Tom.
One last announcement.
Stephen George, who also is part of this committee, will be joining us
via telephone later on during the discussions.
So, with that last announcement, Dr. Hirschfeld?
Labeling and Formulation
Challenges in Pediatric
Therapeutics
DR. HIRSCHFELD: Good
morning.
[Slide.]
The topics for today center around the need for pediatric
labeling and that is reflected in a program contained in the Best
Pharmaceuticals for Children Act which allows for the study of off-patent drugs
which will be explained in greater detail by the subsequent speakers also,
addressing the issues of formulations, as noted by Drs. Pazdur and Santana in
their preliminary introductions. These,
together, form challenges in pediatric therapeutics.
[Slide.]
The Food and Drug Administration was established through
three principles which arose during the course of the Twentieth Century as a
result of healthcare scandals involving children.
The first was the issue of proper labeling which was
established in 1906 in response to the poisoning of infants from an elixir
designed to treat colic, which contained morphine and the product was not
properly labeled and the children were poisoned. This led to legislation establishing the need
for proper product labeling.
In 1938, in response to the poisoning of children through
formulation of the antibiotic sulfanilamide, Congress enacted the Food, Drug
and Cosmetic Act that products must not only be properly labeled but must be
safe and, therefore, must be tested before licensing for interstate commerce
would be permitted.
in 1962, in response to another healthcare scandal which
was the malformations which occurred secondary to pregnant women taking
thalidomide, Congress enacted an amendment to the Food, Drug and Cosmetic Act
requiring demonstration of efficacy before a product would receive marketing
authorization for interstate commerce.
Despite the fact that, during the first two-thirds of the
Twentieth Century, children were the catalysts for the legislation. They were not the beneficiaries.
[Slide.]
So, in the last quarter of the Twentieth Century, there was
an evolution of pediatric information beginning in 1974 with the passage of the
National Research Act which established a National Commission for the
Protection of Human Subjects for Medical and Behavioral Research. Concurrently, the American Academy of
Pediatrics, which was an organization established in the Twentieth Century,
published its report that was commissioned by the FDA on General Guidelines for
the Evaluation of Drugs to be Approved for Use During Pregnancy and for
Treatment of Infants and Children.
In 1977, the National Commission issued its first report on
research involving children and, in the same year, the FDA issued a guidance on
General Considerations for the Clinical Evaluation of Drugs in Infants and
Children and the Academy of Pediatrics issued its first statement on the
ethical conduct of research involving children.
[Slide.]
These reports led to the issuance of a regulation, in 1979,
which placed in the label of the product package insert a pediatric-use
subsection. This was the first time any
national authority had indicated both an interest and a requirement to comment
on the pediatric use.
In 1983, Federal Regulations were issued for the protection
of federally funded research and included specific provisions for the
protection of children and the categorization of research based on the
perceived risk to the pediatric population.
In 1994, there was a revision of the Code of Federal
Regulations which was encompassed in a Pediatric Rule which added a subsection
which allowed extrapolation as a basis for pediatric use. In 1996, the FDA issued a Guidance on the
Content and Format of the Pediatric Use Section. Concurrently, the Academy of Pediatrics
updated their statement on ethical conduct of clinical trials.
[Slide.]
All these efforts did not lead to systematic inclusion of
pediatric information in the product labels or product package inserts. So two initiatives in the late 1990s
attempted to address the problem.
The Food and Drug Administration Modernization Act
instituted a pediatric incentive program and, in 1998, a Pediatric Rule was
issued--rule and regulation are synonymous--which mandated pediatric studies
under particular circumstances.
This was followed, in 2001, by an adaptation of the Health
and Human Services Subpart D Regulations to FDA-regulated research and, in
2002, which will be the focus of the discussion this morning, the passage of
the Best Pharmaceuticals for Children Act, which had a renewal of the pediatric
incentive program from the 1997 Food and Drug Administration Modernization Act
and included a provision for the study of off-patent drugs and, as an
overriding principle, endorsed the concept of public dissemination of pediatric
information.
[Slide.]
By federal regulation, the product package insert, or
label, has sections which are listed on this slide. They are: a description of the product; a
description of the relevant clinical pharmacology; the indication and usage,
which forms the basis for the marketing claims; contradictions; warnings;
precautions; adverse reactions; drug abuse and dependence; overdosage, which
are all a summary of the safety information; dosage and administration for the
indicated use; and how the product is supplied.
[Slide.]
There are additional label sections which are optional,
which can be included: animal pharmacology or animal toxicology; clinical
studies, which are often included and have been a policy in oncology products;
and references.
[Slide.]
The principles of labeling, as stated in the federal
regulations, is that the labeling shall contain a summary of the essential
scientific information needed for the safe and effective use of the drug, that
the labeling shall informative and accurate and neither promotional in tone nor
false or misleading in any particular.
And the labeling shall be based, whenever possible, on data derived from
human experiences.
There is a provision that conclusions based on animal data
may be necessary for safe and effective use of the drug in humans but it should
be identified as such and included with human data in the appropriate section
of the labeling.
This provision has been recently applied to products which
are designed to treat pathogens for which the study in humans would not be
ethical.
[Slide.]
Pediatric information has multiple options for being
included in the product label. There is
the Pediatric Use Section, as defined in the regulations from 1979, which is in
the Precautions Section. There is also
an opportunity for pediatric information in the Dosing Section. Pediatric indications would be specifically
listed in the Indications Section and then clinical pharmacology study results,
contraindications and warnings are all other opportunities for including
pediatric information.
[Slide.]
The regulatory mechanisms to submit pediatric data to the
FDA are as a new indication which would come as a new drug application or as a
supplement to a new drug application or, alternatively, a label change with
clinical data which would come as a supplement to a new drug indication.
[Slide.]
Many of the oncology drugs that are used in the pediatric population are off-patent. They were initially approved for marketing
during the 1950s, '60s and '70s when there was a flurry of activity,
particularly in the arena of pediatric leukemia. The drugs that are now in use have been
refined over the years in their application to the particular diseases and
extended to looking at other diseases.
At the time the product labels were prepared, the
regulatory standards and scientific methods were different than contemporary
approaches so one may ask the question legitimately, if the goal is to put
pediatric information in the label and if pediatric information is already in
the label, what would be the purpose of undertaking pediatric studies.
The answer to that, simply stated, is that the information
in the product label that exists, if it is considered to be outdated or
represents a safety issue, would then be appropriate to update and study that
information.
[Slide.]
The reasons for examining pediatric dosing information and
safety information is because, as many of the speakers will elaborate in more
detail later this afternoon and during the course of the morning, growth and
development affect drug disposition and action.
There are developmental changes in metabolism. There are changes in body composition,
particularly in the ratio of the water and lipid partitions.
There are developmental changes in receptor expression and
function. The growth rate alters and
there are some analyses which now subdivide the growth phases of children into
multiple periods, each with its own characteristics. Organ functional capacity will change and
service-to-volume and distribution change, which are fundamental
characteristics for predicting and understanding drug metabolism.
[Slide.]
In order to administer medications properly to children,
one must have a formulation which can provide a predicable exposure of the
active agent to that patient. Pediatric
formulations have always been a challenge.
There are considered by most
people in the field various categories of formulations. These include bona fide pediatric
formulations such as drops, suspensions, chewable tablets or syrups. That is a formulation that is prepared and
manufactured specifically for the intended use.
Then there are extemporaneous pediatric formulations which
are made with standardized extemporaneous vehicles which are non-formulary or
could be from the U.S. Pharmacopoeia or other marketed vehicles. Then there are extemporaneous pediatric
formulations which are made with food or other carrier substances such as
sprinkles on applesauce or yogurt.
Again, these will be addressed in a little more detail this
afternoon.
[Slide.]
There are some very practical issues which must be
considered, and that is the ability to swallow capsules or tablets--the correct
dose or concentration may not be available in a solid oral dosage form--the
appropriate dosing parameters, whether to use weight or body-surface area, and
the need to change dose as a child grows, which is of particular importance for
medications given over a long period of time, chronic medications such as
antihypertensives, anticonvulsants or some of the maintenance therapies which
are used in oncology.
[Slide.]
One may ask what is appropriate. These questions are raised as questions with
the expectation that some of them will be addressed in the discussions later
today. Is an oral liquid solution the preferred
delivery system for a less-than-two-year old, for the middle child? Are solutions, suspensions or chewable
tablets preferred? Are children greater
than ten years able to take solid oral dosage forms or should alternatives be
considered? And what about children with
difficulty swallowing or who require nasogastric tubes or who have other
chronic illnesses.
[Slide.]
The general purpose of bioavailability studies is to assess
absolute or relative bioavailability of a dosage form or new formulation and to
characterize the pharmacokinetics of the active drug ingredient or therapeutic
moiety. For example, the rate and extent
of absorption, half-life and metabolism further allow dose determination
adjustment and to assess the safety for locally acting drug products such as
cremes or patches.
[Slide.]
But there are a number of physiologic variables that affect
bioavailability which include age, weight, surface-to-volume ratio, protein
binding, carrier proteins, gastric emptying, gastric function, intestinal-residence
time, hepatic and renal function and even the intestinal flora which can change
with age.
[Slide.]
The bona fide formulation approaches that have been used in
approved products include solution, suspensions, chewable tablets and elixirs. But there is some controversy as to the
acceptable amounts of alcohol and other carriers.
[Slide.]
Some of the issues which need to be addressed in terms of
extemporaneous formulations are stability, bioavailability, concentration
variability and an increased risk for medication errors. This is particularly critical in products
with a narrow therapeutic index.
[Slide.]
So, in conclusion, for pediatric formulations, there are
many approaches and many challenges including the minimization of excipients, a
need to determine safety and dosing accuracy, the recognition and management of
unpredictability and, as always, we hope that development could proceed in
partnership with the Food and Drug Administration.
So, I will now turn the podium over to my colleague, Dr.
Louis Cooper, from the Division of Pediatric Drug Development, who will go into
some detail followed by Dr. Anne Zajicek from the National Institute of Child
Health and Human Development who will go into further detail on the process
involved in the study of medications, both on-patent and off-patent, in the
Best Pharmaceuticals for Children Act.
When we have finished our discussions, when Dr. Malcolm
Smith from the National Cancer Institute has presented an analysis and some
proposals, and Dr. Adamson from the Children's Hospital of Philadelphia has
presented some methodologic approaches which may be useful for the types of
studies that we would like to discuss, then all of us will be available for
questions.
Dr. Cooper?
BPCA: for Oncology Drugs
DR. COOPER: Thank
you, Dr. Hirschfeld, and good morning.
[Slide.]
I am Louis Cooper. I
am a pediatric hematologist in the Division of Pediatric Drug Development in
the Office of Counterterrorism and Pediatrics.
I will present, in the next several minutes, a brief overview of the
Best Pharmaceuticals for Children Act as it relates to oncology drug
development.
[Slide.]
The goal, which will include the on-patent exclusivity
process and the off-patent process is to introduce new pediatric information
into the drug label. These mechanisms
utilizing the on-patent and off-patent processes will be discussed in greater
detail.
[Slide.]
The Best Pharmaceuticals for Children Act provisions
include the on-patent process wherein the FDA will issue a written request to
holders of an approved application which is protected either by a patent or by
marketing exclusivity. The second
category are the off-patent older drugs wherein the FDA will issue a written
request to holders of approved application for these drugs that have no patent
or market exclusivity protection.
These are the drugs which this forum will be concentrating
on today.
[Slide.]
Pediatric exclusivity and what does this really
represent. It is called the carrot. Basically, it allows a drug which is on
patent an economic stimulus or incentive to conduct pediatric studies by the
originator of the drug. The incentive
represents six additional months of marketing exclusivity which can attach to
existing patents and/or existing exclusivity.
For the off-patent drugs, there is no financial incentive
to the holders of these drugs as there is no longer any patent protection and,
therefore, there is no financial incentive to the sponsors or originators of
the drug to perform pediatric studies.
An example of this might be if a drug brought a revenue to
a company of, say, $2 billion a year, if that marketing exclusivity were
granted to them for an additional six months, this would bring revenue to that
company of an additional $1 billion considering $2 billion as their revenue for
the year.
So, therefore, it provides significant financial incentive
to the drug companies to consider doing these pediatric studies.
[Slide.]
Written request; the written request is a legal document
that requests pediatric studies. This
document is written and sent by the FDA to the sponsors requesting studies in
the pediatric population. The components
of a written request typically include the intended pediatric indication,
meaning the disease or condition to be studied, the population, the types and
numbers of studies, any general safety parameter and any drug-specific safety
parameter that should be monitored.
Plans for long-term follow up in a time frame within which
the studies should be completed and the results sent to the FDA, the specific
results sent to the FDA. The specific
components of a written request may vary according to the indication,
population and product.
[Slide.]
Who is involved? The
written request process involves several steps and entities. The sponsor is generally the developer of the
drug. The Center for Drug Evaluation and
Research, CDER, at the FDA, is organized into offices and, within each office,
are divisions. The review divisions are
organized on the basis of the disease or condition that a product is intended
to treat.
The Division of Pediatric Drug Development within the FDA
functions as a resource for the pediatric activities of the review
divisions. The Pediatric Implementation
Team, or PdIT, is a multidisciplinary team with representatives throughout
CDER. The purpose of the PdIT is to
ensure consistency and quality.
The Pediatric Exclusivity Board is a different
multidisciplinary panel from the PdIT that makes the determination of whether a
sponsor fairly has met the terms of a pediatric written request and, therefore,
granting of exclusivity.
[Slide.]
I will now walk you through the steps for the study of
on-patent drugs under the BPCA.
Industry, up in the upper left-hand corner, if you will, please, submits
a proposed pediatric study request or the FDA, by its own initiative, may
determine a public-health benefit to support a specific pediatric study.
The FDA subsequently issues a written request. Industry has 180 days to respond as to
whether or not they will perform the studies.
If the sponsor agrees, they inform the FDA and can qualify for
exclusivity. If the sponsor declines,
the written request can be forwarded to the Foundation for the National
Institutes of Health, a non-profit foundation associated with the NIH for
funding of the studies.
In that case, the original sponsor would not be eligible
for exclusivity.
[Slide.]
What does all this mean?
Since the 1997 creating of FDAMA, there have been 334 proposals from
industry of which the FDA has issued 284 written requests. 91 exclusivity determinations were made. 82 exclusivity grants were offered resulting,
at this time, in 61 labeling changes including pediatric information into the
drug label.
This represents a significant benefit to children. Remember, and there is a disparity in the 82
and 61 because the new labeling changes are not able to be including all of the
exclusivity studies which have been requested which, at this time, there are
still studies pending and, as a result, the variance in the 82 and 61.
The studies take two years or longer, depending on the
study. How does all of this affect
oncology? We have looked at the broad
picture within the FDA of the total exclusivity granted thus far in the past
six years. For pediatric oncology exclusivity,
there have been 18 proposals for industry.
The FDA has issued 28 written requests which implies that the FDA has de
novo, on their own initiative, sought some studies.
Exclusivity determinations have been done in five
cases. Exclusivity was granted in five,
resulting in new labeling in four specific drugs.
[Slide.]
The drugs which thus far have been granted exclusivity
include busulfan, vinorelbine, topotecan, temozolomide and fludarabine.
[Slide.]
Now I will speak about the off-patent process involving the
older drugs for which there is no exclusivity and the reason we are here today.
[Slide.]
Legislation created a partnership between the NIH and the
FDA. Within the FDA, the same people and
committees I mentioned earlier are involved.
However, the off-patent also involves the NIH.
[Slide.]
The process for the study of off-patent drugs; the process
for off-patent is similar but differs in several aspects from on-patent
process. The initial source of drugs is
a priority list which will be discussed in significantly more detail by Dr.
Anne Zajicek who will be speaking subsequent to myself.
The FDA written request is issued to all manufacturers or
distributors of the off-patent product and each one has the opportunity to
perform the studies. However, because
there is no financial incentive, the companies usually have not elected to
perform the studies. The time frame for
the pharmaceutical industry response is 30 days compared to the 180 days for
the on-patent process.
If, within the 30 days, companies or sponsors do not agree
to the studies, the written request is referred to the NIH which will be
considered in the next talk.
[Slide.]
I invite you, at your convenience, to review the FDA web
page whose address is www.fda.gov. If
you look down toward the bottom section, which I will show you in the next
slide--
[Slide.]
You see there is a pediatric section that you can refer to
specifically and it will give you significant amounts of new information and
highlights on new drug labeling.
[Slide.]
In summary, the goal of the on-patent and off-patent
processes is to make efforts for new information in oncology labels. We look forward to the remainder of the
conference. If I may, I will turn the
podium over to my colleague, Dr. Anne Zajicek, and I thank you for your
attention.
DR. SANTANA: Thank
you, Dr. Cooper.
BPCA: Role of NIH
DR. ZAJICEK: Good
morning.
[Slide.]
I am going to talk about the NIH portion of the Best
Pharmaceuticals for Children Act.
[Slide.]
The point of the Best Pharmaceuticals for Children Act,
again, for the most part, is to get some pediatric labeling for off-patent
drugs. So this process, as Dr. Cooper
alluded to, is a nice interaction between the FDA and the NIH. So, to start with, the NIH receives from the
FDA a master list of all off-patent drugs which lack adequate pediatric
labeling. This year, there were about
169 drugs that fell into this category.
Now, the job is to whittle this list of 169 drugs down into
some manageable number of drugs that are prioritized for study for the coming
year. So, the goal, again, is to
develop, prioritize and publish an annual list of somewhere around 15 to 25
drugs somewhere in there. The Best
Pharmaceuticals for Children Act mandates that the NIH do this prioritization
in consultation with experts in pediatric practice and research, which is you
in the Oncology Section and, in considering the drugs that should be
prioritized for study, we are mandated to take into consideration the
availability of safety and efficacy data to determine whether additional data
are needed from the literature. If new
studies are funded, will they produce health benefits and are there
reformulation issues.
So these are some things for you to take into consideration
today.
[Slide.]
For consultation for prioritization, we at the NIH have
consulted with members of other institutes of the NIH. The list of oncology
drugs that are off-patent has been sent to the National Cancer Institute; for
example, cardiac drugs have been sent to the National Institute for Heart Lung
and Blood and so on.
A multitude of pediatric subspecialty groups have been
consulted and the American Academy of Pediatrics Committee on Drugs is also
being consulted in this process.
[Slide.]
As Dr. Cooper mentioned, just as a side mention for
on-patent drugs, if the FDA determines that there is a need for pediatric
labeling, a written request is issued from the FDA. If the holder of the NDA declines to perform
pediatric studies, the drug is referred to the Foundation for the National
Institutes of Health. The rest of the
talk will be about off-patent drugs.
[Slide.]
Also, as Dr. Cooper mentioned, from this priority list,
again this whittled-down list of 15, 20 drugs, something like that, the FDA
issues a written request. So the FDA has
given us the list of 169. The NIH
parcels it into this priority list of 20 drugs, somewhere in there, and that
gets sent back to the FDA. The FDA then
issues written requests.
The written request is sent to the holders of either the
new drug application or the abbreviated new drug application, in that case, the
generic holder, and they are given 30 days to either accept or decline. If there is no answer within 30 days, that
assumption is they have declined and, in that case, the written request gets
referred to the NIH for contract.
[Slide.]
The process of contracting is a little complicated. The NIH publishes a request for proposals at
this website which is Commerce Business Daily.
So there are postings of proposals that the NIH would like to have
performed. The proposals are then
submitted to the NIH. The proposals are
reviewed by a scientific peer-review panel.
Contracts are awarded. The
studies are performed with the NIH acting as the sponsor, again funding the
study and holding the IND. And the
results are submitted to the NIH and to the FDA for labeling changes.
[Slide.]
This structure at the NIH is two-fold. The National Institute of Child Health and
Human Development oversees the contracting process, writes their request for
proposals, again reviews the proposals and funds the proposals. The management of these projects that will go
on is managed by a coordinating center which, again, oversees the management,
the data collection from the contracting center. So that is how this will physically work.
[Slide.]
The results so far; written requests referred to the NIH
from the FDA include lorazepam for two indications, one for sedation and one
for treatment of status epilepticus, written requests for nitroprusside and one
for azithromycin. There are others that
are within that 30-day waiting period so there will be others to come.
Requests for proposals have been published for lorazepam
again for the two indications, for sedation and status epilepticus, and for
nitroprusside. The one for azithromycin
is in process.
Scientific peer-review panel reviews have convened to
evaluate the proposals from coordinating centers and, for the two lorazepam
protocols, and a contract has been awarded to the contracting center.
[Slide.]
So, just to summarize what the FDA does as opposed to what
the NIH does, the FDA formulates, again, this list of 169 drugs. The NIH is responsible for prioritizing this
list. The FDA writes the written request
and the NIH is active in providing input with the written request. The FDA refers drugs to the NIH for study if
the written requests are declined and the NIH is responsible for writing
requests for proposals and sponsoring the clinical trials.
[Slide.]
The role of you today, basically, the role of the Pediatric
Subcommittee of ODAC, is to act as consultants to us to prioritize the
pediatric oncology, or the oncology, drug list.
Just to review, we would be interested in your views of what drugs
should have priority, taking into consideration the availability of safety and
efficacy data. So, in other words, if
there is sufficient data in the literature, it is probably not necessary to go
on and sponsor a study.
Is there a need for additional data? Is there data but there is a chunk of it
missing in a certain population, certain indication? Would there be health benefits from
additional studies? The last issue has
to do with reformulation. Are there
oncology products that are good products but should be reformulated in a way
that would be better for pediatric application?
[Slide.]
So, in summary, the NIH is in a partnership with the
FDA. The NIH is responsible for
prioritizing the drug list, for commenting on the written request and for
sponsoring the clinical studies in children that will produce pediatric
labeling changes.
Thank you.
DR. SANTANA: Thank
you. Malcolm?
Off-Patent Drugs for Young
Children with Cancer
Gaps in Knowledge and
Public Health Needs
DR. SMITH: Good
morning.
[Slide.]
I thank Dr. Hirschfeld and others at the FDA for this
opportunity to speak on this issue of off-patent drugs for young children with
cancer and how the Best Pharmaceuticals for Children Act can be used to help us
gain additional knowledge to address the needs of particularly young children.
[Slide.]
The issues that I will be focussing on, especially on the
younger children, and first on the increased susceptibility of young children
to drug-induced toxicities, the reduced outcome that we see for some young
children for certain diseases, the variability in prescribed dosing for young
children for cancer indications, the potential contribution of additional
pharmacologic data, but then potential ways to study off-patent agents within
the context of ongoing clinical trials and possible off-patent agents for
additional study for you to consider and discuss.
[Slide.]
The comments that I will be making are informed to a large
extent by a meeting that CTEP and the Children's Oncology Group sponsored in
May of 2003 on Cancer Pharmacology in Infants and Young Children. The organizers of this meeting were my
colleague, Dr. Barry Anderson, who was unable to be here today because of a
competing meeting, Dr. Peter Adamson from the Children's Oncology Group who is
here, and Dr. Clinton Stewart who is here.
They can correct me when I misrepresent anything from that meeting.
The meeting addressed gaps in the discussion of cancer-drug
pharmacology in infants and young children.
It discussed toxic and therapeutic consequences of these informational
gaps and discussed methods to incorporate pharmacokinetic research into cancer
clinical trials to develop more rationale dosing guidelines.
[Slide.]
A point that I would emphasize to you is that pediatric
oncology is different. I think when we
look at BPCA and how it applies, the significance of agents, drugs used,
off-patent drugs used, can't be measured in how many thousands or hundreds of
thousands of doses are administered.
In pediatric oncology, most tumors are fatal if not
adequately treated. So the risks of undertreatment
are substantial. Most treatments are
toxic and have narrow therapeutic windows and, hence, the risks of
overtreatment are substantial. So
suboptimal use of off-patent drugs can have very serious consequences; death
due to inadequate treatment, life-threatening acute toxicities as well as
long-term sequelae that reduce quality of life.
[Slide.]
So, first of all, now, then, to focus on some examples of
the increased risk of toxicity for infants and young children. I will give two examples. The first is hepatic toxicity associated with
dactinomycin.
[Slide.]
I could go back to the Wilms' tumor literature in a
historical context, but I will focus on a more recent example from actually an
ongoing clinical trial for rhabdomyosarcoma.
The primary purpose of this trial was to evaluate the contribution of
topotecan. So the comparison was between
the standard three-drug VAC, vincristine, dactinomycin and cyclophosphamide,
plus those same three drugs alternating with the topotecan treatment course.
The doses of the agents are shown here. For the vincristine, dactinomycin and
cyclophosphamide, dosing by body-surface area over one year of age. In children less than one year, half dosing
of these same agents.
[Slide.]
In this trial for children with rhabdomyosarcoma, serious
toxicity, serious liver damage, or hepatopathy, was observed, 16 cases among
the 328 children enrolled at the time.
And there were four hepatopathy-related deaths. The estimated cumulative incidence of this
serious toxicity was 7 percent and there was a segregation by age, younger
children at increased risk, zero to 35 months of age, a 15 percent risk,
and over three years of age, three years or older, 4 percent risk.
In terms of children of hepatopathy-related deaths, there was
a trend towards more deaths in the younger age group, so age being a risk
factor for this very serious toxicity.
[Slide.]
Another example goes back into the literature, a report
from Bill Woods, Mara Leary and Mark Nesbitt in 1981 looking at the incidence
of neurotoxicity for vincristine by patient size. The smallest group of patients, those less
than 0.5 meters squared, had a much higher incidence of severe
neurotoxicity. This led to the
recommendation that children less than 1 meter squared should be given doses
calculated by body weight rather than by body-surface area. That has the de facto result of being a
reduction in dose.
[Slide.]
There are other examples that I won't go into of possibly
increased toxicity for infants and young children. When you look at infants with ALL, there is
certainly a higher rate of treatment-related mortality for these and
particularly the very youngest infants than for older children. Ototoxicity among young children treated with
cisplatin, there were reports that the risk of ototoxicity is increased and
also, for cardiac toxicity, reports that young children are at greatest risk
for cardiac toxicity following treatment with anthracyclines.
[Slide.]
So the easy answer to this would be, while there is
increased risk of toxicity, you just need to reduce the dose. But there are at least some examples of these
younger children also being at increased risk for treatment failure. The two I will describe to you are for
rhabdomyosarcoma and for ALL.
[Slide.]
For children with rhabdomyosarcoma, the Kaplan-Meier curve
for event-free survival is shown here.
The top curve is for the one-to-nine-year group. The lowest curve, less than one year, the
infants, have an event-free survival that is only 55 percent, much lower than
that for children 1 to nine years of age.
If you were really paying very close attention, you will
recall that these infants are the ones who get the half dose of chemotherapy
agents. One question would be is this
dose reduction that, in part, is to ameliorate toxicity, but is this somehow
reflected in a lower failure-free survival for these infants.
Let's get all of the curve here.
[Slide.]
The second example is provided by the Children's Oncology
Group and by Dr. Sather, the statistician.
This is looking at two recent COG--actually CCG--trials and the risk of
treatment failure is greatest among children one-year of age--that is, 12 to 24
months--compared to older children, either to two to five-year-olds, or
six-to-nine year olds. The grey, what
should be grey and red bars, are two different clinical trials. The relative risk for infants is almost
double that for children that are two-to-five-years of age.
The possible explanations; leukemia cell biology is
certainly a possible explanation but things like the MLL gene rearrangement that occurs in the very
youngest children are not that common in the one-to-two-year olds. So it is not clear what the leukemia-cell-biology
explanation might be. The other would be
some pharmacologic explanation, the latter being one that is potentially
addressable by better dosing paradigms.
[Slide.]
Another point to emphasize is that the way we use these
drugs in children is variable now. This
is illustrated by The Rule of 30 that I will explain and how it is variably
applied.
[Slide.]
The Rule of 30 is a rule that allows the conversion of any
body-surface area from milligram-per-meter squared-based dosing to
milligram-per-kilogram dosing. You use a
factor of 30 to go from one to the other.
It has the effect of essentially being a reduction in dose
when you go from dosing by body-surface area to by-weight dosing. So you get a dose reduction in the youngest
children when you use dosing by milligram-per-kilogram. But this rule is variably applied in terms of
when it is applied, milligram-per-kilogram dosing may be used for some
treatments in less than 12 months, for others, less than-3 years.
When a weight parameter is used, it may be less than 10
kilograms, less than 12 kilograms, less than 30 kilograms. What is the basis for this and can we have
more, better-data-supported, rules.
Sometimes, we use 50 percent dose reductions as in the case of
rhabdomyosarcoma for the children less than 12 months and for Wilms' tumor.
[Slide.]
So the Rule of 30 does lead to lower doses for younger
children, having the effect of reducing toxicity, potentially also reducing
efficacy. But when you look at the Rule
of 30, it really--this conversion is--the 10-to-11-year old is the one for
which the Rule of 30 converts from the same dose by weight, by body-surface
area.
Depending on whether you apply body-surface-area dosing or
per-kilogram dosing, you can get doses that differ by a factor of 50 or 60
percent, particularly at the extremes of the youngest and oldest children.
[Slide.]
This illustrates the variability in dosing prescribed for
one drug, that being vincristine, looking across the transition from nine
months of age to 15 months of age. The
points, without going into details about the different tumor types and why they
might be different, but you notice a threefold difference in dose and you
notice that, for some tumors, there is a step function at one year of age. For some tumors, that step is a doubling in
dose. For some, it is an increase by 30
percent in dose. And, for some, it is a
smooth transition.
Again, what is the best way to do it. Can we do it better?
[Slide.]
So it gets to the issue of the scaling of doses of
anticancer drugs. The ultimate goal is
to reduce variability in drug effect which is a function of drug exposure and
tissue/tumor sensitivity. Fixed dosing,
which is becoming the rule for adults, obviously, can't be extrapolated to
dosing.
[Slide.]
So, in children, we need to understand the relationships
between drug clearance and body measurements in order to provide the most
appropriate dosing, so, the contribution of pharmacologic data to these
off-patent drugs, where insufficient data exists, to determine the
relationships between drug clearance and body measurements for younger and
older children, use these data in concert with toxicity data to develop
data-drive rules for dosing chemotherapy agents in younger children, and, in
the absence of excessive toxicity, attempt to achieve the same exposures in
younger children as those that are achieved in older children.
[Slide.]
In making the point about a need for additional
understanding of the pharmacologic behavior of these off-patent drugs in
younger children, I show the age incidence profile for cancer in children. The highest incidence for cancer is in the
youngest children, the infants, one-year-olds, two-year-olds.
Most of our pharmacologic data in phase I studies
comes--the median age in those studies is often nine to ten or eleven years of
age. So, for the group where there is
the highest incidence, we actually have a least pharmacologic rationale for the
dosing that we use.
[Slide.]
How can we correct this deficiency? We suggest that a way to do that is to build
upon ongoing clinical trials.
[Slide.]
In terms of studying off-patent oncology drugs, there would
be limited enthusiasm, I think, if FDA or some other body said, you have to do
a phase III evaluation of this particular off-patent drug. Typically, the new phase III trials, to
the extent possible, are looking at the newer treatments, new mechanisms of
action, the topotecan being an example from rhabdomyosarcoma, a new topo-1
inhibitor. Does this increase outcome
for children with rhabdomyosarcoma.
However, ongoing trials use off-patent agents that have
been inadequately characterized across the entire pediatric age range and
children enrolled in this trials could participate in studies to evaluate the
pharmacology of specific off-patent agents.
You could use population PK methods, and Dr. Adamson will talk more
about this in the next presentation, to limit the burden for individual study
participants and, perhaps, make those studies more feasible in the youngest-age
population.
[Slide.]
The advantages to this approach; one, to NIH is that it
reduces costs. The study participants
are already identified from--the ongoing clinical-trial data-collection
procedures are already in place at the treating institutions and the central
data-collection methods are already in place.
You are building on clinically important standard treatment
regimens and so the data that you collect have inherent applicability.
[Slide.]
Now to turn to the question of what off-patent agents
should we focus on and to the question that this committee is being asked to
address in terms of prioritizing--this was not supposed to come up
one-by-one. But I will just click
through. This is on the handout that
each of you have. This is half the list
of the drugs, the potential off-patent drugs that this committee and NIH can
consider.
[Slide.]
The other half of the list is shown here. So there is a substantial list. Of this list, there are probably only about a
fourth of them that are actually used in any major way within current childhood
cancer treatments.
[Slide.]
The two agents that I would draw your attention to for
prioritization, at least initially and not to say that others wouldn't be
prioritized subsequently, but the two agents are one, vincristine, which is
widely used in the youngest-age population, used in Wilms' tumor, rhabdomyosarcoma,
medulloblastoma, low-grade gliomas, acute lymphoblastomic leukemia,
hepatoblastoma, so a very broadly used agent.
Then dactinomycin, or actinomycin D, used in Wilms' tumor,
used in rhabdomyosarcoma, and one where, clearly, the youngest children are at
increased risk of toxicity.
[Slide.]
So these two agents, first of all, they are important in
treating the cancers in infants and young children. Second, as I illustrated, particularly for
vincristine, there is substantial variability in dosing for infants and young
children in current pediatric protocols.
For two of the tumor types, rhabdomyosarcoma and ALL, gave evidence that
the younger children are, in fact, at increased risk of treatment failure.
Then we have limited pharmacologic rationale on which to
base our dosing decisions or to try to improve them.
[Slide.]
Those familiar with the literature will say, well, there
are a number of papers about vincristine pharmacology in children and there
are--Bill Crom and the group at St. Jude published in 1994 a paper of
pharmacokinetics of vincristine in children and adolescents with ALL. Then several subsequent papers, the most
recent being published this year looking at--arguing that there is no pharmacologic
rationale for dose reduction in adolescents based on vincristine pharmacology.
[Slide.]
When you look at the populations studied in these papers,
and this shows the vincristine clearance versus age normalized to body-surface
area and weight, from the report from St. Jude in 1994, very few of the
youngest children in the study.
[Slide.]
Similarly, the report, the most recent report, by Frost and
DeGraf's group, again, no infants and few young children in this study. So there is a gap in terms of our
understanding of the pharmacology of this particular agent in the younger
children.
[Slide.]
So, to close, and to allow Dr. Adamson to talk more about
population PK and how that might be applied, infants and young children are at
increased risk for some drug-related toxicities and for treatment failure for
some types of cancer. There are limited
data concerning the pharmacology of many off-patent drugs, especially in
infants and young children.
An increased understand of the pharmacology of these drugs
in infants and young children could lead to guidelines for dose that reduce the
variability in drug effect.
[Slide.]
Population PK studies incorporated into ongoing childhood
cancer clinical trials may provide the data needed to develop more rationale
dosing guidelines for off-patent drugs used in treating infants and young
children. These dosing guidelines, new
dosing guidelines, could lead to increased survival and diminished toxicity for
infants and young children with cancer who are treated with off-patent drugs.
So I turn the podium over to Dr. Adamson.
DR. SANTANA: Thanks,
Malcolm.
Population Pharmacokinetics
in Childhood Cancer Drug
Development
DR. ADAMSON: Steven
and others, thank you for the invitation to speak a little bit about population
pharmacokinetics and its potential role in childhood cancer drug development.
[Slide.]
Clinton Stewart, who is at the table, is really one of the
pediatric leaders in this field and I am sure won't hesitate to correct me but,
more importantly, will be available, I think, to address some of these issues
during the question period.
[Slide.]
So what is population pharmacokinetics? I think the most important take-home message
about population pharmacokinetics is that you are doing the studies in a
population that is representative of the target population. It is not a highly select group, but is a
real-world population.
It recognizes variability as an important feature that
should be identified and measured and, as importantly, it explains that
variability by identifying demographic, physiologic, developmental or
drug-related factors and is able to quantify the magnitude of the unexplained
variability.
[Slide.]
Like any method, there are pros and cons. First, let's compare it to what we have done
traditionally in pediatric oncology which is a traditional pharmacokinetics or
two-stage method. In the traditional
method, we do extensive sampling. That
might mean anywhere from eight to twelve samples in an individual child. These are usually small studies. As people know, in phase I, when we do these,
we are talking 20 to 30 patients maximum.
The population is relatively homogeneous. In pediatric oncology, we rarely study drug
disposition in young children. The
median age, as Malcolm said, is approximately ten years. When one wants to do correlations between
drug disposition and effect, pharmacokinetics, pharmacodynamics, one
essentially can study one factor at a time with these methods. In general,
these studies tend to use noncompartmental analyses.
In contract, population PK/PD sparse sampling is involved,
usually two to three samples, sometimes as few as one. Certainly the more the better, but you don't
need extensive sampling. You can perform
a single large study or you can actually look across study at pooled data There is a very diverse patient population.
One can study several factors looking for PK/PD
relationships at the same time and, in the end, you have a complex data
analysis that results in what will hopefully be a useful model that can later
be applied.
[Slide.]
The approach that is taken is as follows. One determines the pharmacokinetic, and I
will use pharmacokinetic and, parenthetically, pharmacodynamic, because, more
often than not, you attempt to address both in these models. You develop a structure for the population. You can then estimate the typical or mean
population parameter as well as the interindividual variability.
Not only do you do it for the entire population, there are
methods, then, to make estimates for any individual within that
population. It allows one to estimate
the residual as well as interoccasion variability and then it identifies
measurable sources of variability in pharmacokinetic or pharmacodynamic factors
and describes the relationship to these parameters.
The power of population modeling is it can do all these
things in the intended patient population.
[Slide.]
In practice, what does this mean? Well, if one were to look at individualized
clearance estimates from a population not only do you determine the mean, you
will also quantify the variability as well as understand the factors that lead
to the wide variation that we often see in individual clearance estimates.
[Slide.]
There are certainly advantages to this approach. As I have said, this usually involves less
than intensive samplings but it allows for variations in dosing regimens as
well as sample collection. It can
utilize unbalanced data, study a broader spectrum of patients. In addition, it has a potential to start
screening for drug interactions and, as I said earlier, it can pool data from
multiple sources.
[Slide.]
There are, however, disadvantages to the approach and
limitations. In general, these are
slower than standard phase I PK studies in establishing an initial dosage.
Now, as Malcolm has alluded to, that is not what we are
really after here when we are looking at off-patent drugs. Random samples, if you leave it entirely up
to random drawing of samples, may not always be adequate and you may have to
apply some structure to obtaining samples.
As you have seen, primarily with vincristine, age effects are usually
nonlinear. It is not that you start low
and continue up throughout childhood and adolescence.
As vincristine has shown us, you might start with high
clearance. It might lower during early
childhood only to increase again during adolescence. The QA of data entry is more difficult. When you are doing larger studies, keeping
control of this data is more difficult.
Now, sometimes one of the more informative points is the
six or eight-hour point. But, again, if
you leave this up to random drawing, in reality, that rarely happens. If a child is dosed sometime in mid-morning,
the six or eight-hour time point is in the evening and most children are no
longer in clinic at that point.
Ultimately, these methods, in fact, can't rescue bad
data. You can't have collected all this
data and say, ah-ha, let me do a population analysis. No; you have to do this prospectively if you
want to have an interpretable outcome.
[Slide.]
Population modeling usually uses what are called
mixed-effects models. This allows for
simultaneous estimation of parameters relating to fixed effects and random
effects to observe data. Fixed effects
are observed or measurable variables.
These include the dose, the time of the dose, the weight of the patient,
if you know, the GFR, things that you can actually quantify.
And then there are random effects which then it goes to
explain the unexplained random variability both interindividual variability or
the residual error.
[Slide.]
There are a number of software applications that are in use
today. Probably NONMEM in industry is
most commonly used. But there are a lot
of applications that can undertake a population approach. What I would say is, first off, the interface
to these applications makes the windows interface look attractive.
These are not for the light of heart. In fact, it takes specialized training
actually just to operate these programs.
Interfaces are improving, but this is really a highly specialized field
where one needs a great deal of training and expertise and time to perform the
analysis. The approaches that are used
are often Bayesian in nature.
[Slide.]
Steven asked me if I could pull examples from the
literature. There are a number of
examples where population approaches have been undertaken during pediatric
phase II or phase III trials. One of the
more recent ones is a study of zidovudine in preterm infants, studies
undertaken by the Pediatric Aids Clinical Trial Group, PACTG.
[Slide.]
The study, which was led by Edmund Caparelli, looked at 37
HIV-exposed preterm infants. They
stratified by gestational age. The
regimen was based on data from term infants.
It allows for initially a lower dose and increases, or a higher, dose
over a very short study period of six weeks.
Pharmacokinetic evaluations took place during two windows,
during the first week at Days 4 to 7, during later in the second week, Days 12
to 16. And then Days 24 to 30.
[Slide.]
If one looks at the data from the same group in term
infants and looks at the clearance with IV dosing or the apparent clearance
with oral dosing, one sees that, over the first few days of life, there is a
very steep increase in clearance over time.
The first thing I can tell us is that a population model can
take advantage of the this. It is not
restricted to studying one route of administration at a time. When Caparelli and colleagues looked at the
preterm infants who were greater than 30 days in gestational age, the data was
relatively well predicted by the data in term infants. There was an increase over time, a rapid
increase over time, again, not surprisingly, the parent clearances were higher
than true clearances.
However, when they looked at micro-premies, infants less
than 30 weeks of gestational age, the term model no longer held and was no
longer applied.
[Slide.]
One can basically extrapolate these types of findings to
realize that you can't simply use a model that is derived in one age population
and assume it is going to apply across the age populations. The power of population modeling is that one
can look at this and develop a model that tries to look at factors that explain
this variation.
[Slide.]
It not only gives you population estimates for variables
such as volume of distribution in clearance and bioavailability as well as
absorption-rate constants. It can then
look at factors and the relative magnitude of the impact of those factors. So renal function is measured by serum
creatinine.
The post-natal age turns out to probably be the most
important factor, how old these children are relative to birth, not just their
gestational age, and so on and so forth, to explain not only the mean variation
but what are some of the variables that go into the variability between
patients of the same post-natal age.
You see here that there is an interaction with furosemide
on clearance. One can't assume that is
truly a drug interaction. Whether this
is a surrogate for something else going on in the preterm infant could not be
determined from the study. But, in the
end, you have a model that examines several factors simultaneously and is able
to quantify the magnitude of the impact that these factors have on the ultimate
drug disposition.
[Slide.]
Let's move from the jump-start that our colleagues, looking
at antiretrovirals, have to what we could potentially use in drugs. The example that I have taken is the one that
Malcolm has spoken about, actinomycin D.
Probably the reason there is very little data on actinomycin D is, when
you look at the structure, it starts off as a friendly enough small molecule
and then it just happens to tack on two cyclic peptides onto this making this
an extremely difficult molecule to quantify and, up until this month, there was
no meaningful published method to do this.
Gareth Ville, in the U.K. has now published LCMS method that will
quantify actinomycin D in plasma.
[Slide.]
So, if we were to undertake a population PK approach, where
would be start? Well, there is some data
with radiolabeled actinomycin D in animal models, rat, dog and monkey, but
there is really no data yet, meaningful data, in humans looking at metabolism,
protein binding or elimination.
As I said, there is extremely limited PK data. One of the advantages of presenting
actinomycin D when you have ten minutes is that you can summarize all the human
PK data in a single slide. So this is
what we know. And this is in three adult
patients with melanoma. They received
tritiated actinomycin D. This was
published a little over 25 years ago, but it is a starting place, although it
is an NS3 and these are adults.
[Slide.]
If one were to undertake a pop PK approach, well,
obviously, the objectives would be to describe the pharmacokinetics of
actinomycin D in pediatric patients and then to estimate the population
pharmacokinetic parameters and evaluate covariates. Those covariates could include, but would not
necessarily be limited to, body size and composition, the cancer type,
polymorphisms and drug-metabolizing enzymes, concomitant drug administration as
well as the effect of age and gender.
It may well turn out that the debate about do we dose by
body weight or body-surface area will pale in comparison to other factors that
we may define in such a model that would really define the more appropriate
method for dosing these infants.
[Slide.]
This clearly would be an open-label study. You would obtain not only pharmacokinetic but
as well as additional safety and tolerability data. As Malcolm said, this drug is used in
rhabdomyosarcoma and Wilms'. Depending
on additional preliminary data, this would take at least 100 children in order
to get a meaningful model out of and probably double that number if we were to
extensively study infants throughout their first year of life.
Now, I can point out that actinomycin, except for, I
believe, a single dose during Wilms' tumor therapy, is almost always
administered with vincristine. One could
consider a study design that would look at these drugs simultaneously.
[Slide.]
Now, sampling strategies, as I said; leaving it up entirely
to random sampling has its limitations.
One could randomize to two simple schedules or one could randomize to
schedules that have windows that take time points on the first day and then
time points at later time points. Again,
it is hard to know what the optimal sampling strategy is until we have
additional preliminary data to make educated assumptions about where we should
sample.
One could develop a model using NONMEM, build covariates to
examine the sources of variations and, ultimately, determine individual
predictive parameter estimates that you could use to explore the relationship
between pharmacokinetic metrics as well as clinical outcomes, toxicities as
well response.
So I will stop there and I think turn it back over to Dr.
Santana.
DR. SANTANA: Thank
you, Peter. I have just been informed
that other members at the table have joined us since we started. So could those individuals please introduce
themselves for the record.
DR. ROBERTS: Good
morning. I am Rosemary Roberts. I am the Deputy Director of the Office of
Counterterrorism and Pediatric Drug Development. I am very happy to share this morning with
you.
DR. SANTANA: Thanks,
Rosemary. I think there was a gentleman
over there. Yes?
DR. MATTISON: I am
Don Mattison from NICHD.
DR. SANTANA: Thank
you.
Questions to the Presenters
DR. SANTANA: We now
have an opportunity to ask questions of the presenters. I am going to start with one question. When we have looked at the time lines for the
drugs, the five oncology pediatric drugs that have been granted exclusivity so
far, what has been the time frame from the initial request to the actual point
in which the exclusivity was granted and, related to that, how do oncology
drugs compare to other drugs that are out there that are going through the same
process, some antibiotics and anticonvulsants?
Are we in the same frame or are we different? Are we worse?
Are we better?
DR. HIRSCHFELD: I
could try to address that. The drugs
that so far have been granted exclusivity were products that had preexisting
data. So the time frame was relatively
rapid. It was typically within 18 months
of issuing the written request and the time period was utilized to obtain the
data from the cooperative groups to format it, analyze it, and prepare the
report.
That did not require do novo studies for these particular
products. Now, in other cases, we have
requested de novo studies but, because of the breadth of activity and the
richness of the data collected, particularly by the cooperative groups but also
by other institutions, and the pediatric oncology community in general, it has
not been a barrier to obtain data from studies that were well conducted.
In many cases, though, we have requested prospective
studies. Particularly anyone that does
the arithmetic can readily see that approximately half of our written requests
are for products which are not yet approved.
So we are anticipating that those data would come in but they won't come
until the actual NDA submission arrives.
So that would be the broadest distinction. Now, relative to other written requests, I am
going to make a comment and then I will defer to Dr. Roberts sitting to my
left, if she would want to add some other comments. But I would say that it is, again, highly
variable in the other areas.
I have been attending the meetings of the Pediatric
Implementation Team and the Exclusivity Board since they were first
established, and we find some of the products have submissions that are fairly
rapid and others which take several years.
As a general framework, when we issue a written request, we
anticipate that it will take several years between the issuance of the written
request and the completion of the request, its studies and preparation of the
report. "Several" is usually a
number you can count on one hand.
DR. SANTANA: I think
you made a very important distinction that I publicly want to acknowledge; that
is, for these initial exclusivity determinations, we have a lot of data, like
you suggested, like you confirmed, that have made it a very rapid process. But we should not go back and use those as
benchmarks for the newer studies which I think probably will take a little bit
longer.
So I think, publicly, we need to admit that we are in a
good fertile ground right now but that may change as new requests come through
and we have to do newer studies that may take longer. So the public perception should be that it
will take longer, not shorter. We are
not aiming for shorter because the benchmark is different.
Rosemary?
DR. ROBERTS: I would
say that that is going to be true for the other areas, too. In products where we already had a lot of
information and products that were being used and there was an anticipation by
industry that they might seek some kind of--I mean, industry was aware that
this whole FDAMA idea was brewing. As a
matter of fact, some of industry had already done their studies and were
waiting for the President to sign the legislation.
There was nothing in the legislation that prohibited them
from then submitting those studies if they were consistent with what we
requested. So I think that, for new
products where they have to start from the ground up in order to get the
studies, then it is going to take longer.
We have certainly seen, in some classes of agents where there are
several different members of that class, that, in those sponsors who had
already done, started some initial studies in the pediatric population, they
had much less to do when they got their written request because they had some
information, whereas others who had not studied the pediatric population at all
ended up having to do all their studies after they got the written
request. So they have lagged behind.
DR. SANTANA:
Thanks. One more question, and then
I will let others, so I can stop talking because of my voice. Anne, can you readdress with this the issue
of the coordinating center? I didn't
quite understand how that fits into this and how that is going to be run. Can you clarify that for us?
DR. ZAJICEK:
Absolutely. Don may want to pitch
in, too. So, the NIH is going to fund
studies, off-patent studies, based on the written requests. So the question was how to coordinate or how
to monitor what is going on with these studies.
So, for example, lorazepam, I guess, will, at some point, be contracted
out. So someone needs to monitor how
these studies are going, whether they are getting adequate enrollment, that
kind of thing. Are they on time for some
sort of deadline?
So the coordinating center is being funded to basically
monitor the progress of the studies and to collect the data because the data
will have to come back to the NIH and then be submitted to the FDA for a
labeling update.
Does that answer your question?
DR. SANTANA: In
part. So the coordinating center is at
NIH?
DR. ZAJICEK: The
coordinating center is not at the NIH.
DR. SANTANA: It is
part of the study group.
DR. ZAJICEK: It is a
contracted-out group.
DR. SANTANA:
Contract?
DR. ZAJICEK: Yes;
exactly. So the NIH will be monitoring
the coordinating center but the coordinating center is not the NIH.
DR. SANTANA: Peter?
DR. ADAMSON: This is
a question that actually may be best for you or for others at NICHD or the
FDA. The off-patent mechanism is
obviously a new mechanism for the pediatric community.
DR. ZAJICEK: Yes.
DR. ADAMSON: The
contract mechanism, I should say, is relatively new for us. Can you tell us, when you develop, in
conjunction with the FDA, a written request, what type of cost analysis is
done? In other words, when you outline,
sort of your ideal study, we want to gather all this type of information.
One analysis is done before the written request is issued
to get an estimate of what would it actually cost. Certainly, for the on-patent, that is
probably the first analysis that is done.
We would all wish every oncology drug was a billion-dollar market but,
as you get down to $100 million and $10 million, that is the analysis that
drives are we going to respond to this.
Is there a similar process as far as truly costing out what
is in the written request?
DR. ZAJICEK: I will
send this over to Don.
DR. MATTISON: Yes;
there is. We actually can't issue a
request for proposals until we perform an internal NIH cost estimate for the
studies. However, if I could sort of go
beyond what may in your question, in the context of prioritization, we haven't
been formally looking, up to this point, at cost estimates and population of
children affected.
We are in the process of trying to develop a set of richer
and more explicit data resources which allow us to look at questions like that
for the prioritization process. But that
is taking us some time to put in place.
So the answer is yes, we do perform an internal NIH cost estimate. That is actually required before any RFP is
published.
DR. ADAMSON: And as
a follow up to that, can you--again without getting into specifics, because the
contract mechanism is relatively foreign to people who write grants, when you
get those proposals and the proposals go out with costs not really anywhere
mentioned--and I understand, I think, in the contract mechanism that is how it
has to be.
The proposals you have received back, can you tell us, have
the costs ranged by an order of magnitude?
Have they been within a factor or 2 of what the internal estimates--at
least, early on, how is the community doing, how is the NICHD doing, in
estimating the costs?
DR. MATTISON: We
have published four requests and have gotten back, and have had a chance to
look at in detail, responses for three of those four. The areas where the cost estimates were the
most variable dealt with funding for the coordinating center. It varied with the kind of resources and the
cost of those resources that the coordinating centers thought they needed to
provide.
There, I think, one of the estimates was as much as an
order of magnitude greater than what we had anticipated in terms of internal
costing. In the case of the drugs that
we have gotten back and been able to analyze requests on, the disparity was
much smaller.
DR. PRZEPIORKA: A
question to CTEP and the FDA. Are there
any guidance documents out on using, or conducting population PK studies?
DR. HIRSCHFELD:
There are some draft documents which are being circulated. They are available on the Internet. They outline the general principles but they
don't go into the detail of stating which software or which kind of sampling
methods, but address the issues of data quality and general principles.
DR. PRZEPIORKA:
Thank you. Dr. Adamson did a
great job introducing population pharmacokinetics and cited an example where
the PK study, the pop PK study, showed a true difference by age. Has there been any example of validation of
data that can be obtained from a population PK study?
DR. ADAMSON: I am
not certain I know the answer to that. I
mean, I do know, and Steven can tell me, there are a relatively significant
fraction of labels that have been based on population PK submissions and not
standard PK submissions, not just in oncology.
I am thinking across the board.
So, as far as our pop PK methods an accepted and validated
approach, I think the answer is yes to that but I may be misunderstanding the
question. Maybe Clinton can better
address that than I.
DR. STEWART: What I
was thinking of was this guidance in industry and the exposure-response
relationships that is included in our reading.
It definitely goes into some of that information in that in terms of the
population PK software that is recommended for use there and the sort of guidelines
that were recommended for use.
Specifically, what are you asking?
DR. PRZEPIORKA: Has
there been any study performed that will in which a pop PK study was done on a
drug with a narrow therapeutic index, such as an oncology drug, which then took
those parameters and applied them clinically and showed that, yes, what we have
learned was safe and effective.
DR. STEWART: No; not
to my knowledge.
DR. HIRSCHFELD: If I
may, I could just clarify. I don't think
any of us at the table have specific numbers but my impression is it is
actually relatively few applications come in with pop PK data. There haven't been very many. It is a growth area. The FDA has been looking at it for some
time. We have actually been sent
samples of the software to test--some of the products that you listed on your
slide, I have had the opportunity to get lost in.
There is, I think, an emerging technology. While pop PK has been evolved starting--and
Clinton may correct me if I am mistaken--but I think the initial nest of pop PK
was as UCSF in the 1980s. From there, it
has been slow to gain general acceptance, particularly in the pharmaceutical
industry, because of its high technical demands and the difficulties in doing
the analyses that require a fair amount of expertise.
So there are relatively few centers that, I think, have a
track record, although many people have been interested in the problem.
DR. SANTANA: Dr.
Finklestein?
DR. FINKLESTEIN: In
the interest of organization and time, Mr. Chairman, what I would like to do is
just very rapidly, in a minute or two, go over a number of questions to the
various people and then maybe they could put their comments or add their
comments when they have a chance to speak.
Otherwise, this can go back and forth and I don't want to monopolize
everything.
I obviously congratulate Steve. I always enjoy listening to your
history. I wonder if somebody would tell
me, either you or Dr. Cooper, when its his turn to talk, whether exclusivity
really applies only to pediatrics or is it a general term that has other
applications.
Does the foundation have any problem in getting access to
the drug considering that it is non-patent, and how do yo get the drugs? I am interesting in knowing why you are
prioritizing even oncology drugs. I am
also interested in knowing why no one has ever mentioned steroids today? We don't have an idea on how to use steroids
in oncology and in general in pediatrics.
Should we cap the dose for big people?
This is something we have struggled with. We would also mention obesity, a big problem
in the United States. We are talking
about the infants. What about the obese
child? I would like somebody, perhaps
Anne or Steve, to handle that.
Of all your 169 drugs, some of the ones that were chosen,
the three that you are choosing, other than maybe the antibiotic, has very
little use--maybe Ativan has a little bit of use. Once you finish your contract, will the data
be acceptable to the FDA because they have certain criteria? And how are we going to move from your data
to the FDA?
That also holds for all of us who do clinical studies,
Malcolm. We have been doing clinical
studies for decades. Yet, is it in the
format that the FDA will accept? Better
still, why won't the FDA accept our format because we know our format is the
right way to study pediatric oncology?
For Peter, and for Malcolm, I mean, actinomycin D, I think,
came in from Sidney Farber in 1956.
Vincristine was 1960. If we are
starting off, and I agree, we have to study those drugs, but if we start off
with drugs that are over 50 years old, it is going to take us another 100 years
to get the drugs that we are currently handling. So we need some kind of practical time line
on how to handle this great challenge.
Otherwise, the group that takes over from us five years or ten years
from now will be discussing the same topic.
We do have one study that I can think of in acute
lymphocytic leukemia, and Peter, you may want to comment, which is our 1991 COG
study where, in actual fact, we increased dose to toxicity. That is sort of our practical clinical way to
trying to handle maximum dose.
Last but not least, if a counterterror person would like to
tell us in about three sentences what they do for general information, I would
appreciate it.
I yield, Mr. Chairman.
DR. SANTANA: That is
a lot, Dr. Finklestein. I will allow
Steve and Peter and Malcolm, I think were the three primary people that were
mentioned in these questions, to go ahead and do their best.
DR. HIRSCHFELD: I am
going to defer most of it to Rosemary Roberts.
But I just want to touch on a couple of things and then I will let
Rosemary certainly handle the counterterrorism part and maybe touch on some of
the other more general questions.
So exclusivity is a regulatory and legal term which refers
to a process where someone is given marketing rights where they are the only
person that can legally sell that product for that intended use. The pediatric exclusivity is not something in
isolation. There has to be exclusivity
granted by a number of complex mechanisms which we don't need to go into now,
but there has to be preexisting exclusivity.
What pediatric exclusivity can do is that it can extend the
preexisting exclusivity. As far as
looking at the steroid question, Malcolm and I discussed this at some
length. Here is where we ran into sort
of a regulatory corner and that is that our charge was to identify drugs that
are listed or catalogued as oncology products.
Even though some of the steroids have oncology indications,
within the framework of the FDA, they also have multiple other uses and fell
out of the purview of what we were charged with examining.
As far as formats go, I think the FDA is quite flexible
with the format of data that comes in.
As good data are good data, and inadequate data are inadequate data, I
don't think any two NDA submissions or any two study reports submissions in
response to written requests have been identical.
We have general guidelines but format, I don't think, has
been a barrier. I will yield now to Dr.
Roberts.
DR. ROBERTS: Let me
just take up on the last question here.
One of the things that the--actually, Steve has made us aware of, is
that in the United States, there is a very good system for studying children
who have cancer. As a matter of fact,
most children are in trials in this country.
That is the standard of care.
He made it known to us that we don't want to disrupt this
process as we try to figure out how to implement FDAMA and make it so that the
oncology-drug industry could, indeed, benefit from the incentive and not
disrupt the cooperative group process that exists in this country and that is
the mainstay of care.
So we do recognize that the studies that you do are
good-quality studies. In putting
together a package for the on-patent products there is an entirely separate
guidance for study of oncology drugs.
That template is totally different.
For the new products, one of the things that was very clear to us from
the cancer advocacy groups as well as from the NCI and from the cooperative
groups was that you all wanted to get drugs much earlier.
You didn't want to have them go through the adult pipeline,
be approved and then you could access them for children. So, hopefully, with this oncology process
that we put into place, you are actually able to study drugs much earlier. Literally, a drug that is studied in a phase
I type that you all would do, if it is so toxic that it really cannot even go
further into phase II studies, that, alone, can qualify a sponsor of a new drug
to get exclusivity once they bring in the studies for the adult.
If it is not so toxic at that point, and you can go into
phase II, and you complete those studies and get some information as to what
tumors these particular products might be advantageous for, then, at phase II,
they can get the exclusivity.
Now, indeed, they have to submit the NDA and get it
approved so they have something to hook that exclusivity onto. But there is no other group of drugs at the
agency that has this innovative way to apply the FDAMA incentive, now that has
been renewed through BPCA.
We told sponsors that you are to go through the cooperative
groups. We don't want you independently
setting up studies and competing with the cooperative groups. So we recognize that you do good-quality
studies.
For products that are on patent, the sponsor has to submit
the data. So we are encouraging them to
go through you, get that data and submit it.
For the off-patent products, as far as how does that information get to
the FDA, how does it get into a label, well, it is a much more laborious
process.
One of the other functions of this coordinating center that
the NIH has contracted out to is to put together the data in an application
that is reviewable by the agency. So one
of the criteria that these particular sponsors or research organizations has to
show or demonstrate was they had some experience in putting together an FDA
supplement because, essentially, unless that data comes in in a format that is
reviewable, it is worthless to the agency.
So that is a key part of what they are to do. Once that data comes into the agency, that
data is put up on a docket so it is immediately available to the public and the
public can comment on it. The data is
referred to the appropriate review division and, in this case, it is going to
be the Oncology Division, to review the data, to look at those studies to see
if, indeed, the studies obtained information on how to appropriately use the
product in the pediatric population, look at any comments that have come in,
and then, in addition to taking an action, propose labeling.
So the division will actually propose labeling. Then they will have to negotiate that
labeling with the innovator, if the innovator still exists in the market, or
with the generic that has the greatest market share. So that is how the labeling will be done.
DR. SANTANA:
Malcolm, did you want to comment?
DR. SMITH: I will
say a couple of things and let Peter address it as well. The question about studying drugs that are
from the '50s and '60s, that is the challenge here, is that the BPCA has these
provisions for studying off-patent drugs and NIH has funds to study these
off-patent drugs in children.
So our challenge is can we make--are there things that we
don't know about these off-patent drugs that, if we knew, would benefit
children with cancer. So that is the
territory. These drugs that are from the
'50s, '60s, '70s. I think the challenge
to all of us is to identify what the most important gaps in our information are
that are addressed by additional research and then to try to see if we can't
fill those gaps.
The two we suggested were for vincristine and
dactinomycin. We are certainly open to
other suggestions about important gaps from this list of off-patent drugs and
ways that we could use them better.
Also, there are other types of drugs that are used for
children as part of the supportive care for children with cancer and so
steroids have multiple uses and other drugs for pain control and so on. So those are other areas that wouldn't
necessarily be specific to oncology but which this committee might also want to
consider if there are gaps in the off-patent drugs that are used for supportive
care as well.
The final point I would make is that this, again, is about
drugs that are from the '60s and '70s.
We wouldn't want this to block studying--doing phase III trials,
studying new drugs, new mechanisms of action, that are more scientifically and
potentially more clinically relevant. So
I think that is something that we would be very cautious about in terms of
saying we want to do something with the off-patent BPCA funds in oncology.
We should make sure that, when we do that, we are not
blocking something that would actually be more contributory to improving
outcome.
I think this proposal that you could kind of put together
from my presentation and Peter's presentation wouldn't block the study of any
new drugs because this is building into existing trials and the way we are
using the drugs now in collecting more information.
I think a potential benefit of it is that it then provides
a model or a paradigm for how we look at some of the new drugs as well because
when we do our phase I studies of the new drug, the new inhibitor of this or
that molecular target, again, we are looking in nine and ten-year-olds in
getting PK the that population. Then
when we move to phase II or phase III, we may be able to build in to those
studies the kind of paradigm that we are talking about today with the
population PK studies to actually learn from the start more appropriate ways
for using the drugs across the entire age spectrum.
DR. SANTANA: Peter,
were you going to say something?
DR. ADAMSON: Yes, I
was. I first wanted to jump back, if I
can figure out how to do this, to Donna's question.
[Slide.]
This is a list that I happen to have on my laptop of drugs
where there is population pharmacokinetics in the current label. This is probably a few months old now, so I
think Steven is right, it is not a large number. But it does exist and this information does
appear in the label. I think the agency,
and I don't want to speak for them, a well-done population PK study is an
acceptable form of gathering clinical pharmacologic data.
I want to echo what Malcolm said and just expand on a
couple of issues because I think Jerry has really hit the point on the head
here. We don't want to come back five
years from now and realize that, you know, we are now only 35 years behind and
not 45 years behind.
The paradigm that we have to develop drugs from phase I to
phase II, phase III, will always leave us with large gaps in knowledge unless
we change what we are doing. By that, I
mean, we have to extend pharmacology studies beyond phase I. We are never going to capture meaningful pharmacologic
data in infants and young children on phase I.
We are rarely going to capture it on phase II.
If we don't start doing it in phase III, twenty years from
now, we are going to have the same thing and, up on the board, it is going to
be irinotecan. How are we dosing
irinotecan. It will be the same story
all over again. So, with the new drugs,
we have to clearly start changing how we are gathering this information.
Population PK is one way to do that. The problem, and the greatest challenge, is
not the technological challenges anymore.
We have the computing knowledge.
We have the analytical methods to do it.
The challenge is that physicians, nurses, staff that comprise a very
productive network, are stretched to the limit on their capabilities with the
funds they have.
The grant, as critical as it is to supporting these trials,
when industry looks at--when we tell industry how we are doing this phase III
trial that is gathering data for five years and what we are paying an
institution, I think it is what, $1500 or $2000 or something like that, for the
whole study, they look at us like, well, there is no way the data is useful
because you probably don't have it.
The reality is we have it.
It is not up to industry standards in most cases. What falls by the wayside is, as we look at
important correlative studies, and I would say pharmacology is an important
correlative study, if we don't specifically fund those correlative studies, it
is not going to get done in the way we need it.
A pop PK without accurate dosing time and sampling time and
specimen handling is worthless. So you
need qualified people. You need
dedicated people who are going to explain studies to families, who are going to
enroll children and who are going to make sure that all the data, even though
it is limited data, if you are talking three time points, that data is
"Q-A"ed and you can use it in the model because, if you don't, you
are not going to have a model that is interpretable.
So I think the discussion that we are having for the
off-patent, you can clearly put prospectively in the new drugs that we are
studying. We have to figure out
mechanisms to appropriately fund these studies.
Certainly, BPCA for off-patent for off-patent can help us go a long way
and relative to other drugs, because we have an infrastructure in place, is
probably going to be a bargain.
For new drugs, we have yet to figure out a mechanism for
how are we going to extend these important studies beyond phase I into phase II
and phase III.
I probably didn't address everything you asked, Jerry, but,
hopefully, hit the high points.
DR. SANTANA: I think
Dr. Reynolds had a question or a comment.
DR. REYNOLDS: First
I would like to agree with Jerry. I
think that, although I understand, Steve, your charge here is primarily
antineoplastics, I think that agents that are used as antineoplastics in the
pediatric population, as Jerry mentioned, in the steroids, I would add to that
the retinoids, should be included in this as off-patent drugs that need to be
studied and we need to learn more about.
I really specifically had a question for Anne. I was intrigued by the concept that you
mentioned that, if there was the need for a pediatric formulation on an
off-patent drug that, somehow, that could be studied through this
mechanism. The cost of doing that would
be substantially greater than simply doing a PK analysis. I wonder is this program prepared to do that
costs? Are they prepared to do the
preclinical IND-directed toxicology that is necessary?
What is available here because there are some very
substantial needs in that area?
DR. ZAJICEK: I think
I would safely say this is probably the least explored area of the BPCA. I started life as a pharmacist so formulation
problem is a big problem. Just to
complicate things, if you are going to compare a formulation that already
exists to a new formulation, then the FDA has requirements for exposure, Cmax,
that kind of thing.
So I can't say we have explored that at any length, but it
certainly is an issue. Don, do you want
to add anything?
DR. MATTISON: It is
clear if you look at challenges in treating pediatric patients that formulation
represents one of the greatest challenges, probably one of the most significant
causes of medication errors. I am telling
you folks things that you already know.
The issue of making drugs appropriately usable by pediatric patients, I
think, needs to be addressed.
We do have the resources, I think, to be able to do it in
selected drugs. If folks from your home
district that are serving in Congress are educated to the fact that this is a
critical issue, then additional resources could be directed to it.
Kind of in response to the question that Dr. Adamson
mentioned, we have to prioritize testing for drugs that are currently available
in formulations that can be used. But
that is kind of a backwards and not the world's best approach to drug
development. So we would like very much,
with the help of our various advisory groups, to identify a small group of
drugs for which formulation changes will make a big difference and we will do
our damndest to work with the FDA to get those formulations produced and
marketed.
DR. REYNOLDS: One
intermediate to this that you might want to consider is that there are probably
some generally used extemporaneous formulations and, perhaps, formal study of
those could be done as a less costly endeavor than developing a totally new
formulation and would allow for some product labeling that would give guidance
on using some of these drugs that simply doesn't exist.
DR. ZAJICEK: It is a
great idea. If, during this meeting, you
want to mention specifics about what compounds you think we should consider?
DR. REYNOLDS: One
that comes to my mind is--
DR. SANTANA: We will
have time for that during the discussion of the questions.
DR. ZAJICEK: Good.
DR. SANTANA: I think
we would do that. I think Rosemary or
somebody had a comment over here, or Richard.
I'm sorry.
DR. PAZDUR: The one
point I would like to emphasize is let's not be guilty of age discrimination
against drugs. Jerry. I love accusing Jerry of age discrimination
of drugs. The issue here, just because a
drug is old does not mean that it is not important to study. Remember, and I feel almost I shouldn't have
to mention this in this group is that many of these drugs are being used in
curative regimens. Therefore, I think it
is especially important here that some of these older drugs be studied.
Remember, if we are really effective in the incentive
program, there really shouldn't be this lag that exists for generations and
generations of medical oncologists because the newer drugs should be studied
under the incentive program and really the life span of this off-patent thing
in oncology should be somewhat limited if we--and I think this is important--if
we are truly successful in the incentive program because that lag should be a
finite lag here.
DR. SANTANA: Steven,
you had a comment, too?
DR. HIRSCHFELD: I
was just going to say that if the legislation pending before Congress, which
would give us also a mandate under particular circumstances, comes into
passing, then that could also address the problem. This committee has formally identified areas
where a pediatric rule type program could have an impact and benefit children
with cancer.
DR. SANTANA: Dr.
Boyett, last question to the presenters.
DR. BOYETT:
Actually, I want to agree with Peter that I think it is appropriate to
study PK in phase III settings where the drugs are actually given and we don't
know much from the phase I. I also think
that applying nonlinear mixed-effects modeling to PK data is appropriate. However, I would like to point out it is not
a free lunch. I got the idea from
listening to you that we could solve just about every problem, that the modeling
you talked about and the software you threw up there could handle any
situation. And that is clearly not the
case.
The issue you have is not with the software. What you need is to get statistical sciences
involved whose areas of research are nonlinear mixed-effects modeling. Those are the people who write some of the
better softwares that are up there and they understand it. So it is not a matter of using the tool. It is plugging it in.
I would point out that, in linear modeling, there is a
"seat of the pants" rule that you need about ten patients per
factor. Nonlinear mixed-effects modeling
is much more complicated. I am not sure
there is such a "seat of the pants" rule yet. But the study that you quoted, the zidovudine
study, in my mind, is grossly underpowered.
I shuddered when you put up the number, we need about 100,
and then maybe you said 200, in, I forget, the rhabdomyosarcoma setting. Maybe you said actinomycin D. Statistical scientists need to look very
seriously at it and help you decide what sample size you really need given all
the factors that you are going to try to adjust for because, you know, it is
worthless to do an underpowered study.
It may be more dangerous to the children to do an
underpowered study and misinterpret it than it is to leave things the way they
are. I also would disagree with the
interpretation of the plot that you showed from the ZDV study for concluding
that the term IV was a good fit for the preterm greater than 30-week CA. I don't think that fits it at all, and the PO
doesn't look very helpful as well.
So I think we have to be very careful in interpreting the
results from these studies. You can
publish any study in some journal someplace.
DR. SANTANA: One
last comment. Ms. Hoffman?
MS. HOFFMAN: I just
wondered about a mechanism, I guess, if you do the population studies phase III
and you are looking at possibly increasing dosage in infants, then,
counterbalanced to that, is looking long-term at toxicity results. So, if this coordinating center is going to
be subcontracted out, what is the mechanism to protect that information? Companies come and go. Is there going to be some way to make sure
that we have a very committed subcontract that is going to be watching these
kids long-term to be able to see what the potential impact on increased dose in
infants would be? They could be
committed for ten years, 15 years, whatever.
If they are not, then what is the mechanism to take that information
back into the NCI or who is going to have access following?
DR. MATTISON: It is
clear that, just like formulation is an issue, long-term safety is an issue in
infants and pediatric populations. The
current, the Best Pharmaceuticals for Children Act, expires in 2007. So we have got whatever funds we can sort eke
out of Congress through that period of time.
Let me say, though, that, in collaboration with the FDA and
with folks in the industry, it is clear that infant, childhood and adolescent
toxicity and its developmental consequences are an issue that we have to give
substantial attention to. Just like we
are looking at the development of methods for studying the off-patent drugs in
terms of characterizing appropriate dosing and regimens, and so on, it seems to
me that we could use these long-term safety studies as a model that might be
useful in some of the new drugs as well.
Our hope is that we will be funded as long as is necessary
to clear up the backlog. But that it not
our decision. That is a Presidential
decision.
DR. SANTANA: Do I
dare ask the unspeakable which is currently what amount of money do we have to
do this?
DR. MATTISON: Up
until the beginning of this fiscal year, we had zero dollars for this. This is an act that was signed in January of
2002. We are currently authorized to
spend $25 million in this fiscal year.
The Secretary has said that $50 million would be available in Fiscal
Year 2005.
My sense is that we can easily spend that money in
pediatric clinical trials. The real
question is getting advice to make sure that these clinical-trials investments
yield substantial benefits for children.
DR. SANTANA: Thank
you. Malcolm, one last comment. Dr. Blumer, did you have a comment? Since you haven't said anything before, I
will let you go ahead.
DR. BLUMER: Thank
you. I have one concern about the
approach and it sort embodies several of the comments that were made. I think that Malcolm laid out a very
important paradigm in talking about, number one, you have drugs that have been
used for years and years and years. You
have patient groups that have not responded at the level that they are expected
to respond in terms of clinical efficacy.
And you also have, to some extent, unexpected adverse
events occurring in the context of the these protocols. We have heard that. And then we heard presentations about
pharmacokinetics. As a pharmacologist,
that is always very exciting. But where
we let you down is that we don't bring them together.
The worry I have, and it extends from two of the comments
that I heard before, is that if we endorse this approach of integrating
pharmacokinetic trials, we run the risk of simply collecting pharmacokinetic
data. I am not sure that we have
targeted what is that purpose, what does it mean.
So I would just wonder and ask if we couldn't at least say
okay, the reason for collecting this is either to determine why patients don't
respond or why they have toxicity and use that as a target and then consider
whether population PK is really the way to do that.
Coming from an historical perspective, our approach to
pharmacokinetics was really individualization of drug therapy and therapeutic
drug monitoring. That sort of went by
the wayside. One of the inherent goals
in population PK is to try and find a dose that, on average, works for
everybody in a certain group.
But when you are dealing, as has been pointed out, with
drugs with very narrow therapeutic indices, with life-threatening toxicities,
maybe that is not the approach that we want to take. In fact, maybe what we wanted to know is what
concentration or area under the curve or some pharmacokinetic characteristic is
associated with some of these efficacy or toxicity paradigms and then should
we, instead of a population PK approach, incorporate
individualization-of-therapy approaches.
I am just concerned I haven't heard that. I don't know what the right answer is,
necessarily, but there hasn't been that balance here.
DR. SMITH: I was
looking to Peter to answer that.
DR. SANTANA: We will
have time to discuss that when we come back after the break. We will have plenty of time when we come back
to answer the questions to carry the discussion further.
DR. SMITH: I think
the one point to Ruth's comment that I would say is that we have been
envisioning--it is this type of approach goes forward that it would be in the
context of ongoing clinical trials where there are follow-up mechanisms for at
least substantial periods of time so that at least some of the effects that
would occur later after treatment could be recognized, so it wouldn't be dependent
on necessarily the duration of a contract.
DR. SANTANA: Thank
you. We are going to go ahead and take a
fifteen-minute break, because we are running okay on time, and reconvene at
10:30. Please be back on time so we can
get started. Thank you.
[Break.]
Open Public Hearing
DR. SANTANA: We now
have an opportunity for public comments.
If there is anybody in the audience that wishes to address the
committee, please step forward.
If there is anybody that wishes to address to committee
publicly, we do have a letter from a member of the committee, Dr. Reaman, who
is unable to be with us today. He did
send a letter to the FDA that he wanted publicly read and written into the
record. So I will do that now.
It is dated October 3, 2003 and it addressed to Dr. Steven
Hirschfeld.
DR. REAMAN: (Read by
Dr. Santana) "As I am unable to
attend the meeting on October 9, I would like to take this opportunity to
provide input on the initiative to evaluate off-patent oncology drugs in the
pediatric population supported by the FDA, the NCI and the NICHD in response to
the Best Pharmaceuticals for Children Act.
"I applaud this effort to address a very serious gap
in knowledge impacting the public-health needs of young children with
cancer. In light of information related
to excessive therapy-associated toxicities, the variability of dosing
recommendations which are oftentimes empiric or dependent on anecdotal
experience, and the age-dependent discrepancies in outcome for common pediatric
cancers for the potential contribution of additional age-specific and
population-based pharmacology studies within the context of ongoing clinical
trials of the Children's Oncology Group, to the health and safety of young
children with cancer is enormous.
"Compromised outcome related to non-evidence-based
dosage reductions and unanticipated life-threatening toxicities of conventional
chemotherapy in young children, because of absent or incomplete pharmacology
studies, are public-health hazards which could be avoided by such investigations
of widely used agents in young children, specifically vincristine and
dactinomycin. Other agents which should
be considered for investigation include cisplatin, cyclophosphamide,
doxorubicin and daunorubicin.
"Evaluating relationships between drug
metabolism/clearance, body measurement and assessing systemic exposure and
correlations with toxicity and treatment outcome would be best accomplished by
performing such studies within the context of controlled clinical trials. Utilizing the existing national
infrastructure for pediatric cancer clinical trials would enhance efficiency
and assure evidence-based rational dosing strategies for off-patent drugs used
off-label in children with cancer.
"The positive impact of such studies in advancing the
likelihood of cure and improving the quality of life of young children with
cancer cannot be overestimated.
"Sincerely, Gregory H. Reaman, M.D., Professor of
Pediatrics, The George Washington University School of Medicine, Chair,
Children's Oncology Group."
So entered into the record.
Committee Discussion of
Questions
to the Subcommittee
DR. SANTANA: Let's
go ahead and try to discuss the questions that have been put forth before
us. I am not going to read the
introductory bolded section because it defines what we are here to do this
morning.
So I will go directly into the first question; the BPCA of
2003 provides a mechanism to study to study off-patent medications in pediatric
populations. Question No. 1; what
factors should be considered in selecting off-patent drugs for study in
children with cancer; these may include use in only a pediatric population, use
in particular diseases, use in particular age groups or toxicity questions of
particular concern?
So these are some examples that we have before us. Obviously, we could consider other examples
or other criteria that should be used.
So this question is now open for discussion.
I think one issue that I would like to add as one of the
criteria is, since many of our children are now cured, I think one of the
criteria for drug selection is if there is a particular drug that has a unique
end-organ toxicity that would be relevant to the growth and development of the
child. So the example that always comes
to mind, because I use it a lot, is cisplatinum.
Cisplatinum is an effective drug. We really don't know a lot about its
pharmacokinetics but certainly we know a lot about its toxicity. If we could use the end-organ toxicity as one
of the criteria in this selection process, that would be something that I would
consider.
Donna?
DR. PRZEPIORKA: I
was struck during the discussion earlier by two things. One is how incredibly important it is to dose
drugs appropriately in the pediatric age group since their life span is
huge. The other thing I was struck by
was how little money we have to do this.
This is not too dissimilar to things that happen in the GNP
lab where you have a very small budget and everybody is breathing down your
neck. I have to put on my
quality-management hat and essentially say, under those circumstances, how we
choose what we look for depends on what is high cost and high risk.
So I would actually wonder if COG has a database that can
tell us what are the drugs used most frequently in the pediatric population in
the last five years and what are the drugs that have the most toxicity and in
which age groups and hope that they would be able to share that information
with the other institute that does the Herculean job of prioritizing which
drugs to get funded.
DR. SANTANA: Malcolm?
DR. SMITH: In
response to that, I think we can provide estimates of the number of children
treated with different drugs because they are standard treatments and we know
the age distribution of children with different types of cancer and how many
approximately are diagnosed each year.
So it actually is a number that we could provide to NICHD and to FDA.
In terms of the risk--and one confounding factor is that
the risk can be lower, the risk can be high, depending on how large the dose is
and the patient population. If you look
at carboplatin as one example used in the Good Risk Neuroblastoma Trial that
COG is doing now, it is a lower dose.
The risk is relatively small.
Then you look at that same drug when it is used in the
high-risk population, in the transplant setting, and the dose is three or four
times as much, then, obviously the risk is much higher. So it is a complicating thing to assess the
risk because the risk is so modulated by the anticipated outcome of the patient
and the risks that are perceived as appropriate to try to achieve cure.
DR. SANTANA: Peter?
DR. ADAMSON: This is
going to be more of a tangential response to that and it comes back to some of
the earlier questions. I think, as we
not only think about factors that should lead to a study of a particular drug,
we have to look beyond what pharmacokinetics might be able to tell us.
What I mean by that is I don't think pharmacokinetics is
necessarily going to always provide the answer.
In fact, there are some examples where it clearly hasn't provided the
answer. So the studies that we take
forward have to look at factors in addition to what knowledge is already out
there on PK. But that can't be the only
factor that drives this.
There is a great example of a drug that we use in oncology
that we probably know more about than any other drug but it hasn't helped us
with dosing and that is 6MP.
6-mercaptopurine, we know its plasma pharmacokinetics in detail. We know polymorphisms and drug-metabolizing
enzymes. We know active metabolites in
the form of thioguanine nucleotides and we have studied this now for over
twenty years.
Despite knowing all that, none of those turn out to be a
good surrogate for toxicity and probably for response. The best surrogate we have for dosing that
drug remains looking at the CBC. So
pharmacokinetics aren't always going to be able to provide the answers even
when we do them well.
They are a surrogate.
They are an important surrogate for most drugs. Getting to what Jeff said earlier for therapeutic
drug monitoring, we are so far behind the antibiotic literature on this, we
will never catch up. We don't know what
effective exposures are. We don't know
what toxic exposures are for virtually all drugs, except, perhaps, for
methotrexate and toxicity.
So we don't know that in the adult population. We certainly don't know it in the pediatric
population. It is a step towards,
hopefully, more rational dosing and, hopefully, potentially towards
individualized dosing, but we have to look at other factors. There are likely to be other factors other
than plasma pharmacokinetics that might be better predictive of efficacy or
toxicity be it polymorphisms and receptors that have yet to be described on
down the line.
So, as we look at one of the factors that should go into
that as far as what do we know, yes, we want to look at what do we know about
the plasma pharmacokinetics but that, in and of itself, may be insufficient
knowledge and there are still going to be a lot of areas we don't know. I would second--as far as what we do know
today, is we have a good description of what the short- and long-term
toxicities are. We have a much harder
time trying to refine what has the impact on efficacy been. Those should weigh heavily into the decision
process as far as prioritization.
DR. HIRSCHFELD: If I
may comment. I just want to build on
what Dr. Adamson stated in that, even though there are limits to what is known,
the approach, I think, is so critical.
One of the historical facts is that there have been no approved drugs
for pediatric oncology for a long period of time. Between the 1970s and the year 2003, there
was only one drug that was approved.
Yet, without having new drugs approved through the
systematic application of principles of evidenced-based medicine, in the
context of an infrastructure, the survival and the outcome data have continued
to improve.
So, just for the public record, I don't want--that there is
the lack of knowledge means that the approach is not validated.
DR. SANTANA: Yes?
DR. BLUMER: Just to
expand on that, I think that really is a key issue because I think, as you
prioritize these off-patent drugs, in addition to the frequency of use and the
safety profile that the drugs enjoy, two of the things that I mentioned before
I do think have to help guide the process, and that is, given the favorable
outcomes that so many pediatric-oncology patients now have, where you see drugs
or drug regimens that are not working as well as expected, I think that should
raise a red flag and move that drug to the head of the list, or somewhere in
the upper echelon.
The same is true for unexpected toxicity. When you have an effective drug that, in a
certain age group or a certain regimen, is leading to unexpected end-organ
dysfunction, that, too, should trigger this.
I think the other thing that we haven't mentioned before,
and it is interesting listening to people who focus on oncology talk about this
all the time because it is glossed over, but as sort of a more basic
pharmacologist, all of your regimens are multi-drug regimens. You are trying to close your eyes and pick
the effects of that one drug out of these regimens.
I think that the issues of drug-drug interactions have to
come to the forefront here and be considered in part of what you are doing
because you are, in fact, creating a very complex scenario. You are not just using 6MP but you are using
6MP and methotrexate or something else.
Those things do count. It is not
that you just want to focus on it.
Certainly, you may know that actinomycin D, for example,
may, in and of itself, be hepatotoxic.
But is there something about it in the context of these other--with
vincristine, for example, that makes it more so in a certain age group because
of the way that they handle vincristine, not the way they handle the
actinomycin D.
I just think those things have to be considered as well.
DR. SANTANA: Alice?
MS. ETTINGER: In our
historic phase I and in our phase I studies, we are always looking at
pretreated patients who have other end-organ toxicities, albeit their numbers
may look okay at the moment. But I think
we have to consider that that is how we have always looked at those things as
well.
DR. SANTANA: Peter?
DR. ADAMSON: I think
that the challenge of prioritizing is probably not as daunting as we think
because, in reality, what we recognize as pediatric oncologists, we are really
using a small family of drugs and just changing the order of the acronym.
So, in solid tumors, you are--really, for the vast majority
of tumors, you can count on one hand the drugs and, for the others, you could
expand to the second hand. With
leukemia, again, you can count on ten fingers the drugs that are currently used
and that has virtually complete overlap of the solid-tumor drugs.
So we are prioritizing probably--realistically talking
about a list as short as ten drugs and, for the newer agents and uncommon
drugs, you probably could expand it to fifteen.
So it is not as daunting a task but it is certainly an important task.
DR. SANTANA: Jerry?
DR. FINKLESTEIN: I
think Dr. Blumer obviously also hit the nail on the head because we do
everything in combination, as Peter mentioned.
So I would ask the basic scientists and the statisticians, if we are
going to do these scientific studies, should we not, at the outset, design them
as combination-drug studies and figure out how we are going to analyze the
interrelations because, doing them as single-agent studies is not in keeping
with the way we manage children with cancer today.
I don't know enough about the statistical analysis nor the
science to say more other than the interactions would be very important anyway
from a clinical point of view.
DR. SANTANA:
Malcolm?
DR. SMITH: I would
just echo that. I think, to study these
drugs outside of the context of useful combinations, the way they are actually
used in the clinic, wouldn't be very contributory. So the challenge, then, is the appropriate
study design that can include that data or else isolate the specific
combinations.
DR. SANTANA: Any
other comments? Let me try to summarize,
then, what I have been hearing. Dr.
Boyett?
DR. BOYETT: One of
the ideas that you might consider is that, obviously, you take leukemia, where
you have a lot of drugs, and suppose there is a drug that you want to study
that is used in a particular regimen.
You might take the opportunity to consider--and suppose it is used in
combination with another drug, just one other drug for simplicity--you might
take the opportunity--in COG, you are going to register a couple thousand
patients a year. You might take the
opportunity on Day 1 to randomize patients to get the drug of interest with
nothing else. The other alternative
would be get the combination of that drug and the other drug which they would
receive during whatever time of the regimen.
That gives you the opportunity to look at the PK data over
one day or two days, whatever, a very short period of time. It wouldn't impact the outcome of the
patients. These are active drugs. Also, then, you get the opportunity to pair
that information within a patient when they actually get this same combination
or a little different combination later, it gives you an opportunity to study
drug-drug interaction and a potential impact of chronic treatment from the
beginning to that particular point in time.
I think if we thought about those issues, we may be able,
in some settings, to ferret it out. Now,
in leukemia, there would be some differences because if you were studying 6MP
and methotrexate, traditionally given in maintenance where there are no
blasts. On Day 1, of course, there are
blasts around and that might change some of issues, but you could learn some
things, then, about outcome, as you mentioned, Jeffrey.
If you look at the impact of these drugs in the very
beginning in circulating blasts or even if you could be so lucky as to get a
bone-marrow a day or so after you gave these drugs, you would be able to see
the impact of the efficacy as well.
DR. SANTANA: Pat?
DR. REYNOLDS: I
think the flip side of the combination issue is that, in some of our
combinations, we know what the contribution of individual drugs is because
randomized studies have pointed towards that.
In others, we don't. These
combinations were empirically derived and the individual contribution of any
particular drug to it may or may be defined.
I would suggest, then, the prioritization, that you might
want to take into account those drugs in which phase III studies have
demonstrated conclusively that the individual drug contributes to outcome and
use that as factoring the priority, if there are opportunities for potentially
improving that outcome by understanding better how that drug is delivered.
DR. SANTANA: Let me
see if I can try to summarizes what I hear the committee saying in relation to
this question. I think what I am hearing
is that there is no one unique factor that one can use to prioritize any one
drug versus another and that it is a matrix of factors that will help us decide
which drugs get studied up front.
The matrix that I heard goes from issues of addressing
toxicity in drugs that may have a narrow therapeutic index but toxicity not
only in the context of acute toxicity, like one would predict with actinomycin
in terms of VOD but also issues of long-term toxicity for the majority of
patients that are being cured and, related to that issue of toxicity, to also
look at drugs that may have specific end-organ toxicities that may be relevant
to patients that ultimately will be cured.
So I think that, in a nutshell, synthesizes the toxicity
issue in terms of how one could use it to prioritize.
The second issue that I heard was there has to be some
sense of the frequency of use if you are going to have an impact on
populations. So I think the comment that
was made earlier of getting some sense of which drugs are out there, how are
they frequently being used and in the context of what combinations, to then
provide some idea of the appropriate templates of study designs in which one
could then address these questions, whether they be in combination studies, in
single agents early on, periods of time where they can be studied uniquely.
So I kind of heard that comment, that the frequency of use
and how they currently fit into the clinical trials that are out there would be
an important issue to try to help us prioritize.
We didn't really talk about cost because I suspect most of
these drugs--well, the drugs we are talking about are off-patent but I think we
do need to know what impact of cost it would have in terms of adding more costs
to the current studies that we think could serve as templates to do these
analyses or ask these questions on.
I heard some comments about special populations. There was a lot of discussion about younger
children and how unique they may be and so, if there are particular drugs that
are used commonly in young populations, that we would use that as one of the
tools to select the drugs we want to prioritize.
There was another special population that was not mentioned
that I do want to mention as my own contribution which is the
bone-marrow-transplant population. There
are a lot of patients in pediatrics that are undergoing bone-marrow
transplantation with very high doses of therapies. I think that will be true for the next five
or six years until the phase III randomized studies are out.
So, bone-marrow-transplant-population patients particularly
solid tumors, are a unique population in which, if there were drugs in that
population that one wanted to prioritize, would be relevant because they are a unique
population in terms of their prior history and what is going to happen to them
after that.
I heard some comments about when drugs are prioritized for
these off-patent studies, that we have to pay some attention to combination
usage and what opportunities we may or may not have to then, ultimately, get
the answers that we want.
I heard some comments about drug-to-drug interactions and
bringing that into the forefold of studies that we want to do so that if we are
addressing issues of safety and toxicity, we will have the right answer at the
end.
And then I heard some comments about how we really should
be selecting drugs from the off-patent list in which there is a track record
that they are efficacious. So,
ultimately, if we get the answer that we want, it will improve the safety and
will improve the efficacy and we won't be compromising anything for our
patients.
So that was kind of my summary of the comments that I heard
as people commented on. Other people can
contribute to additional--yes?
DR. STEWART: Could
you, perhaps, elaborate a little bit more on your selection, in terms of the
special population. You indicated the
bone-marrow-transplant population is a special population. Were you thinking of that from the
perspective of those patients getting higher dosages, having prior therapy,
organ dysfunction.
DR. SANTANA: All of
the above. That population of patients,
to me, represents patients that historically have had very aggressive therapy
early on in their treatment. They are
now going to undergo another modality that, in most protocols, involves much
higher doses of therapy, primarily the majority of them alkylator based.
They have unique toxicities to liver, to kidney, to CNS
that we haven't really investigated very well. Some of those patients are being
cured with that modality. I think that
is a special population in which some of these drugs are being used in the
context of clinical research and we really don't know very well how to use them.
Pat?
DR. REYNOLDS: Vic, I
would just echo that. I think you raised
a very good point, that the use of these drugs in the myeloblative setting is
quite different than the use in the nonmyeloblative setting. By bone marrow transplant, I assume you mean
self support.
DR. SANTANA: Yes; that
is what I meant.
DR. REYNOLDS:
Whether it is autologous, peripheral bloods or bone marrow or
allogeneic. I think that is clearly a
different population and probably needs to be considered differently from the
general population. The pharmacokinetics
will be immensely different.
DR. SANTANA: Dr.
Finklestein?
DR. FINKLESTEIN:
Victor, I would like to hear from the pharmacologists. Although I mentioned obesity in terms of
steroids, I would like to hear about whether they consider obesity as a challenge
in terms of all our other oncologic drugs and whether that should be considered
in the mix because we are well aware in pediatrics, obesity is a problem.
DR. STEWART: Victor?
DR. SANTANA: Yes?
DR. STEWART: I would
certainly like to echo that that is especially a problem considering, I guess,
some of the more recent reports that the adolescent population of the United
States is starting to become more obese.
Yeah; I would definitely think that is a population we would consider.
DR. SANTANA: Peter?
DR. ADAMSON: I would
echo that. I think it has some very
practical implications because, on a day-to-day basis, we actually don't know
how to dose the obese child. Do you do
ideal body weight? Do you do actual body
weight? It is a variable we are probably
not tracking particularly well.
I think, as this discussion could probably go on for a
while, we are going to uncover more and more of what we don't know. As far as drug interactions are concerned, I
think the drug interactions of the cytotoxics--between cytotoxics--are the tip
of the iceberg because what we don't ever consider are the antiemetics that we
administer routinely with these cytotoxics.
That is probably having as likely an impact on their
disposition as any of the other cytotoxics.
We use corticosteroids almost with impunity not thinking about what
impact it would have on efficacy. What
struck me recently is aprepitant, a new antiemetic. In the label, it is specifically talking
about CYP 3A4, CYP 3A4, 5, and drug interactions and data on specific drug
interactions which is remarkable data for the label but what it really
highlights is all the antiemetics--I mean, people, I think, are going to avoid
that in certain situations but we shouldn't take comfort that using other
antiemetics are, in fact, safer because we simply don't know the interactions
that are taking place.
So, understanding drug interactions has to be a major
component of any study we do and it is not just limited to other cytotoxics,
something that we don't have any control over right now as far as gathering
data. It is probably as much so the
supportive-care medications that are administered concomitantly with the
cytotoxics.
DR. SANTANA: Any
other comments on this particular question?
Okay, let's go on and move to the second question. Are there any comments, and I am sure there
will be, on the proposed selection as discussed by the National Cancer
Institute on the drugs actinomycin D and vincristine as priority choices and others
to follow?
DR. HIRSCHFELD: May I
just clarify the question here. The
limitations are essentially resource limitations. So what this committee will do is make some
recommendations or endorse some recommendations. Those will be carried forward into a master
list for all of pediatrics.
What we anticipate is that, within that master list of
prioritization, there will be some slots available for oncology-related
drugs. But we don't have any assurance
if and how many of the recommendations would go into the master list. So we are going to operate on the assumption
that we will have at least one, and potentially two, in there and the
limitation, as Dr. Mattison pointed out, is the current-year funding.
But it doesn't mean that, in some subsequent framework,
other drugs could also be part of the general mechanism.
DR. SANTANA: Steve,
and the people from NIH maybe can help me, what is envisioned in the process if
there are twenty drugs, let's propose, that ultimately make it to the list and
there are only enough funds to study three?
What happens to the other seventeen?
Do they come up again for review in a year when more money comes
up? Do we have to reprioritize
those? Is there an allocation system of
how we go down the line? Can you clarify
that for us?
DR. MATTISON: The
way that we have currently been operating, once a drug gets on the list, it is
then available to us for exploring in a variety of ways including preclinical
evaluations, clinical trials and so on.
We have tried to keep the list small so that we can operate
in a reasonable way with the FDA in terms of looking at once a drug is listed,
what needs to be done in terms of filling data gaps to make that drug more
appropriately useful in pediatric populations.
During that discussion phase, we sometimes discover
information that puts a drug on a somewhat slower track for clinical
trials. We may not be able to agree on
what the endpoints for the trials should be.
We may not agree on how the studies ought to be conducted. And so we need to bring in other folks to
look at the drugs and help us think through the strategy for studying them.
If we are not able to get to a drug in a given year, we
will continue to look at that drug until the data suggest that there is no
further need for information about that drug.
So, yeah; they will continue to be on a waiting list. We may get additional funds across the course
of a year that we hadn't anticipated at the beginning of the year which would
allow us to pop a drug into a study.
We may be able to negotiate with an institute like the
Cancer Institute in terms of some sort of collaborative activity to study the
drug. So all of the above, I guess, is
the answer to that question.
DR. SANTANA:
Malcolm, can you clarify for me a process issue? How do you envision--for the purpose of
discussion, we say vincristine is the drug that we are going to push. How do you envision that in the current
clinical research protocol scenario how you will get to the point of making
sure that that drug gets studied the way we are recommending that it be
studied?
There are going to be some process issues, some maybe
regulatory issues. Have you thought that
through, how that mechanism is going to help us get to where we want and what
barriers we could be finding down the road?
DR. SMITH: I think the
process issue goes, and probably Anne could address that, should address that,
as well--the process would be an agreement that this drug should be
prioritized, then the FDA's written request, NIH, NICHD preparing the RFP and
then a response to the RFP. So there
would be those steps along the way.
I think, in advising NICHD, we would want to make sure that
the RFP that was being prepared was consistent with the priorities of the
experts in childhood cancer in terms of the clinical trials that they are doing
through the COG and would really make the greatest contribution for our
understanding of the drug selected.
But the process does go through the RFP and then,
presumably, the Children's Oncology Group responding to that with a
proposal. So there are multiple steps
along the way to make sure we get it right.
DR. SANTANA: Can I
clarify that? You are not excluding
other groups like, for example if the Brain Tumor Consortium wanted to
participate in one of these RFAs or two or three major institutions wanted to
respond. How do you envision that?
DR. SMITH: I think
it depends on the scope of the RFP. If
we want to do the population PK study, if that really is the intent, and
particularly if we are interested in young children receiving, or infants receiving,
vincristine, it has got to be nationwide.
Really, the only feasible way to do a study like that, if that is the
study that needs to be done, is to build up on the nationwide clinical-trials
mechanism, so I think the extent to which any RFP might be directed or not
would really depend on the focus of the RFP.
DR. SANTANA: Jerry?
DR. FINKLESTEIN:
While I recognize the interest in actinomycin D and vincristine and, I
guess, as a user for over forty years, it would be kind of fun to know a little
bit more about them. On the other hand,
actinomycin D has a very limited use in pediatric oncology today.
I think we understand a fair amount of vincristine in terms
of the immediate toxicity. One of the
drugs that was mentioned both by Greg, by our Chair and by other people, which
I consider quite frightening as a user, is cisplatinum. If this question is asking us to prioritize
or at least to give a view and what we would think should be really number one
on the list, with due respect, Malcolm, I really think cisplatinum, which is
used in just about in every child who has a brain tumor--the second most common
cancer in pediatrics are brain tumors--is used in our patients who have bone
tumors and a whole host of other diseases.
Considering we know very little about cisplatinum, I wonder
if this committee and, perhaps, other individuals would comment on whether the
prioritization should be looked at in terms of cisplatinum as our number-one
choice.
DR. ADAMSON: I am
going to have first a response to Jerry.
I think cisplatin is certainly on the list. It would be important to actually look at the
patient numbers, I think, because I don't know where it would rank as far as
utilization relative to vincristine and actinomycin. I think that is a number we can get, we can
look at, but I don't know that.
As far as doing pharmacokinetic studies of cisplatin, I
think we need to carefully look at the literature to see what the likelihood
that that is going to potentially sort out the issue because there is free
platinum pharmacokinetics which are very brief duration and whether we are
going to actually be able to sort out, even if we do it, based on that, I am
not certain.
But there may well be, and we have to look--there may be
other questions we ought to be asking that can say what is the risk, what are
the risk factors, for toxicities, what should we be looking at. It may be that plasma pharmacokinetics there
has much less of a role, potential role, than others.
But I agree, as far as when it comes to dosing, what makes
pediatric oncologists more nervous, cisplatin is probably at the top of the
list when it comes to the concerns that you have as far as long-term toxicity.
I did actually have a question, if I can remember it now,
on the process. So the paradigm that we
currently have in place with the coordinating center and proposals, I am
assuming that that is not the only paradigm and, for cancer drugs, in fact, may
not be the paradigm you would utilize.
In other words, a separate coordinating center, if you are going to be
doing studies on the backbone of an ongoing phase III trial, would not seem to
be sort of a good use of resources. Am I
correct in that assumption?
DR. ZAJICEK: I think
that is correct. Again, we haven't
talked about the nuts and bolts but it makes intuitive sense that if the NCI
has their own coordinating center, that we wouldn't want to be reinventing the
wheel here by having them report to another coordinating center.
DR. MATTISON: We
have had a series of discussions with several of the institutes that have
fairly extensive networks of clinical-trial studies and we are working out the
mechanism by which we preclude duplication of effort and look at ways of
developing efficiency in implementing and conducting these trials.
DR. ADAMSON: My
other question I should know the answer to but when you are up to capacity, how
many studies do you envision launching every year? Is it two to three? Is it five to ten?
DR. MATTISON: We are
looking at probably something in the range of six to eight a year, maybe more
initially. The issue is going to be
staffing and the ability to continue to provide oversight to these tracking
adverse events, dealing with the reporting requirements. So something like that, given the appropriate
level of resources is what we would hope to achieve.
DR. ADAMSON: The
appropriation, though, is then set aside--when you say you are going to do the
study, that year's appropriation is set aside to complete that study or--
DR. MATTISON: We can
use either mechanism. We can fund for
actual costs or we can fund into the future through the completion of the
study. Obviously, the first mechanism
allows us to get more studies going and then potentially provides some leverage
for our colleagues in Congress or for you to use.
DR. SANTANA: Dr.
Boyett?
DR. BOYETT:
Actually, I have two comments.
First off, cisplatin, I definitely would move above actinomycin D,
perhaps certainly not above vincristine.
But it is an important drug in medulloblastoma and it is use is limited
due to toxicity and maybe it is not because of the PK and maybe there are
problems with studying it, but I haven't heard discussions about those
technical difficulties with the other drugs.
Maybe they exist. Maybe they
don't exist. But I certainly think it
should be considered.
The second has to do with the process. Obviously, if you are studying vincristine,
COG--if you want to extrapolate to the population of children in the U.S. is
the U.S., COG is the appropriate research tool to target. But then when you also say that you are going
to make sure that--you are going to try not to duplicate effort with the coordinating centers, et cetera, you are
really sole-sourcing and limiting, I think, your opportunity to be successful
in your endeavors.
Maybe that is what you want to accomplish, but I think that
you have to look at the efficiency of existing systems and things and how they
might serve your needs for the future.
DR. MATTISON:
Agreed.
DR. STEWART: I would
just like to make a comment in regards to selection of the drugs. It is very difficult when you have a list of
drugs to make a decision. Cisplatin, to
speak to that in terms of it is a very important drug, a very important
compound, for pediatric oncology.
Obviously, it is used very extensively.
However, I can speak very directly to the pharmacokinetics
of it and the methodological considerations.
It is a very difficult compound to measure. There are a number of studies that are
published with cisplatin in pediatrics.
I am not sure that that is exactly the compound we need to be going
after.
What I think you need to think about is what Jeff said a
little bit earlier this morning and that is, when you want to think about what
compound to study, you think about compounds that have--when you start losing
efficacy or a compound starts demonstrating toxicity. That is exactly what happened with
dactinomycin. It started demonstrating
toxicity in a very young population.
That was sort of the stimulus for us to have the meeting
that we had in May that Malcolm was talking about a little bit earlier and what
causes us to want to look into why is it that these kids are getting
toxic. That sort of was the prompting
that led us down that path and what caused us to want to propose to look at dactinomycin
and subsequently vincristine.
So I would strongly urge the panel to consider studying
those two compounds. They are two very
important compounds in pediatric oncology and I think these are two compounds
we need to be looking at.
DR. SANTANA: From a
personal point of view, as an investigator, I would support those two drugs if
somehow we could get both of them funded because I think these--like somebody
mentioned earlier, the concern with both of these drugs, particularly in the
younger population, they may have some interactive effects. It may not be the actinomycin. It may be the vincristine that they can't
handle very well.
So this is an ideal pair of drugs to study if one is
trying, for example, to address this issue of toxicity in the young age
group. But I think separating them and
competing one and the other is one comes first and the other one comes
second. If there are not enough funds,
then we may not be able to get the real answer to at least one of the problems
which is the issue of toxicity in the very young.
I think somebody over there was shaking their head.
DR. ADAMSON: This
may be a situation where we really have to think out of the box because I think
we can potentially do a single study with vincristine/actinomycin as a single
study because actinomycin is always administered with vincristine.
As a single study--I mean, we should be able to figure out
from the same specimens what is going on.
Vincristine is used beyond that and so we have to it take into account,
and it gives us an opportunity to look for an interaction because there is
clearly a population that gets vincristine that does not get actinomycin.
But, in this case, we may be arguing over something we
shouldn't be arguing because I think, if you are going to study one, you can
almost, at the same time, study them both.
So the discussion, perhaps, should be can we prioritize the combination
vincristine/actino and cisplatin. I mean,
I don't know if I would try to separate them out simply because we don't admit--except
for one dose on one protocol, actinomycin--I think that is right--is always
given with vincristine.
DR. HIRSCHFELD:
Although it wasn't specifically mentioned in your excellent summary of
factors for prioritizing and for consideration, being practical and for the
success of the program, I think feasibility is also a consideration. I would just want to, without reflecting any
biases, state that if assays exist for one drug over another, or if conditions
exist to favor the study of one drug over another, in order to establish the
credibility of the program, that could be a consideration.
DR. SANTANA: I
agree. Malcolm?
DR. SMITH: I was
going to make the same point that Peter did.
If, in fact, the pharmacologists think it would be feasible to, since
they are always used together, to do both of those together, that would be a
great use of resources in terms of kind of minimizing the burden all around.
One question that I would have, and I take the points about
cisplatin, we haven't discussed the anthracyclines, particularly in the younger
population. If there is any sentiment
that we should look at the effect--at something about the anthracyclines,
particularly in the youngest population.
DR. SANTANA: Any
other comments on that issue of anthracyclines?
Peter?
DR. ADAMSON: I think
the other population gets back to Jerry.
Anthracyclines in the obese, I think, are a real big question of what to
do. There is some data from the adult
literature as far as changes in drug disposition in the obese, but it is really
an unstudied area.
DR. SANTANA: Dr.
Mattison?
DR. MATTISON: Could
I ask for comments on another issue that came up earlier which is how should
supportive care be prioritized against the active agents? Should we focus to any extent on some of the
other therapeutic modalities that are used in this population? Should it be given higher or lower
priority? Can you help us think through
a little bit about how to deal with that issue?
DR. SANTANA: I think
one of the problems in dealing with that, I have to admit that, for example,
when it comes to supportive care issues of antiemetics, the practice is not as
structured and is not as adhered to as what we do with the oncology drugs.
So, even in my own institution, there are 50 different ways
in which you can give steroids and ondansetron and Ativan and everybody has
their own little recipe. So the problem
with, for example, the antiemetic supportive-care issue in how to use this
mechanism to do this is that I think we lack the rigor currently, in the
current protocol structure that we have, to be able to approach that
successfully early on in this process.
So, when I look at supportive-care issues in contrast to
oncology drugs, I think we are a little bit ahead in oncology drugs of having a
successful outcome with this initiative than we will be with, for example,
antiemetics. That is just my general
comment because the structure is just not as tight there.
If what we are looking is to advance the public-health
needs, the structure already exists for the oncology drugs and we may be able
to have some success after a few years.
I think the others should be done but, in terms of priority, I don't
think, right now, we have all that structure in place to be able to do it
effectively.
That is my own bias.
Peter?
DR. ADAMSON: I think
if you were to tell us realistically, keep your list to three, there wouldn't
be an antiemetic on that list. I think,
having said that, we should look, in the broader pediatric population where
antiemetics are used for post-operative nausea and vomiting and, if we can
impact on the priority of what antiemetics are going to be studied in the
broader pediatric population, then I think it would make sense to say, well,
which of these are being utilized more heavily in the oncology population.
But I would be interested if anyone thinks, if we had a
list of n equals 3, that we would have an antiemetic as one of those three.
DR. SANTANA: Alice?
MS. ETTINGER: But if
we were going to take a combination of vincristine and actinomycin or a
platinum, we could build in a structured antiemetic regimen at that same
time. I mean, just as combining it as
well.
DR. SANTANA: My
comment, Alice, was primarily because I heard Malcolm very astutely say that
there already exists a clinical trial--there already are clinical trials in
which some of these questions can be "plugged in" without having to
reinvent the wheel. So I was just
responding from a strategy point of view that the advantage of some of these
oncology drugs that we are discussing is that you could plug in the questions
relatively easy.
I still will have to be convinced but the structure already
exists that we may be able to do that more efficiently rather than having to
design another new trial that will address these questions separately. I think the more drugs you add, the more
complicated it gets.
But I do like the comment that Peter made. I think the group at the NIH obviously, in
terms of supportive-care drugs, supportive-care drugs are used across different
diseases in pediatrics. It is not only
unique to oncology.
So if you guys get a sense that there is an interest from
anesthesiologists in studying antiemetic in
radiation therapists or use antiemetics, then one of those drugs
potentially may make it to the top ten where there may be some funds to
study. Then, certainly, we would find a
way to plug it into our systems because I think it would be appropriate.
MS. HOFFMAN: Adding
onto that, Congress just mandated money through the M.D. Care Act for Muscular
Dystrophy. Their main drug is
prednisone. So it might be through NINDS
or NIMS because they are actually just meeting about clinical trials and they
don't have official clinical trials going.
But it would be different. It is
a male population. It is three and
up. But it might be a good way to get
prednisone with that as well.
DR. MATTISON:
Yes. One of our colleagues in
NICHD is responsible for that area and we have already begun a discussion with
them about the potential of looking in that area.
DR. SANTANA: Dr.
Roberts?
DR. ROBERTS: I would
like to go back to Peter's comment about studying actinomycin and vincristine
together because they are used together.
From a regulatory perspective, we would really have to think outside the
box to figure out how to do this process.
That doesn't mean it can't be done. But the written request is issued to the
application holders of the approved products.
That would be if there is any innovator left for vincristine and to any
generic houses that have vincristine for a vincristine written request. For actinomycin, it would be for the
application holders of those approved products.
So you could--and I am thinking off the top of my head
because we haven't had this, but it is a significant problem when you do a
combination. If we, in conjunction with
our colleagues at NCI-NICHD, and the Division of Oncology, could come up with a
set of studies that would address how to label both of these products when used
in combination, then you would issue the same written request to each of the
sponsors.
But there would have to be ways to get information to
ultimately label those individual products because that is what the goal
is. So, throwing into the mix in the
vincristine/actinomycin studies to study them in combination and now trying to
study some antiemetics at the same time, there is just no way. It just logistically and from a regulatory
point of view couldn't be done.
DR. ADAMSON: Just to
clarify what I am thinking as far as antiemetics, I think you have to include
antiemetics as a covariate. It is not
something that I would say you could study in the context of a single
study. As far as the combination, this
is a question for you, then. The written
request, when it goes to industry, my guess is there won't be a stampede to
respond for these two drugs.
Can the written request, when it then comes to the NIH, be
different?
DR. ROBERTS:
No. The written request that is
issued to industry has to be identical to what we send to the NIH. Now, the reason is that industry, the
industry that owns that product and owns the label, is going to look at that
written request and they are going to look at the studies that are involved and
say, as you have predicted--probably, they will say they aren't going to do
them.
But at least they have received an outline of what those
studies are. Once those studies are done
under a contract and come back, if those studies don't look at all like what we
asked industry to do, that is a real problem for us because we are going to ask
them to put that information in the label and now they may have studies that
they never even had a chance to say they didn't want to do them.
So it is going to be problematic for us to get them to put
that information into their label.
DR. SANTANA: I think
Richard has a comment related to that.
DR. PAZDUR: Couldn't
you have the two studies independently going out to each of the sponsors. When they come back to the NIH, could you
then combine them together?
DR. ROBERTS: Well,
what I was proposing--
DR. PAZDUR: If they
are identical studies but you putting together.
DR. ROBERTS: If they
are being studied together then I would assume that the group of studies would
be identical. So the vincristine
manufacturers would get X written request and the actinomycin manufacturers
would get the same X written request.
So, in essence, when they all turn it down, we will be sending a single
written request to NIH.
DR. HIRSCHFELD: Just
a point of information. I am positive
there is only one source for actinomycin D and I believe there is only one
source for vincristine, just as a point of information.
DR. SANTANA: NIH, I
think, had their hands up over there, generically.
DR. MATTISON: Yeah;
we have generic hands.
DR. SANTANA: Since
we are talking off-patent; right?
DR. MATTISON: We
have had a series of discussions with our colleagues at the FDA about this and
we are still working through some of the interpretation of the law. But, Rosemary, it was my understanding that,
after the written request was refused, we essentially become the sponsor and we
can negotiate with you the studies that ultimately get performed. That was the agreement that we had at the
retreat, at least.
DR. ROBERTS: I would
say that this is not the forum for us to get into that. I think that we have had some
difference--basically, the law indicates that the contract is to contain the
elements of the written request. So I
don't see how there can be negotiations of any significance since that is what
the law says. I think that is what we
discussed at the retreat.
DR. SANTANA:
Malcolm, are you going to respond to that? If not, Jim has been having his hand up.
DR. SMITH: I was
going to respond to that. I don't know
what the law is but I think it is, perhaps, a moot point because, if there are
two requests, if there is one request that says, we want you to study
dactinomycin. Here is what we want you
to do. That's fine. And there is another request, we want you to
study vincristine and here is what we want you to do. That's fine.
That request goes out.
The fact is, the way it is functionally implemented, at the end user,
can be one protocol that is going to study both of those, the same patients,
one informed consent and so on. So, the
request can still be as two. When the
study actually done, the same patients are participating. The same samples are being used to test both.
The response back can give you the dactinomycin data. The data that you get can give you the
vincristine data. I think we can work it
out. The pragmatic issue that I was
worried about earlier was whether you could do it, the same patients could be
used for both drugs, if that can be addressed, and I think there is some way
that we can find a way to make the RFP process work.
DR. ROBERTS: I think
the key factor is the fact that FDA and NIH and the appropriate NCI and the
people that are vested in these studies are going to work on that written
request together to make sure that it contains appropriate information to label
these products for us in this group of patients.
So, hopefully, Don, we have worked out that before we issue
that written request to industry because, again, we can't change that written
request because industry needs to look at it and to know what they are denying doing.
DR. SANTANA: Dr.
Boyett? You withdraw your question? Any further comments. Let me see if I can summarize. Yes; I'm sorry.
DR. REYNOLDS: Just
to address what Malcolm said, I think, of the practical natures that needs to
be considered in this, since you are targeting, studying very young children,
is the amount of blood you can obtain which IRBs will limit. It may not be possible if the blood
requirements for particular assays are such to do both in the same
patient. So that has got to factor into
this as well.
DR. SANTANA: Yes; I
think that fits into the comment that Steve made about feasibility. I think he was talking about feasibility of
assays but I think feasibility is much broader in terms of making sure that you
have the right patients, the right amount of blood, all these other feasibility
issues hopefully have to be considered in the prioritization of the drugs
because it may be that if you are using an assay that requires a lot more
sample, that it may not be feasible to do it in a 2-week-old or a 1-month-old.
So I think those issues, also, to me, encompass feasibility
in terms of prioritization. Yes?
DR. FINKLESTEIN: I
have a question for the FDA. Since most
of the drugs we use in pediatrics are in combination, does that mean, and this
has undoubtedly been discussed at other meetings but, perhaps, we could use a
refresher or I can. Does that mean that
labeling the drugs as drugs that are used in combination is something that you
really can't do?
DR. SANTANA: And,
kind of as a corollary to that because I have been thinking about this, so when
a brand-new entity, a brand-new drug, is approved, I am thinking of when I used
to participate in the adult committee, anthracycline X is approved for the
treatment of metastatic Y in the context of this regimen. Isn't that how it is approved? The drugs are not approved uniquely just
sitting by themselves. They are usually
approved in the context of a number of trials that have other drugs in them.
So why is this different?
DR. HIRSCHFELD: Rick
might want to comment further but we have addressed this, as Jerry pointed out
before, and it is the labeling reflects what the data support. If the data support its use in combination,
and we have some very concrete examples of recent approvals, if I could mention
a product, oxaliplatin was approved in combination with 5-fluorouridine and not
as a single agent.
In fact, in that specific case, the single-agent data would
not have supported an approved indication.
So this is rather common.
Rick, did you want to add?
DR. PAZDUR: I think
that is a good example. So, if the drug
is studied in a combination, the label for the product that is being
investigated will be labeled with that drug that is was being studied. Now, that doesn't necessarily mean, for
example, the 5-FU label was updated to reflect its use with oxaliplatin
because, in order for that to happen, you must isolate that you definitely need
that 5-FU and that brings us into study design here if there was a single-agent
5-FU arm, et cetera.
DR. SANTANA: Yes; I
think in the context we are talking about is a strategy to study both of these
drugs and then get information for a change for both labels in the context of
using them in combination. Good.
Any other comments on Question 2 before I try to
summarize? So I sense that there was
some support from the committee in terms of prioritization of vincristine and
actinomycin D because of some of the issues that were discussed before by
Malcolm and others. But, in the context,
if they could be prioritized equally, if the opportunity exists to do that in a
reasonable study design, so that we could get two bangs for the same buck.
I got a sense that the committee was supportive of these
drugs but far more supportive if there was a strategy in which we could study
them together and that probably could move us up in the last of drugs that
could be studied.
Then I heard some discussion about cisplatinum. I didn't put my two-cents worth, but I guess
it will come up with Question 2. We might
as well open Question 3 which is, what are other drugs that could be studied
and what would be the rationale.
I think we have talked about some variables that could be
considered in prioritization and we really--at least I didn't come prepared to
discuss cisplatinum in detail but I think there were some things about
cisplatin that were mentioned that are relevant in terms of the populations at
risk in which the drug is going to be used.
End-organ toxicity is a major issue with cisplatinum.
Feasibility is a question of cisplatinum in terms of the
assays and how pharmacokinetics predicts toxicity and/or efficacy. So, to me, cisplatinum, in response to
Question 3, would be a drug that I think needs to go through the same rigorous
process that you guys have already done for actinomycin vincristine and also,
hopefully, come to the conclusion that it is a drug that should be moved up in
the priority list.
Peter?
DR. ADAMSON:
Actually, I was going to ask Steve to clarify. When I read Question 3, I thought--my
interpretation was are you talking about agents other than anti-cancer agents
that should be studied in the population.
DR. SANTANA: Oh; was
that the gist of that question?
DR. ADAMSON: Because
I sort of thought we would agree that cisplatin would be high on the list if it
were feasible. That was my sense.
DR. SANTANA: Let's
clarify. Question 3 relates to this list
of other off-patent drugs; right, oncology off-patent drugs?
DR. HIRSCHFELD:
Right. Specifically, the
oncology.
DR. SANTANA: Yes?
DR. ZAJICEK: We have
an interest in that answer, too, though.
If there are any other classes of drugs that you think should be
studied, we would be very interested in discussing those.
DR. SANTANA: We can
discuss it as a corollary to that question if people want to advise. Dr. Reynolds?
DR. REYNOLDS: I
would add 13-cis-retinoic acid which is used as standard-of-care therapy for
neuroblastoma and is not off-patent to that list as a nononcologic but it is
used as an antineoplastic.
DR. SANTANA: I would
support that but I want to make sure that we use the same model for all drugs,
that we go through the exercise of asking the question, the population numbers,
the usage numbers, the populations in which it is at risk, the issue of
toxicity. I want to make sure of that.
I would agree with you, it is an important drug to study
and, because of my own bias for that drug, I want it studied. But I want to make sure that we apply the
same rigor to whatever drugs we advise that should be on the priority list.
So could you respond to that in retinoic acid?
DR. REYNOLDS:
Yes. I mean issues of population,
it is really restricted in pediatric oncology to high-risk neuroblastoma. So we are talking within the U.S,, what,
approximately 200 patients a year would be getting the drug.
As far as toxicity, there hasn't been a whole lot of
toxicities that one can point to with this that would be life-threatening. Within our phase III study, we did have some
uremic syndrome that may have been attributed to the drug in small numbers of
patients.
But I think that it is an understudied drug in terms of the
variability in terms of the metabolism and, in particular, in terms of the
bioavailability. It is a suboptimal
formulation especially for young children.
So there is a great potential with this drug for there being underdosing
and subtherapeutic dosing going on in a substantial number of patients.
Because, in a phase III randomized study, as a single
agent, it is shown to contribute significantly to event-free survival in
high-risk neuroblastoma. Then there are
opportunities, if one could avoid underdosing those patients, to improve
outcome.
DR. SANTANA: Pat,
how do you respond to one of the concepts that was circulated earlier that one
of the criteria for making it to the list would be a drug in which we have some
evidence that we may be losing efficacy because of increased toxicity. How would you respond to that in the context
of the retinoids?
DR. REYNOLDS: In the
context, at least of 13-cis-retinoic acid, I would say that I don't know that
we have evidence that toxicity is causing loss of efficacy. I think that we have some evidence
accumulating that lack of appropriate dosing might be potentially leading to
subtherapeutic levels. But I would have
to say that we don't have the evidence on toxicity.
I would say that there may be that evidence for
transretinoic acid in the setting of APL.
But I would defer to Peter and Malcolm to comment on whether they think
that is the case.
DR. SANTANA: Dr.
Stewart.
DR. STEWART: I guess
maybe I should ask this question of Dr. Hirschfeld, but in some part, Peter and
Malcolm have come with their homework prepared in terms of numbers and what
not. I am just wondering, is it possible
that there be a committee or a subcommittee or some more formal mechanism by
which this homework could be done to select other drugs, I guess is what I am
trying to ask, so that these numbers and the detail that you are trying to get
could be obtained.
DR. SANTANA: I guess
what you are asking is now that we have advised the FDA and, indirectly, the
NIH in this forum of what criteria we would want for you guys to weigh on in
the prioritization, who, now, does the homework to go out there and do this for
this list of drugs. Is that what you are
asking?
DR. HIRSCHFELD: It
is done collaboratively between the FDA and, within the FDA, the Oncology Drug
Division and the Division of Pediatric Drug Development and with other
colleagues including the clinical pharmacologists and pharm-tox colleagues.
It is done in collaboration with colleagues in the NICHD
and in the other relevant NIH institutes which, in this case, is the NCI. So the short answer is we don't have to
appoint a new working group. We have a
process in place but, because of limited time in our own sense, based on the
meeting that you helped organize, we got a starting point.
So we took the discussion from the meeting earlier this
year as a basis to proceed and we are taking now the discussion that would
occur today as further basis to proceed.
In that process, we are not shy about asking for help or outside
consultation. We both formally and
informally request consultation in this area.
DR. SANTANA: Rich,
did you have a comment?
DR. PAZDUR: That is
the point that I would like to make is just follow up from Steve. We could easily, instead of having a
subcommittee, have external consultants before we make a decision. Whenever we make a decision, if we don't take
it to ODAC, et cetera, generally we have always asked ODAC members or other
consultants about NDA approvals, other details that we do. So a lot of that is behind the scenes but,
nevertheless, has external input.
DR. SANTANA: Will
this committee have an opportunity in the next year or two years from now to
revisit this list? I was trying to get
at that a little bit earlier in terms of process.
DR. PAZDUR: Yes.
DR. SANTANA: I
didn't hear that clearly.
DR. PAZDUR: Yes.
DR. SANTANA: How is
this going to a dynamic process?
DR. MATTISON: We are
required to produce a prioritized list and publish it at least once a year on
the anniversary of the Act. This year,
we actually published two lists and, from those two lists of drugs, have
identified ten, one on-patent and nine off-patent, studies that are in the
process of being developed for implementation.
We will continue this discussion around the listing
process. We are actually transitioning
the leadership of the listing process within NICHD to a new individual who is
going to put the process in a two-year cycle.
So there will be multiple opportunities including public comment periods
to provide input from a variety of perspectives on the listing process itself.
In addition, after we get recommendations from groups like
this, we ultimately will develop a list, as Anne said, of about 20-some drugs,
20 to 30, perhaps more, that will be reviewed again by external consultants to
NICHD. Prior to those reviews, we
actually create fairly detailed literature reviews of the drugs to help the
external consultants understand issues like you have described; frequency of
use, concerns about efficacy, a more detailed description of gaps in knowledge
about dosing and safety to help us think through ultimately what will go into,
as Rosemary indicated, the dialogue around the development of the written
request.
DR. ADAMSON: Just a
comment on Pat's suggestion and to follow up on your comments, Victor, as
interested as I am in the retinoids and wanting to know everything that Pat has
mentioned, I actually don't think Accutane belongs on the list when we compare
it relative to some of the other drugs right now.
It has a therapeutic index that is quite different from
cytotoxic agents with toxicities that are usually readily reversible with
discontinuation. As far as underdosing,
it is an open question. We don't
know. I agree it is a question but there
are many drugs where we know that there is a dose-intensity-response
relationship or potentially an exposure-response relationship. The anthracyclines fall into that class.
I would agree with what Greg put in his letter. The anthracyclines and alkylators that I
think would be at the next level of what we ought to understand,
cyclophosphamide, Iphosphamide, doxorubicin, daunorubicin. I think we have a lot to learn there and we
do have varying degrees of data, certainly as far as toxicity, as well as
potentially as far as impact on efficacy with undertreatment.
DR. SANTANA: Another
way to get around the issue of retinoids in terms of oncology is that retinoids
are used in other patient populations that are also pediatric within our
oncology patients.
DR. ADAMSON: But not
the age group we are talking about.
DR. SANTANA: No; I
am saying. But they are used in
teenagers and so on and so forth so one could potentially, if one wanted to
push the retinoids, there may be other disease categories that potentially
could help us make it to the list and at the same time do oncology.
DR. MATTISON: We
have to build it into Roche's care program in terms of the use of these
drugs. In individuals of reproductive age, it
represents a set of concerns that we would have to deal with. I really appreciate the discussion. I think it is very helpful. But we would have to think about how we would
structure that.
DR. SANTANA: For the
record, I want to point out that I did not mention a particular sponsor. I used retinoids generically.
DR. BLUMER: I just
wanted to echo what Peter said, not in terms of the retinoids but in terms of
the other groups. We have talked about
anthracyclines. I think that the
aklylating agents and, in particular, Iphosphamide as opposed to
cyclophosphamide because you do seem to have a unique predilection to
nephrotoxicity in younger kids which is something that we don't see that often
so that that may make it something to focus on.
DR. SANTANA: Any
other further advice on other drugs, Malcolm, before I open up a new question?
DR. SMITH: Another
question?
DR. SANTANA: Yes; we
have another question.
DR. SMITH: Oh,
okay. Just for the record, another drug
that is of interest is 6-thioguanine. It
is the drug--we have one study now that suggests it may actually be beneficial
in childhood ALL. But that study also
found unexpected very serious toxicity in a small minority of patients. So I think one of the things that the ALL
committee is considering is can one figure out ways to potentially take
advantage of an increased efficacy profile while minimizing the risk. Again, it is liver damage.
So it is another agent that, probably not this time, but is
an agent that is off-patent for which there is active interest in one of the
COG disease committees.
DR. SANTANA:
Richard?
DR. PAZDUR: I just
wanted to affirm that this will be an ongoing discussion with this
committee. This is not a one-time event
and I think that this is an excellent use of this committee to get your advice
on specific drugs and probably one of the major intents of it.
DR. SANTANA:
Good. So I think we have given
you some advice on Question 3 without having to repeat all the drugs. We have kind of talked around the table.
During the discussion this morning, the issue of population
PK was discussed to some degree. Dr.
Przepiorka approached me and said, we really need to discuss this in the
context of a question. So I will give
her the microphone and maybe she can express her thoughts of maybe how the
committee could further advise the FDA on this particular issue.
DR. HIRSCHFELD: I
will just state that we would appreciate any input on designs as well as
identification of products because the identification, while it is the first
step, the next step is how does one approach it. So we are grateful to receive any comments
related to study design.
DR. PRZEPIORKA:
Actually, the question that I had posed to Victor which he thought was a
good question and had an immediate answer for was are population PK studies an
appropriate mechanism for determining safe and effective dosing for pediatric
patients.
The immediate response that came to my mind was no because,
in my mind, it is an hypothesis-generating study rather than an
hypothesis-testing study and specifically for the reasons that Jim had brought
up, that it simply doesn't have enough power.
If I were to be looking at data from such a study to
determine whether or not it is adequate for labeling change, I would say, well,
maybe two studies or three studies or four studies would have enough power in
replication. But even if you had limited
power or accepted a higher error rate, it would still just be hypothesis-generating.
So, for the purposes of NIH funding, if I got this as a
transnational research grant to review, I would say, well, this is a really
nice, interesting, useful piece of information but it really won't change the
practice of medicine. It has to be
followed up with some small validation study to say what we learned in this big
population study is actually true when we study it prospectively.
But what concerned me more, and I haven't had an
opportunity to review the draft on the guidance for population PK studies, was
hearing that it was largely--what was the computer program? I am, over the past several years, becoming
more and more concerned about the amount of time it takes to get anything
studied nowadays or getting grants approved.
You have to keep going back in cycle after cycle.
Being a user of FDA guidance, I can tell you that, if it is
well written, it really gets used. So I
would hope that protocol design is considered as important as data analysis and
that the guidance should include something about protocol design.
Just in what we have been talking about this morning, we
talked about having, in the protocol design, the rationale for what is the
population, what is the disease, what is the dose method, what is the age. If it is a limited age population that we are
concerned about, why include all ages?
Why not a smaller study with just that age group. The genetics; that can be done
simultaneously.
Other chemotherapeutic regimens, other supportive care,
timing of sampling and what do you measure; plasma samples, a PD. What?
I think if the people who are going to be doing these studies either for
the FDA or maybe even this should be in the RFP knew exactly what people were
looking for when they are reviewing the protocols, it would help get protocols
through a little bit faster.
DR. HIRSCHFELD:
Thank you. I just would like to
comment, just to help frame the discussion, it is not uncommon for FDA written
requests to have staged studies. It is
rare that there is a single study in the FDA written requests. In fact, they are often one, two, three,
four, sometimes up to six studies that comprise--it is the package that is
designed to elicit appropriate information.
These studies, again depending on the circumstances, can be
either staged and there is a particular sequence and we are explicit in those
cases that Study 1 must be done before Study 2 and the design of Study 2
should be, in turn, based on the results of Study 1. So that is a model that has been used before
and may apply.
DR. SANTANA: Peter
and Clinton, do you want to comment on the population PK?
DR. ADAMSON: Yes; I
think I want to comment and I will yield to Jim on this. A population approach is not simply a
hypothesis-generating approach. I think,
at least the message I get from Jim and what I would agree with, you have to
sufficiently power the study to answer the question, but you can answer
questions, and this is a valid way to answer questions. They are not trivial studies to design.
We discussed this and we proposed this as a method that may
be a very realistic method to address the problem of dosing in infants and
young children. There is probably no
other realistic method to begin to understand drug disposition in infants and
young children when you think of the patient numbers, when you think of
blood-drawing requirements and when you think of the tremendous developmental
changes that occur during the period of zero to 12 months and then zero to 36
months.
You can't simply understand it at one point in time. You really have to study infants and young
children truly across an entire 36-month spectrum. A population method is probably a very
reasonable method if it is well designed and if it is sufficiently powered to
get answers and not simply generate hypotheses.
But, Jim, maybe you can expand on that.
DR. BOYETT:
Actually, I hope my comments didn't kill it because I think it is a
potentially useful tool. My only comment
was that it does require careful thought in designing the study. Where you have factors that you can control,
you should control those factors and that reduces the variability.
Given a particular situation, I could probably manufacture
an hypothesis that the design would be there to test. But I think we know what the end result is
that you would like to get out of it. So
I think it is. I just sort of thought
that it was a little bit--it is a much more complicated situation and there are
statistical scientists who devote their whole career to developing methodology
for nonlinear mixed modeling.
It is a hard problem but it is not an unsolvable
problem. There is methodology out
there. I was remarking that the one I
saw, I certainly thought was a little bit underpowered, or a lot underpowered.
DR. STEWART: I would
just comment that the use of NONMEM, or the nonlinear mixed effects modeling,
has been used extensively in the AIDS population especially in the neonatal
population to learn a lot from that population.
So I think that the use of population PK has been a real boon to that
particular area and especially to learning how to use those type drugs in that
population.
I think it is something that--one of the things that we
wanted to do during this particular symposium that we had was to try to learn
from that group of individuals and apply that particular approach in
oncology. So I think that we really want
to apply that but one of the things we have to be careful about is the things
that Jim brought up. We have to be very
careful about study design.
I think whenever Peter gave his presentation, he did a
really nice job of giving these provisos of population PK doesn't make bad data
good. I would certainly, you know, echo
that. The other point I was going to
make, and I really didn't want to say too much bad about it because I am
certainly a proponent of pop PK is that you can, if you are trying to come up
with these covariates to explain clearance, you can do it as long as you design
your study to collect the data for that covariate.
But if you don't design the study to collect that
covariate, you will never figure it out.
So you have to be very careful about what data you collect. So these studies have to be done right, and
they have to be well thought out prospectively going into it.
Peter has a lot of experience doing this. We have a lot of experience. So I think that the population PK approach
can be done and a lot of information about the disposition of drugs in these
children can be learned from it. But
that is only one part of it. That is the
point Jeff brought up and that is where we need to carry it the next step.
What do you do with the disposition data? What do you do with the information about the
disposition of the drug in the kids?
What does it really mean? What
does it mean to efficacy? What does it
mean to toxicity? I think that is the
step we have got to really think out very carefully, how are we going to use
that, how will we use that, information.
These are all things that we can do. You can do it in the context of a population
analysis.
DR. SANTANA: Dr.
Boyett?
DR. BOYETT: One
other comment. I think another appealing
thing to it is, and I will probably get run out on a rail when I say this by my
colleagues who have M.D.s--
DR. SANTANA: That
has happened in this committee before, Jim.
DR. BOYETT: But I
think what you have to have in defining doses is you have to have very simple
rules to follow. I think the
population-based approach would give you those types of rules on the
average. If you look like this, this is
the way you should get it. I don't think
we would ever get to where an individual patient walks in and we check the
color of their eyes and what day it is, et cetera, and we can tell you exactly
how to dose this individual.
I don't think there are too many physicians out there could
follow that. It has got to be very
simple rules. And I think it gives you
the opportunity to develop rules, I'll bet, within several subsets of
populations of patients you would see.
So that is another appealing thing to it, I think.
DR. SANTANA:
Richard?
DR. PAZDUR: Just perhaps,
in closing, if and when we get this data in, okay, this has to be the same
rigor and scientific validity that anything that goes in the product label goes
through as far as review and our scientific comfort that is a real and true
finding here because, obviously, folks, we are not in that much of a rush here
to relabel vincristine and actinomycin D that we would put things that we
didn't feel comfortable with.
You know, the principles that you are talking about,
adequate power of a study, adequate data collection, et cetera, are things that
we want from any study, basically So I
think we could basically have a whole session on population pharmacokinetics
here and argue the pluses and minuses of it.
But, to address Donna's comment, I think Steve also already
did it, if we really didn't feel comfortable that the magnitude of change that
we saw in these population pharmacokinetic studies or pop-PK studies warranted,
we could request other studies to look at it closer.
So I think that this isn't the end. It could be viewed as a start and, as with
everything in the FDA, we have a kind of blanket statement; it will be a review
issue when we get the data.
DR. SANTANA: Having
said that, if there are no other further comments. Dr. Reynolds?
DR. REYNOLDS: I just
wanted to say that I think we are missing one opportunity here, at least I
haven't heard it said, and I know it is beyond the scope probably of what is
envisioned from the funding of this which is to focus on PK, but a large
component of the effort here, as Malcolm was mentioning, national efforts with
large numbers of children are necessary to define this.
A large part of the effort will be actually going through
IRBs, getting studies open and securing the blood specimens from the patients
throughout the cooperative group. If we
are going to go to that effort, I would hope that we could, at the same time,
maybe ask questions related to pharmacodynamics, if there are any, and
pharmacogenetics especially if you can do it from the same sample where the
plasma goes to the PK and the cells go to the other.
So I would encourage that to be incorporated into this in
some fashion even if it is beyond the scope of the funding that is available.
DR. SANTANA: My
sense was, during the discussion this morning, that there was some thought to
that.
With those last comments, we will reconvene at
1 o'clock. I am advised by the
Secretary that there is a designated area downstairs in the restaurant, that we
could all sit and have lunch if you want to go eat lunch. If not, we will reconvene at 1 o'clock. Thank you so much for your discussion this
morning.
[Whereupon, at 12:05 p.m., the proceedings were recessed to
be resumed at 1 o'clock p.m.]
AFTERNOON SESSION
[1 o'clock p.m.]
DR. SANTANA: We will
go ahead and get started with the afternoon session.
As we are starting this new afternoon session, the issue
that will be discussed will be the age-appropriate formulation changes as it
relates to pediatric oncology setting.
As, is customary, we will start by introduction of all the members that
are here today.
So, if we could start with the people that are here. The gentleman sitting on my left. Please identify yourself by name and
relationship.
DR. SHAW: Walt Shaw,
Avanti Polar Lipids.
DR. FLANAGAN: Douglas
Flanagan, the University of Iowa.
DR. ZAJICEK: Anne
Zajicek, NCI--or, excuse me; NIH, NICHD.
Excuse me would you.
DR. SMITH: Malcolm
Smith, NCI.
DR. STEWART: Clinton
Stewart, St. Jude Children's Research Hospital.
DR. BLUMER: Jeff
Blumer, Case Western Reserve University.
DR. ADAMSON: Peter
Adamson, Children's Hospital, Philadelphia.
DR. REYNOLDS: Pat
Reynolds, Children's Hospital, Los Angeles.
MR. PEREZ: Tom
Perez, Executive Secretary to this meeting.
DR. SANTANA: Victor
Santana, practicing oncologist at St. Jude Children's Research Hospital.
DR. PRZEPIORKA:
Donna Przepiorka, University of Tennessee Cancer Institute.
MS. ETTINGER: Alice
Ettinger, St. Peters University Hospital.
DR. BOYETT: James
Boyett, St. Jude Children's Research Hospital.
DR. DINNDORF:
Patricia Dinndorf, FDA.
DR. LOSTRITO: Rik
Lostrito, FDA.
DR. HIRSCHFELD:
Steven Hirschfeld, FDA.
DR. PAZDUR: Richard
Pazdur, FDA.
DR. SANTANA: Thank
you. Do either Richard or Steve want to
have any introductory comments? If not,
we will go directly into the items.
Okay.
Open Public Hearing
DR. SANTANA: We have
an opportunity for an open public hearing session. If there is anybody in the audience that
wishes to address the committee, this is the opportunity to do so. If there are no takes on that, we will go
ahead and get started.
I think we will just go like we did this morning through
all the presentations and then we will have an opportunity for questions, and
then we will have the discussion of the item at hand.
So, Dr. Shaw.
Lym-X-Sorb
A Revolution in Oral Drug
Delivery
DR. SHAW: Thank you
for the opportunity to present our information here.
[Slide.]
What we are going to talk about is an oral drug-delivery
system that is lipid based.
[Slide.]
It is a lipid-base but it is non-liposomal. It is made of three components but, when you
mix the three components, it is monomeric.
It transports the active drug components through the intestinal villae
and into thoracic lymph. It is an
organized lipid matrix consisting of lysophosphatidylcholine, monoglyceride and
free fatty acids. These are the three
components of lipid digestion.
It is this analogue of the lipid digestion that makes this
unique because, once you have a drug in it, nothing in digestion can metabolize
any of these components so they are stable.
It has been used in a clinical trial in Montreal to deliver essential
fatty acids to cystic-fibrosis patients.
This was a two-year trial. The
outcome of that trial was that the patients gained weight, they grew taller and
they had better lung function.
[Slide.]
These components; this is the structure of the
components. You can see there is a
charged component to this. There is a
negative charge on the phosphate, a positive charge on the nitrogen. There is a hydroxy for hydrogen bonding. Then there is a hydrophobic agent so you can
have a charge-charge interaction, a hydrogen bonding and a Van der Waals
interaction with the drugs. With the
monoglycerides, you can have hydrogen bonding and the hydrophobic. The fatty acids, you have a charge-charge
potential and a hydrophobic.
These components make this eutectic monomeric structure in
the ratio of 1:4:2 to 1:3:3 and any ratio in between. So you can change the structure of this
monomeric component by changing the individual components.
[Slide.]
This is our representation of what goes on. We call this the glove. It is a lipid glove. The three components are the lyso PC, the
fatty acid and the monoglyceride. The
drug then would fit in this cavity. We
do know that all drugs that we have tested with this, you have 1 mole of the
complex with one mole of the drug. As
soon as you exceed 1 mole of the drug, you exceed the capacity and the drug
isn't taken up by the complex.
[Slide.]
This is a cartoon, although this is generated from a
computer model where we put the components--and the drug is in yellow. This is fenretinide in yellow--and we let the
computer come to the minimal energy.
This is what the computer told us this complex looks like. We have no confirmation of this with real
X-ray data. This is a cartoon.
The lipid glove, you can think of it as a first baseman's
mit during the playoff season. You can
pick your own team that this belongs to.
[Slide.]
The current liposome technology is that you have a
nonhydrated layer of lipids. They become
hydrated. They swell and they
spontaneously self-assemble to these multilamellar vesicles. You can put energy in the way of sonication
and make small unilamellar vesicles or you can extrude and make large
unilamellar vesicles.
This complex that we are working with fits into this scheme
at this stage where we have a solid anhydrous lipid mix. You can put it in water and it will
swell. Now, what it makes is not
described in this scheme. There is no internal
space. All these liposomes have internal
space and what we make has no internal space so it is similar to liposome
technology but different.
[Slide.]
The manufacture of this complex is made from
phosphatidylcholine in the presence of monoglyceride and fatty acid. The phosphatidylcholine is a soybean source
of phosphatidylcholine and it is represented in this beaker, large chunks of
phosphatidylcholine. You react that with
a phospholipase A2. This is a pancreatic
phospholipase A2 and we have maximized the conditions so that, in five to six
hours, this reaction is complete. You
will go from phosphatidylcholine to lysophosphatidylcholine, essentially 100
percent phosphatidylcholine.
The PLA2 does not react with the monoglyceride or fatty
acid. These are cofactors of the
reaction. What you get at that point is
an oil, after you have dried this mixture, pulled off the water of the reaction
for 18 to 24 hours. You get this
oil which is in the gel phase at room temperature.
This is what we call Lym-X-Sorb, LXS. This is what you react with the drug to
surround and complex the drug. If you
work at 0.8 moles of drug, you can all the drug in if the drug is going to
react with the complex.
You can use this as your final formula that you can homogenize
with SlimFast or some other source to make a liquid drug-delivery system. We have also been able to make a powdered
formulation of 25 percent of the Lym-X-Sorb drug in a powder.
[Slide.]
So the production of this is that we have a novel lecithin
hydrolysis that, in five to six hours, gives us 100 percent
lysophosphatidylcholine. At that point,
the dried material you can mix with your drug.
We can verify this uptake of the drug by a polarized light microscopy
study. The reaction is fully scalable. We have done this in--our usual reaction
conditions are in a 5-liter reactor. We
have done this in a 130-liter reactor and the reaction is perfectly scalable. The production of this is done in a Class
100,000 clean room facility.
[Slide.]
This is our test for uptake of the drug. At room temperature, the Lym-X-Sorb is in the
gel stage. You heat the Lym-X-Sorb to 55
degrees and it melts. This is a
polarizing light microscope look at the Lym-X-Sorb. Once you add the drug at 55 degrees, if the
drug is taken up, the field that you are viewing does not look any different
than the Lym-X-Sorb. If, however, you
exceed the capacity of the Lym-X-Sorb with the drug--this is 1.2 moles of
fenretinide with the Lym-X-Sorb. You can
see crystals of the fenretinide.
You can also use this to screen, to look at other drugs of
choice that you could put in the system to determine very quickly whether the
drug is actually going to react with the Lym-X-Sorb. Not all drugs will react with the Lym-X-Sorb.
[Slide.]
This is the reactor that is used. The difference between this and the larger
reactors is this bowl. You can extend
that bowl out. Of course, it would take
bigger motors. We have seen actual
reactors that have 20,000-liter capacity.
The 130-liter reactor is what you need to collect your data to scale up.
[Slide.]
The powder formulation; this is what the powder formulation
looks like. It is formulated with flour,
either a wheat flower or a rice flour, sugar, and you can put--this is 26
percent weight-weight of the Lym-X-Sorb with the xenobiotic. It is a free-flowing powder. There are a few aggregates that break up
immediately upon stirring.
You can take this mix and put it in with oatmeal pudding or
applesauce and the taste of this complex has been referred to as, this tastes
like cookie dough. I don't like this in
pudding. This has a texture to it. The taste--you don't have a bad taste in
pudding, but you have this texture in a smooth pudding. You certainly want to stay with a textured
food such as oatmeal or applesauce.
There are probably other foods that would work well with this.
[Slide.]
With the fenretinide, the study is, at present, being
prepared through an NCI RAID grant with Barry Maurer. The Lym-X-Sorb and the fenretinide then are
taken up through the intestine and it is assimilated, absorbed through the
jejunum and delivered to the thoracic duct.
[Slide.]
The studies have been done in mice. This was done at Children's Hospital Los
Angeles, in dogs at McNeil Labs, McNeil Pharmaceuticals, and in humans at
McNeil Pharmaceuticals. The present
study with NCI is going to include rats and additional human studies next year.
What we have produced is a drug that has more
bioavailability and it has improved delivery to the plasma, liver, lungs,
kidneys and brain.
[Slide.]
This is the data out of Los Angeles, Children's Hospital
Los Angeles. The yellow and red bars
represent Lym-X-Sorb in SlimFast and DI water.
The blue and green bars represent Lym-X-Sorb dissolved in an oil and
this oil is a corn oil and put into Slimfast in a high oil content. In every case, in plasma, the Lym-X-Sorb has
a much higher concentration in plasma, liver, lung, kidney and brain.
[Slide.]
The absorption of this--this is the data out of
McNeil. On a time basis, the red is a
corn oil at 200 milligrams--300 milligrams of drug. The yellow is the Lym-X-Sorb with the
fenretinide at one-fifth the dose, 65 milligrams of drug. The reason that the study was done with
one-fifth of the Lym-X-Sorb, and we don't see a high spike for the Lym-X-Sorb
delivery, is of the night blindness associated with fenretinide.
From the animal studies, it was shown that the Lym-X-Sorb
was five times better so the dose was reduced one-fifth and the kinetics
certainly indicate a delay in the uptake which would indicate a thoracic duct
and then a fall-off in the plasma with time.
[Slide.]
What all this means, from our perspective, is that we have
a drug that is compatible with a large number of drugs. What you have is a complex that has available
hydrophobic bonding, charge-charge interaction and hydrogen bonding, Van der
Waals forces and it self-assembles. So
when you put the drug in, it will self-assemble to represent a glove in
relation to the drug that is in it.
It protects the compound from oxygen, heat and light. The fenretinide is historically not stable in
heat, light and oxygen. In the
Lym-X-Sorb, it is very stable. It
protects the drug in the acid and base conditions and in the stomach and
intestine.
It minimizes the taste of the drug and minimizes the effect
of food taken with it. The
bioavailability of the oral Lym-X-Sorb; it is a readily absorbable delivery
vehicle. It is absorbed in the upper intestine. Enhanced absorption of the drug, we see a
fivefold increase and minimizes variation and bioavailability of the drug.
[Slide.]
This work was done--the complex was actually conceived by
Dr. David Yesair and Avanti has contributed to the manufacture and the
stabilization of this complex, and the complexing of the drugs and the
Lym-X-Sorb.
Thank you.
DR. SANTANA: Thank
you. We will hold the questions until we
are done with all the presentations.
Dr. Flanagan?
Best Pharmaceuticals for
Children
Best Formulation for
Children
DR. FLANAGAN: Thank
you. I appreciate the opportunity to
speak with you today and I particularly appreciate the FDA awarding me two
degrees that I don't have. My mother
will be quite impressed.
Also, I have two purposes in coming to the Washington, D.C.
area. One is to speak with you today and
I was also given, by my colleagues, a big satchel to pick up the new
twenty-dollar bills that are being issued today as I understand by the Bureau
of Engraving and Printing. So, if
somebody can direct me to where I should go, I would appreciate it.
[Slide.]
Anyway, I was contacted about eight weeks ago to attend
this subcommittee meeting because of my particular interest in drug-formulation
issues. I was aware of the Best
Pharmaceuticals for Children Act but have become much more familiar with the
issues in the last two months. My
particular parochial interests are in the realm of drug formulation.
[Slide.]
So I would say, for me, best pharmaceuticals for children
should be our best formulations for children.
I have read some of the transcript information available at the FDA
website from previous meetings of this subcommittee and I have noticed a
seeming lack of discussion of the formulation issue so I am very pleased to
hear that that is coming to the forefront.
I also read the documents that were sent to me in
preparation for this meeting. From my
own particular point of view, what I took note of in the articles that were
labeled PM1, PM2, PM3 were those related to formulation issues. So it is pretty easy for me to go through
articles quickly because, in this area, there is very little emphasis, often,
on the formulation aspects.
[Slide.]
The first one indicated that there are a lot of drugs that
aren't available in suitable forms for children, that formulations, meaning,
medications, are complex mixtures, contain a lot of components and, over the
last decade, there has been an effort to get new drugs simultaneously approved
for children.
What I have highlighted is an optimistic statement about
these efforts resulting in more appropriate formulations of new drugs for
children. My comment is what about the
off-patent or the old drugs?
[Slide.]
Dr. Nahata, in his article, discusses the extemporaneous
formulation which is what we resort to when appropriate children's formulations
are not available. He encourages an
action plan involving government, academia, industry, U.S. Pharmacopoeia,
professional organizations, everybody, to develop pediatric formulations which
I think we all agree with.
[Slide.]
The third article was a specific one describing a
particular drug being developed as a dispersible formulation that could be
easily swallowed by children. Somebody
indicated that, beyond just children, and this article indicates that geriatric
patients or other patients that have difficulty swallowing normal oral dosage
forms, so there can be a potential for the pharmaceutical industry to gain more
remuneration than just from the pediatric patients with such formulations that
are easily ingested.
[Slide.]
I also learned about the Pediatric Rule that I really
didn't know anything about. I was
impressed that the FDA, from the source that I received, the information about
the Pediatric Rule can actually require new formulations, or a new formulation
if it is needed, for pediatric patients in an age group in which the drug is
needed. But the FDA can't require
off-label-indications studies.
This particular author indicated FDA seemed to have not
used their full authority in this realm, though.
[Slide.]
In reviewing the guidance information, of course, FDA cites
the need for timely development of pediatric medicinal products--
[Slide.]
--and provides information and encouragement for developing
these formulations for accurate dosing and enhancing patient compliance. I think we all know the kinds of formulations
that we need.
[Slide.]
I might also highlight for injectable formulations, since
these seem to be neglected from a reformulation or a new formulation point of
view, that we probably need, for a lot of drugs that are given by IV or other
injectable routes, appropriate drug concentrations that allow more accurate and
safe administration of these drugs. Also
a separate consideration that I will elaborate on a little more later is to
reduce the number of steps in the handling of these cytotoxic drugs by health
professionals who are regularly being exposed to these drugs as they administer
them to pediatric patients.
Also, we know that there are certain additives or
excipients that are inappropriate for certain age groups of pediatric patients
like benzyl alcohol and there has also been the effort to reduce the use of
alcohol in formulations. For those
formulations that contain in appropriate excipients like benzyl alcohol, just
diluting them down, then, for pediatric use is not appropriate if some other
additive is toxic.
[Slide.]
I have also found some other article like Conroy this year
discusses the use of unlicensed or off-label uses of oncolytic agents for acute
lymphoblastic leukemia. This is, of
course, in the U.K. These drugs were
also used for other cancers.
[Slide.]
It also mentions, besides the extemporaneous preparation
which immediately makes the product or the formulation or the prescription
unlicensed, mentions special formulations that were prepared for named patients
by pharmaceutical companies. So there
were, or are, occasions where these might be prepared if they can be done
simply by the pharmaceutical firm.
This author also indicated 40 percent of these cytotoxic
prescriptions were involved in unlicensed formulation. The term "unlicensed" always sounds
bad, but that means "needed to be modified."
[Slide.]
It concludes with it is disappointing that formulations
suitable for children have not been licensed in all the years since many of
these drugs, as we have discussed in the morning session, have been around for
20, 30, 40 years.
[Slide.]
Another big issue gets to be compliance because many of
these patients, of course, have to be treated on an outpatient basis. There are lots of factors that affect
compliance in terms of palatability and ease of administration of the
preparations. If the patient doesn't
take the drug, they don't get the therapy.
[Slide.]
Conroy also mentioned a disappointing case of special
formulation being withdrawn by the company without notifying health
professionals, medical pharmacy professionals.
So these things can happen. Drug
companies can lose interest for one reason or another, mainly economic, but
there could be other reasons, and drop these kinds of formulations.
[Slide.]
I had also come across that the Europeans have developed
their own initiative to obtain better medicines for children.
[Slide.]
I look particularly for parts of their guidance or
information about formulations. They do
make statements about the pharmaceutical industry tending not to develop
specific pediatric formulations and go on to highlight other issues. They said one of their objectives is, in
fact, encouraging the development of suitably adapted formulations for children.
[Slide.]
Conroy also had an article in 2000 about the general area
of use of unlicensed and off-label drugs in pediatric wards and noticed that
that is quite widely done in a number of areas.
[Slide.]
For this meeting, I also contacted a local clinical
pediatric pharmacy specialist, Mr. Mark Sorenson, whose name is down at the
bottom of the slide--he is also involved heavily with the Children's Oncology
Group--to tell me about what they do in our University of Iowa hospitals and
clinics with regard to treating pediatric patients.
So he mentions, for this particular disease, three
oncolytic agents, one adjunctive-therapy agent that has to be extemporaneously
prepared so that they can be ingested by pediatric patients.
[Slide.]
The problems that he highlighted were the lack of
availability of these dosage forms for outpatients because even compounding
pharmacies, those pharmacies that will come up with unique formulations, are
reluctant to compound cytotoxic formulations.
This leads to reduce compliance and negative cure rates.
The child goes home.
The patient's family doesn't know where to get the particular drug and
if the patient looks like they are in remission, which they, of course, may not
be, the therapy ends.
Also, there are drug-supply shortages, especially for
community pharmacists. Last, but not
least, the topic of exposing healthcare professionals to these oncolytic agents
was brought up by their repeated handling of them, needing either, at the
lowest level, to do multiple transfers for diluting these adult-level doses down
to pediatric dose levels or compounding or recompounding tablets or capsules
into liquid formulations exposes healthcare professionals to more of these
oncolytic agents.
[Slide.]
I just cite a couple of papers about female pharmacists,
pharmacy technicians, nurses, nurses aides, showing a significantly elevated
odds ratio of self-reported infertility associated with handling these kinds of
agents even though, for men, that didn't seem to happen and another paper, in
2003, indicating a variety of antineoplastic agents that were found in the
urine of pharmacists and staffs of hospital pharmacies.
[Slide.]
So a separate concern is what are we doing to our health
professionals that are having to handle these cytotoxic drugs on a daily basis
and exposing them to possibly harmful low-levels of these agents.
So one possible solution, of course as we are pointing
towards, is preparing unique pediatric oncolytic formulations that need no
extemporaneous compounding and far less handling by health professionals and
caregivers.
[Slide.]
So my modest proposal would be to use academic centers,
since I have a particular interest in an academic center, that have
capabilities to develop the formulations, study their stability and
manufacture, clinical supplies and also use academic centers that can test
these formulations in pediatric patients to demonstrate efficacy and safety.
[Slide.]
Are there any such centers?
Well, let's see. I think I know
maybe one. This is now what I call the
shameless commerce part of my talk which is the University of Iowa where I am
employed, where we have an NIH-funded comprehensive care center in our hospital
and we have an FDA-registered drug-manufacturing facility.
We also have a separate service facility that develops
analytical methods and executes stability protocols. Last, but not least, I am part of the
Pharmaceutics Division that has over 50 years total experience in industry or
formulation-contract research with industry or government agencies.
[Slide.]
Our Holden Comprehensive Cancer Center has 166 open
clinical trials for cancer patients and many of those are trials in pediatric
patients.
[Slide.]
Our pharmaceutical service has operated for over 25 years
as a contract manufacturer of formulations for clinical trials. It has had over 25 years of NCI manufacturing
contracts for investigational oncolytic agents.
For those that might worry that academicians like me or just students
are making formulations, I will indicate that there are 50 full-time employees
that might have been students at one time but they are full-time employees that
manufacture these formulations. Our
separate service divisions provide support services for drug development,
particularly analytical-methods development--
[Slide.]
--and stability studies which are an important part of any
new drug or formulation development.
[Slide.]
Then we have ten faculty in our Pharmaceutics Division that
have participated at various levels in everything from preformulation studies
to formulation development, pharmacokinetics and pharmacodynamics.
Thank you.
DR. SANTANA: Thank
you. Dr. Blumer?
Drug Formulation in
Pediatrics
If It Tastes Bad, It Must
Be Good For You
DR. BLUMER: Good
afternoon.
[Slide.]
I was asked to give you some perspective on drug formulation
from a clinical perspective of a pediatrician.
I will try and do it. You have
heard a lot of this and I am indebted to Steve Hirschfeld for sending me a copy
of one of his presentations from which I borrowed liberally.
[Slide.]
So, in thinking about drug therapy for kids, I always start
back here because there are three determinants of efficacy therapy. Talking about pharmaceutics and, in
particular, formulation is one that we often talk about the least, in fact. Yet, it is one of the driving forces behind
whether or not our patients, indeed, get the benefit of the therapy they
received.
[Slide.]
We spend a lot of time waving this flag. In fact, in this area, children are, indeed,
different because they are not, in general, capable of dealing with the dosage
forms that are most commonly made available in the marketplace.
[Slide.]
But they are not Martians.
They still breathe oxygen. They
metabolize glucose and they have some fundamental biologic characteristics that
are very similar to adults.
[Slide.]
When we think about drug treatment, there are some
challenges. The challenges largely fall
into those pharmacokinetic and pharmacodynamic realms that do, then, lead us to
focus on providing effective formulations.
So when you look at pediatric patients, they are dynamic. They have changes in body composition,
changes in developmental drug metabolism, changes in organ function.
When you begin to think about some of these things, some of
the initiatives that we have heard about this afternoon and, in fact, this
morning, begin to resonate. In fact, if
you are going to give, and make, these different formulations, we have to take
this into account. What happens if you
take a dosage form that is a solid dosage form that has a set of bioavailability
characteristics and make a liquid?
We learned the hard way very recently in doing that with a
drug that was a hypnotic agent, that you really can dramatically change how
that drug is delivered and you change the overall pharmacokinetic profile.
[Slide.]
There are pharmacodynamic challenges as well. Receptor function and expression change over
time. The children also have greater
regenerative and recuperative potential.
So we heard this morning that children tend to have a greater risk in
some cases for toxicity but they also bounce back higher which is one of the
nice things about being a pediatrician.
There are some unique disease processes that we have to
deal with as well, and some of the things that we didn't talk about earlier
were the fact that we are dealing, in many cases here, with tumors that often
don't occur in adults and are very specific to pediatric patients and,
therefore, need specific therapeutic interventions.
When we have patients with chronic diseases, and what I
mean by chronic diseases here, diseases that not only may span a lifetime but
may span a year or two. We are looking
at patients who are going to dramatically change in terms of their drug
requirements. That is a very different
paradigm than we are used to in adults.
[Slide.]
That leads to some practical issues. When we dose children, we tend to dose on a
milligram-per-kilogram basis, on a weight basis, for most drugs. In oncology, we probably need to add dosing
in terms of meter squared or normalizing to meter squared and body-surface
area. But, having said that, we also
don't know when to stop.
Some of these things become problematic as we are looking
at the changes in drug disposition over time.
These dose requirements will change as the children grow and, as was
alluded to just a moment ago, a lot of the parenteral dosage forms require some
significant dilution prior to administration.
I will share with you some of the things that are derived
from the neonatal population, but they do translate into older children as
well. What happens when you do that?
Then we have this whole issue of oral dosing forms. There is this sense that, well, once we reach
six years of age, the children ought to be able to swallow tablets. I don't know of many of you have kids, but,
you know, it is like, "I will respect you in the morning." It is one of the great lies of the modern
world. They don't. In fact, some children never are able to
swallow solid dosage forms.
That is reality. It
is a reality we have to address especially when we are dealing with children
who need chronic therapy for life-threatening diseases.
[Slide.]
There are complex solid dosage forms that are very, very
revolutionary but they are not engineered, not only for pediatric GI physiology
but, of course, as pediatricians, as soon as we see a solid dosage form, what
do we do? We crush it. It is almost a reflex. As soon as you do that, you destroy all of
the engineering that went into developing that solid dosage form and it becomes
useless.
Another issue is that palatability is, indeed, the major
determinant of compliance in our patients.
We have the most wonderful medicine in the world but, if it is not
palatable, and I was interested in hearing about sense of the grittiness and
the texture, because palatability is not only flavor, but it also deals with
the texture of the medication.
So oral liquids and chewable and dissolving dosage forms
may be alternatives. Then, remember that
our patients really do depend on someone else to give them the medicine. That has a lot of dynamic implications. First of all, we need to have families that
remember.
All of you are familiar with the data even on training
acute lymphocytic leukemia where the compliance with treatment, the recognition
that these children, indeed, need to get their medicine every day is not always
adhered to. You superimpose on that a
child who looks like they are doing well and is fighting with their parents to
take the medicine, the incentive to actually deliver the medication goes down
exponentially.
So these are some real practical issues that, in thinking
about developing pediatric dosage formulations, we need to take into account.
[Slide.]
We have lots of formulations available. We do have to spend a little bit of time
talking about intravenous formulations.
There are a whole bunch of different oral formulations and, as we heard
today, there are more to come. Rectal
administration, cutaneous creams, percutaneous delivery systems, all of which
offer some specific opportunities for enhanced delivery.
[Slide.]
Now, as I said, this is a slide that just sort of
emphasizes this concept of dilutional intoxication. If you take a number of drugs that are used
in the intensive-care unit on a fairly regular basis, look at the available
concentrations that they come in and then calculate how the individual doses
have to be delivered--this is, again, in the neonatal intensive-care unit.
We can go through the same calculation in the pediatric
intensive-care unit. Remember that the
most sensitive measurement that we can make in a clinical setting is a
tuberculin syringe. So all we have is
the tuberculin syringe. We don't have
Mettler balances and things like that.
You end up with significant overdosing with many of these
medications. We can just extend that on
and on. So it is not only looking at
formulations that are oral formulations for kids but we have to be sensitive to
those situations where we need parenteral formulations as well.
[Slide.]
What is available?
You have seen this before. I just
have a couple of comments to make on it.
This was from one of Dr. Hirschfeld's slide. Yes; he rightly points out that we do have
some pediatric formulations. We have
drops and suspensions. I don't know how
much experience all of you have with chewable tablets. It sounds like a great idea but when you
watch children take chewable tablets, some of them think they are great. Some of them think they are god-awful and
spit them out. It is not a particularly
reliable way of getting medicine into children.
The whole idea of syrups is another one. It is always interesting to look at the
flavors that some of the pharmaceutical companies come out with. My favorite was, long ago, when trimethaprim
sulfate was being formulated and one of the iterations was a licorice-flavored
suspension. They thought this was going
to be great.
You would talk to them and they would say--I think was
Roche--and you would say, children don't like licorice. Oh, yeah, yeah; it is great. We put it through our taste testing. Of course, it was a group like this. It just was awful. So we have to be sensitive to that.
We have talked a little bit this afternoon about
extemporaneous preparations. I will only
say the following things. There are
places like the University of Iowa that does an outstanding job and we have
used their facilities in some of our studies.
There are places like Ohio State where Dr. Nahata, whose work you have
heard quoted, has spent a significant amount of time putting together at least
recipes for extemporaneous formulations.
Now, the problem with that is, even when you are using
national-formulary or USP-marketed vehicles, it is like using the Betty Crocker
cookbook and everybody sort of adds their own twist to these things. If you take extemporaneous formulations from
day to day, week to week, month to month, and actually just take them out of
the pharmacy and analyze them, there are tremendous differences. No one is trying to do this maliciously, but
when you are dealing with drugs with narrow therapeutic indices, where you are
really trying to get the dose right, this is a problem.
It is a problem in some of the compounding pharmacies. We have a wonderful pharmacy in Cleveland
where we had historically sent patients who needed drugs compounded for young
children and our hospital pharmacy wasn't interested in doing it any more. This particular pharmacist and his colleague
embraced this and they really gave it their all. But the fact is that there was not great
uniformity from day to day and from time to time, even with their best efforts.
Then you have this whole issue of food. All of the concerns about food, and you will
see a quote later from Dr. Hirschfeld which I think will go down in the annals
of pediatric pharmacology because I think it is true, but most of the data that
we have on the effects of food on drug bioavailability are absolutely
irrelevant to children.
I don't know any three-year-olds who eat fried eggs, slices
of bacon, coffee with cream and toast and butter. It is not that. And I don't know of any drugs that have been
studied with peanut-butter and jelly sandwiches, or Fruit Loops or Happy
Meals. This is real life. So, do these things impact? Yes; we have studies in infant formulas and
yes, we have studies in applesauce. We
will have a comment on that.
[Slide.]
So what are the determinants of formulation? I think we have talked about age and that is
obvious. The ability to handle solid
dosage forms and, really, it depends on what the solid dosage form is because
there are many of them.
Then there is the disease and the disorder that we are
talking about. That is key, as
well. So there is a sense, and I think
we will get to it, that when we talk about pediatric formulations, we want an
oral liquid. That is what we are
after. But that may not be the right
formulation for all comers, for all diseases.
If you have chronic suppressive therapy, if you are taking
drug over a long period of time, if you want to ensure that the patient is
compliant and you can't get rid of the bitter taste, these are all
considerations that may make a liquid not appropriate.
[Slide.]
What would I recommend?
Well, until hearing some of the presentations today, I think certainly
oral solutions are up there, suspensions.
I think we ought to give more, or at least closer looks, to some of the
rapidly dissolving tablets because at least, then, you can fake out these
little kids because, once they get it in their mouth, it is there and done and
it gets in. That is important.
The transcutaneous delivery systems is another route that
we haven't spent as much time working on.
Certainly, with pediatric patients, every time someone gets to the point
where they would like to look at it, they are unwilling to go through all of
the formulation problems and dosing issues that, even if there is an adult
formulation, like some of the opioid transcutaneous delivery systems.
Those are great and they have been licensed for adult
patients, but there are different parameters that we have to deal with in terms
of changes in the integument, changes in dosing strategy, et cetera, that are
fairly expensive. Yet, for young
children where you can put a patch somewhere where they can't get at it, this
may be a very effective strategy.
The use of implantable reservoirs is something else that we
may need to look at in kids. So I don't
think we should eliminate those from our consideration.
[Slide.]
As I indicated, the pediatric holy grail some people think
of as the oral liquid--again, I borrowed this.
This is from the Pediatric Pharmacy Advocacy Group--that really sort of
makes it our imprimatur to try and develop a liquid formulation.
[Slide.]
But I want to say, is that really what we want or
need? I challenge this group to go back
and say, okay, in certain contexts, this is wonderful, but this is not an area
where one size is going to fit all and I think we have to start with what are
we trying to treat, then look at who we are trying to treat and put those
together and decide what the appropriate formulation may be.
[Slide.]
So the approaches we take, we have some proprietary ones
that are liquids in suspensions. The
extemporaneous ones still exist. As I
said, our chief approach to solid dosage forms is to crush them.
[Slide.]
The downside of the oral formulations we have, the
solutions often contain potentially toxic excipients. I want to underscore this. This is something that we haven't spent
enough time looking at and it is something that we do need--these are some of
the silent problems that we have and we are not sure how significant they may
be because we haven't looked at them.
The suspensions are my favorite because you take a
suspension and you give it to the average mother and generally, when they
start, especially if you give them a month's supply of it, for the first ten or
twelve days, the children are either seizing or having arrhythmias or whatever
it is that the medicine is for and then, for the last twelve or fifteen days,
the children are toxic because you can never get them dispersed well enough.
This is not a reasonable strategy. It just doesn't work well. We also have to consider who is administered
the drug and under what circumstances.
As I indicated, palatability is key and that deals with both taste and
texture. There are some very
good-tasting drugs that children will shy away from, in some cases violently,
because it is like taking a mouthful of sand.
They just don't tolerate it.
The sprinkles and sachets have some advantages but they
often have erratic absorption. Some of
that erratic absorption depends on what we are putting them in. Some of it just is inherent to the dosage
form and, yet, if you are dealing with a drug that doesn't have a narrow
therapeutic index, this, too, may be a very effective way to administer drugs
to particularly young kids.
Then I have talked about transcutaneous delivery systems.
[Slide.]
The extemporaneous preparations, we have talked about these
problems; stability, bioavailability, nonuniform composition, the variable effects
of food.
[Slide.]
Now, are they important?
Well, we know that food will affect bioavailability. It may not be clinically important. I think this is the key, though, and I think
this will go down in the annals of pediatric pharmacology; not all applesauce
is created equal. And it is not.
It is sort of like the old adage about delivering drug
doses to kids in terms of teaspoons. If
you go into a group of homes in any city and say, let me see your teaspoon, the
sizes vary by a hundredfold. The same is
true with the contents of the applesauce.
For most drugs, the impact is small, especially with the
foods that kids eat. That doesn't mean
we should ignore it. We need to know,
especially for a drug with a narrow therapeutic index, especially for a drug
for a life-threatening illness, we need to know. But, at the end of the day, there haven't
been a lot of drugs, especially those that we use in children, where food has
been shown to have a clinically important impact. As I said, there are no studies that really
deal with the foods that kids eat.
[Slide.]
To date, and, again I borrowed this and it is true; we have
a number of bona fide pediatric formulations but I will talk about these in a
moment. We have some extemporaneous
preparations that are standardized. In
his talk, and I didn't reproduce this, Steve showed the menu that you need to
go through to make the extemporaneous preparation for Sotalol. That is accident
waiting to happen. It really is. This takes major compounding time.
The sprinkle formulation, taking sprinkle with Montelukast,
for example, where you have a drug where you can give a whole elephantful of it
and probably not hurt anybody, it does have advantages. I don't think we ought to dismiss that as a
dosage form. It is not going to be as
reliable as some others, but it may offer something.
[Slide.]
So then you get to these antivirals. Because of the tremendous interest in HIV
infection, most of the antivirals have come out with some sort of oral
solution. These are terrible
formulations. They just sort of cut the
mustard. They are liquid so you can take
them if you can't take a solid formulation.
How reliable are they in terms of drug delivery to children
and are we able to minimize the exposure to things like--you know, we want to
dilute it in antifreeze or something like that, that is fine. I mean, these are problematic. So I am not sure that going to this kind of
length to just sort of eke out something barely acceptable, even in a situation
where we are dealing with a life-threatening disease like HIV infection, is the
appropriate strategy.
I think we can do better and I think that is where we need
to put our mind set. So I just think
there are some very real clinical issues that we have to consider. I don't think we should limit our focus to
oral liquids and I think we need to explore both focusing not only on the age
of the child or the fact that they are children, but what it is we are trying
to achieve with the drug.
DR. SANTANA: Thank
you, Jeffrey.
Questions to the Presenters
DR. SANTANA: We now
have an opportunity to ask questions to the presenters. I want to start by asking a question
regarding this Lym-X-Sorb technology. Do
you need active bile salts to absorb it?
Is it absorbed through the bile-salt intestinal transport system or is
it absorbed uniquely by itself?
DR. SHAW: I don't
have any data on that, absorption without bile salts.
DR. SANTANA: It just
occurred to me. It is a lipid
formulation; right?
DR. SHAW: It is
lipid but the components are all the products of digestion. You have lysophosphatidylcholine which is the
product of phosphatidylcholine digestion.
You have monoglyceride which is a product of triglyceride. And then you have free fatty acid. So you don't need any pancreatic lipase to
act upon this to be digested. It is the
end product of digestion.
DR. SANTANA: Dr.
Stewart?
DR. STEWART: I had a
few questions for Dr. Shaw. You
mentioned that the bioavailability had been increased. I guess, since we are here at the FDA
meeting, we should use the strict FDA definition. I did notice that the extent had been
increased but I guess the strict definition includes rate also. I didn't really see how the rate had been
increased. Does the rate of absorption
also increase?
DR. SHAW: No; I
would think not.
DR. STEWART: So it
is really just the extent of absorption.
DR. SHAW: The
extent, the amount.
DR. STEWART: The
other question I was going to ask was you had mentioned that the variability
decreased, the variability in absorption was decreased. I guess the one graph that you showed didn't
really have error bars, the graph of--it was a study from CHLA. I didn't really see any measure of variability. Do you have an idea, can you tell us how much
variability is--how much it decreased the variability in absorption, because I
think that is a very important point.
Based on the studies that we have been involved in at St.
Jude, obviously, you want to increase the bioavailability but you also want to
decrease the interpatient variability.
That is a very important point in regards to oral drug formulation.
So if the formulation is able to do that, I think it is a
very important contribution that it makes.
Are you able to quantitate? Does
it decrease it from 100 percent down to 10 percent, or 100 percent to 50
percent? Can you quantitate that?
DR. SHAW: I don't
have any quantitative data. The clinical
trial that was done in Montreal on the cystic-fibrosis patients, the Lym-X-Sorb
complex was given as a unit. There was no
drug associated with that. It was a
delivery of the essential fatty acids that were in the complex.
That was a two-year study and the result of that was that
the patients all gained weight and grew taller and had better lung
function. But I don't have the data to
show what the variability per each patient was.
DR. STEWART: I just
think it is real important for, whenever we do consider the formulation
considerations that we consider variability as one of the aspects of it.
The other question I was going to ask you was, when you
showed the tissue and plasma levels and you were showing the fenretinide, were
you measuring, in your assay, the complexed drug, the glove, or were you
measuring the fenretinide?
DR. SHAW: That was
the fenretinide that was being measured.
DR. STEWART: So it
released in the tissue?
DR. SHAW: Yes. Well, it was taken up in the plasma and then
the tissue would take up the fenretinide from the plasma, or from the blood.
DR. STEWART: Okay.
DR. SANTANA: Peter?
DR. ADAMSON: I
actually had three questions for you, Dr. Shaw, because I think, if the--and I
am going to say "theory" but please tell me if I am wrong--if the
theory is that absorption is virtually exclusively through the lymphatics, that
actually has significant impact in that it avoids first-pass metabolism.
DR. SHAW: Yes.
DR. ADAMSON: And so
those studies, can you tell us a little bit about how you have proven that that
is route of absorption?
DR. SHAW: I think
the time of the drug presence in the plasma is delayed so that you could assume
that it doesn't go directly to the hepatic system. It goes through this lymphatic system.
DR. ADAMSON: So you
haven't actually sampled from the thoracic lymphatic duct.
DR. SHAW: No.
DR. ADAMSON: Again,
I think that would be important to document because a lot of our drugs are
probably limited, in good part, by first-past metabolism, and knowing that with
certainty.
My next question is that this is useful for a large number
of drugs. How many drugs have you
actually studied in either preclinical or in humans?
DR. SHAW: There has
been cyclosporine, which is a cyclic peptide, and fenretinide.
DR. ADAMSON: Those
are the two?
DR. SHAW: Those are
the two. Now, there have been many drugs
that have been looked at to make a complex with the Lym-X-Sorb that have never
been put into animals or humans.
DR. ADAMSON: The
last one, and, again, it, in part, is following up to Clinton again and,
because we are at the FDA, I feel like we can throw this out on the table,
although I believe it will increase bioavailability, I don't think your data
support that. The reason I say that is
that it is resting on the assumption that the pharmacokinetics are linear and
not saturable.
I think the only way you can show increase is actually to
study the same dose, albeit a lower dose, but, otherwise, if the absorption is
saturable, you are not showing increased bioavailability. It might just be saturable absorption if it
is no different. I tend to believe that
you have increased it, but I don't think the data, and there may be more data
there, but I don't think it demonstrates that.
DR. SHAW: Okay.
DR. SANTANA: Donna?
DR. PRZEPIORKA: For
Dr. Shaw. It is a very interesting
formulation and the moment you put up your first technical slides, I thought,
my, this looks very familiar to somebody who has done gene therapy in the
past. My question is, do you know the
charge of the pocket in the glove and will that actually complex with virus or
nucleic acid?
DR. SHAW: We have
not put a virus or nucleic acids in this complex. We have some people that are talking to us
about doing that.
DR. PRZEPIORKA: The
reason I ask that, of course, is because this is one of the routes that we use
to transfect cells with genetic material.
DR. SHAW: Yes.
DR. PRZEPIORKA: If,
in fact, your drug is not covalently complexed with the lipid, there may be
some opportunity for mass action to move drug out and virus or nucleic acid in
since it is going in via a non-sterile route.
Alternatively, if the drug is not totally complexed, or
rather if your lipid formulation is not totally complexed with the drug, you
would have, around the open glove--if you were going into a place that could
pick up anything. I would be concerned
about what the potential would be for transformation and long-term safety in
these kids. So I would just want to
raise that concern.
DR. SHAW: Thank you.
DR. SANTANA: Peter?
DR. ADAMSON: This is
a question for either Jeff or Dr. Flanagan.
I think, if we were to look at pediatric cancer therapy today as far as
where is formulation, perhaps, going to have the greatest impact, I would
potentially argue for the thiopurines for 6MP.
That is a medication that is administered daily. It is administered daily for years and we
know, from the extensive studies that we have done, that the inter- and
intrapatient variability are extreme for this drug.
To me, because it is continuous administration, it is
almost begging a transcutaneous route.
How complicated is it to make a drug into a transdermal delivery
system? Maybe, Dr. Flanagan, you can
tell me that, or tell us that.
DR. FLANAGAN: Well,
the transdermal delivery systems are rather complicated. At the simplest end would be some kind of
topical, let's just say, ointment. If
the drug is permeable through the skin, then possibly, if you could do this in
a controlled fashion, applying an ointment or a topical formulation with the
drug in it might work.
At the other end of sophistication, to make something like
the fentanyl patch or the nitroglycerine patches, that is a lot more
technically involved and isn't something that usually people do. They don't do it on an extemporaneous
basis. They don't do it in a hospital
setting. It takes some rather
sophisticated equipment, but if you can demonstrate that the drug can be
delivered transdermally, then you could probably interest a transdermal
delivery company in going further with it.
DR. ADAMSON: Because
I think the greatest potential impact, if you look at standard risk ALL, the
largest number of failures occur during maintenance therapy. Whether they are because of ineffective
delivery of maintenance therapy, we don't know that. But both from a quality-of-life standpoint
for medications daily as well as trying to decrease the extreme variability,
that would seem to be a significant area of potential formulation development
when it comes to pediatric formulations for children with cancer.
DR. SANTANA: Dr.
Finklestein?
DR. FINKLESTEIN: As
a follow up to Peter's question, is there any data to show how effective the
transdermal application is correlated to the age of the child's skin
thickness? So then we would be back to
square one.
DR. FLANAGAN: To my
knowledge, that is not known.
DR. FINKLESTEIN: And
is it important?
DR. FLANAGAN:
Additionally, you don't get a lot of drug transferred through the
skin. So if you are going to need many
milligrams of drug, the skin isn't going to be the route to do that. But if pediatric doses are much reduced
compared to adult, that is a possibility.
But you are not going to get tens or twenty-fives of milligrams across
the skin.
DR. BLUMER: But this
is the kind of thing where you might want to consider changing the strategy and
saying, okay, if you had an implantable pump to continuously deliver
6-mercaptopurine, would that not get rid of some of your variability? That is why I say, these are things that we
shouldn't abandon, again, looking for liquid formulations and things like that.
There may be alternatives that will give us more reliable
delivery.
DR. SANTANA:
Jeffrey, can you comment on--you kind of touched on it very lightly in
your presentation. But can you give us
more detail how industry decides when they need to rethink about a new
formulation or a new vehicle of giving a drug. Is it empiric?
Is it all market driven? Is there
any science to the madness because I got a sense from you that it was the
later.
DR. BLUMER: I think
that there is certainly science to the madness because some of these things get
quite complex. But I think it is still
market driven and I don't know that pediatric patients will ever be the kind of
market that will drive that without some significant incentives. So I just can't see going out there. What we are lacking, while there are a number
of small pharmaceutical companies today, boutique firms that are looking to
reformulate drugs and patent new dosage forms, most of them are looking at
liquids or something else. They are not
looking at some of the more complex dosage forms.
So I think I would be pretty pessimistic that some of the
large pharmaceutical companies are going to embrace this without some
significant--
DR. SANTANA: Can I
take that further? How does the maker of
the biggest analgesic decide that they want to do a cherry flavor or a chewable
and they want to do another one? How is
that process? Who decides that? What information is brought into that
decision?
DR. BLUMER: I think
the flavoring is done--to me, it has been a mystery, quite frankly, because,
when you work with these companies in the beginning of the development of an
oral dosage form, and one that we were just involved with, one of the things
that did determine it ultimately was the flavorings, one of the flavorings,
did, in fact, dramatically affect the stability of the suspension.
So I guess there are some of those. But why they start out and say, well, we
really believe that lemon creme is going to mask the flavor of this better than
banana nut. There doesn't seem to be any
real rhyme or reason to that.
DR. SANTANA: Dr.
Stewart?
DR. STEWART: This is
actually a comment that I was thinking of.
I am going to wear my hat as a parent now. I was thinking during Jeff's talk about what
kind of formulation could I come up, or could I think of, that would give my
ten-year old to take medication and I started thinking, well, if I came up with
the ideal formulation, that might be actually sort of a drawback because then
you start thinking about, if you get such a good formulation, you have to worry
about kids wanting to take it and poisonings.
So I think one of the things--maybe it sounds a little
absurd, but you do have to worry about kids getting into medications and taking
them and the poisonings. Maybe I am
going a little bit overboard, but I am sounding a note of caution, I think, in
terms of medications being too tasty and too much like candy and kids getting
into them. I think that is a concern we
have to think about.
DR. BLUMER: I think
it is a legitimate concern. At this
point, we do have some experience with that.
Fortunately, it hasn't been a bad experience. When the ability to really flavor liquid
medications became a commercially viable entity, so you could go into your
pharmacist and say, yeah, I want my child's amoxicillin to taste like Welch's
grape juice or something. They can now
do that.
I think one of the concerns that maNy of us had is just
what you were articulating, Clinton. But
it has turned out that, after a number of years, that hasn't been a big
issue. So, while I echo your note of
caution, I think we now have some real-life experience to show that that hasn't
contributed significantly. Running one
of the poison centers around the country, that certainly--in fact, I can't
think of a time where that has been a problem.
DR. REYNOLDS: I have
a question for Jeff. Your point about
flavor, I think, and palatability is extremely key in this whole situation with
the oral medications. We have been
frustrated with trying to find, in the literature, any kind of body of
literature, even single papers, dealing with how this flavoring is done.
I hear through the grapevine that it was a tour de force to
disguise the taste of Tylenol in the oral McNeil preparation, yet there is
nothing on that. It seems to be a trade
secret. I was wondering if you could
comment on whether there is some literature that I am just missing or whether
there is some opportunity to get together in some place a body of such
literature which would not only be useful for extemporaneous formulations the
pharmacist might do but would be extremely useful for those of us trying to
develop pediatric formulations for specific use in the future.
DR. BLUMER: I know
that a literature exists, and Dr. Flanagan probably has a better sense of that
than I do. It is not something that I generally
read. But the medicinal chemists
certainly do this. Most of the
pharmaceutical companies have people who do nothing but deal with flavoring.
DR. FLANAGAN: A lot
of the information is proprietary, but there is a publication for compounding
pharmacists or health professionals interested in compounding that has a lot of
material about flavoring. Sometimes, I
am reluctant to recommend some of these things because there is a kit of
flavors that pharmacists can purchase and just add whatever flavor they would
like into a product viewing a flavor as not a chemical entity but just
something that changes the taste and you never know what it does to the
stability or the bioavailability of the drug.
But there are flavor kits available.
DR. REYNOLDS: Just
to follow up on that comment, then would you think it is safe to say that one
of the issues that we do need to study, then, is the impact of these and
develop a scientific basis for what flavors an what compounds used to flavor do
affect drug bioavailability.
DR. FLANAGAN: Sure.
DR. SANTANA: Alice?
MS. ETTINGER: I,
after twenty-five years of being a nurse and getting meds into kids, don't
think that there is any one flavor or any one anything that is going to get any
kid, even the same kid five minutes later, to take a medication. That is a real problem. The applesauce isn't the applesauce.
I have a compounding pharmacist where we are. He has used every flavor kit not nailed down
for one particular kid. And then the
next kid liked one of them and that one went right in. So I think we are spinning wheels here in
terms of every single solitary kid trying to take every medication.
In the other hand, I liked the comment about the
parent. I think that that is something
that we cannot overlook and the impact that the parent has on having a child
take a certain kind of a medication over the long haul.
DR. SANTANA: I was
thinking about this, that there is a big piece missing in this discussion which
is this whole issue of behavioral medicine and modifying behavior of kids
taking medications. It is no offense to
anybody on the team here, but we really should have given some forethought
about discussing that too, because that is important in terms of compliance.
But that relates more to compliance rather than to issues
or formulations and things like that which is what the FDA wants us to
discuss. But I agree with you. The issue of compliance is completely
separate and the behavioral-medicine impact to that is something that needs to
be addressed across all pediatrics.
DR. BLUMER: I would
just emphasize that I think, at least for pediatric formulations, compliance is
so intertwined that they can't be separated.
So, as the FDA considers issues of pediatric formulations, that has to
be something that has to be on the table and how do we do that. For example, a lot of the oral antibiotics
have been put through so-called taste tests.
Generally, children are not part of that.
Can you actually give them a taste test without exposing
them to the medicine? These are real
challenges.
DR. SANTANA: It will
be interesting if those studies have to go through the IRB, too.
DR. SANTANA: Ms.
Hoffman?
MS. HOFFMAN: I
guess, as a parent who had to try to convince my child to take chemochip
chocolate ice cream unsuccessfully--she had learned to dissolve the ice cream
in her mouth and spit out the pill that was all crushed up into minuscule
little pieces. I mean, the ideal would
be having a Mary Poppins scenario where, every time you poured out the bottle,
it was a different flavor and a different magical color.
But we don't have that kind of world. I think the other factor in terms of
compliance is, again, as a parent, these kids learn really fast. I take that medicine and I feel like shit and
I am going to get sick in X number of--a half hour or hour. So it is not only a matter of not wanting to
take the medicine because it tastes really yucky. I don't want to take the medicine because in
a few minutes I am going to feel really, really even worse.
There are so many factors involved in making sure that they
get the antiemetic beforehand so they don't feel nausea and all the
associations.
DR. ADAMSON: I just
wanted to follow up a little bit about Jeff's comment as far as industry's
interest in formulation. Rick, I will
direct this to you, but you can sort of turf it. If I recall correctly, a formulation was
developed for intrathecal Ara-C deposition that would seem--am I bringing up a
bad topic?
DR. PAZDUR: Steve
was the reviewer on that.
DR. ADAMSON:
Okay. Maybe I will direct this to
Steve. For people who don't know, it is
a long-acting intrathecal Ara-C. When
you think about the market there, children's cancer becomes an epidemic
relatively speaking. So the question is
what motivates industry, not big PhRMA, but could you give us some--what do you
think motivates industry to develop a formulation for a small market.
DR. HIRSCHFELD: That
is a very complex question. I couldn't
even pretend to answer it thoroughly.
But there are a number of factors and they have to do with establishing
credibility as an entity with demonstrating something that is going to
differentiate them from their competitors that, even though the sales may not
be eye-popping, the stock price of the company can reflect either a capability
or a promise of not necessarily that product but maybe a technology.
And there are also grants that are available which, in some
cases, are a very strong motivating factor.
The FDA has grants, the Orphan Drug Program. The NIH and the NCI, in particular, have
grants. There are some entities which
essentially establish the credibility and are able to survive through funding
mechanisms.
So all of those are motivating factors.
DR. PAZDUR: Very
politically correct, but, Peter, the real answer is one and one only;
profit. The issue is off-label use for
the most part. That is where they see a
niche. We get this so many times, people
coming in for just, I want to approve this drug in fifth-line relapsed
patients, knowing extremely well that that is not the market that they are
going after. Or, we want to develop this
drug for people on respirators that are getting acute leukemia. They are not developing that drug. That is one of issues.
Here, again, Steve is right. These are different areas. But one of the things that propels things,
the market, in general, is can they use these drugs off-label. This is obviously a big area in medical
oncology.
DR. SANTANA: Peter?
DR. ADAMSON: I was
just going to follow--for a drug like 6MP, if you were to extrapolate that, you
might say get it labeled for children with leukemia and then use it in all the
patients with inflammatory bowel disease.
So I think there may be small companies you might be able to interest
even though we can't--or, at least I couldn't envision the profit. It may be there when you put someone who has
an MBA behind it.
DR. PAZDUR: I don't
want to seem glib or something. There
may be altruistic benefits, obviously, but, ultimately companies have to be
viable. Will this have potentials? Will they be looking at this technology to
export to different products down the line that may have larger markets trying
to develop it in a small market first. That
might be one situation that comes to mind.
But, ultimately, there has to be a market for a drug. When we see many of the pharmaceutical
companies coming to us, although the niche market may be for the treatment of
leptomeningeal disease from a particular rarer type of tumor, the larger market
is for solid tumors from breast cancer, et cetera, coming down the line. It tends to be an easier, perhaps, way to get
the drug initially approved. But, given
the fact that off-label use is common practice in oncology, that is a
consideration.
DR. REYNOLDS: Are we
done with this issue?
DR. SANTANA: I think
we are done with this issue, yes.
DR. REYNOLDS: I just
have a comment on this issue.
DR. SANTANA: If you
have a comment on this issue, go ahead, Pat.
DR. REYNOLDS: If I
could just ask you, Rick, what you are seeing here, basically profit is the
motivating factor. Yet we see generic
drugs made all the time. I am wondering
is there some possibility for some of these kind of formulation issues to be--the
cost of development born by the government and then handed off to generics as a
model for getting around this.
DR. PAZDUR: That
could be a consideration and if they wanted to partner with the NCI in
developing these, this would have to be under discussion with the NCI. But that is not an unheard of example, either
for formulation--well, for new molecular entities, definitely--
DR. REYNOLDS: Here,
I was just talking about for
formulations.
DR. PAZDUR: But for
formulations, that would have to be something discussed with the NCI.
DR. HIRSCHFELD: I
will just add on the same topic that, depending on the extent and elaborateness
of the new development, it could quality as a new product and, therefore, would
be something entirely--be patent protected, et cetera, which would be a
different model.
DR. LOSTRITO: My
question is for both Drs. Blumer and Flanagan.
Dr. Flanagan had mentioned--showed some interesting information about
occupational-exposure hazards to formulating chemotherapeutic agents. The issue of percutaneous or transdermal
dosage forms came up. I would like you both
to respond to this briefly that, traditionally, the products that are marketed
to date for transdermal systemic absorption usually employ anywhere from 5 to
10 milligrams extra in the device for every milligram you want absorbed as
a dose.
That is to maintain a linear absorption profile. To me, this poses a different type of
toxicity issue in terms of familial handling of it and what is a huge dose
relative to what the patient just absorbed left in the device at the time you
throw it away. I would like your
comments on that with regard to the patient population, family considerations
and also exposure.
DR. BLUMER: I think
your points are very valid and very important.
What we have to balance here is the importance of delivering the
medicine to these children and then what kind of safety precautions you can
take at home. Over the years, we have
changed how even over-the-counter medications are packaged to ensure safety in
the home.
Obviously, if we were going to introduce, if it were
feasible and it may not be for the some of the cytotoxic agents, to deliver
them transcutaneously, we would have to set up the kind of safety situation in
the home to do this.
When you think of all the therapies that have now been
translocated out of the hospital into the home with home IV teams and all sorts
of dressing changes and drug deliveries, it is probably not out of the
question. I think the first thing we
need to do is figure out whether you can really effectively deliver these kinds
of drugs that way and what advantage it holds.
But I am not as pessimistic about it, perhaps. But I think that those are very key questions
in terms of rolling this out on a commercial level.
DR. FLANAGAN: I
guess I agree.
DR. SANTANA: Any
other comments? Malcolm?
DR. SMITH: We have
had some experience with drugs coming through adult development. There are tablets. There is going to be a pediatric formulation. And then we end up using the crushed tablets
and it just didn't work out. My question
is a generic one. Is there a strategy
that we--is there a generic strategy, generic in a different context, that we
should be pursuing, kind of an off-the-shelf approach, that would be feasible
for a range of therapeutics? Is that
something that is tenable, whether it is for 6MP off-patent or the newest drug
that is coming down the pike? Is there
technology that is on the horizon that could do that for us?
DR. FLANAGAN: I am
not aware of any off-the-shelf technology that would work across a range of
drugs. But you have your pharmacy
specialists in the hospital that are often very good at compounding things and
taking anecdotal information from the patients and going back to the drawing
board to modify it.
DR. HIRSCHFELD: I
was going to comment to Malcolm's point.
This is something which we have been interested in for some years and
have had discussions with some of the major corporations in America, not just
pharmaceutical companies but others. If
there were some general approaches that could be used to look at pediatric formulations,
could they be somehow into fine particles and dispersed or something that would
be stable and have all the properties that Jeff discussed in his talk.
The short answer is no one has come up with an approach
that would be sort of the general starting point for it. We remain interested and keep inquiring but
it hasn't appeared yet.
DR. SANTANA: No;
there is no general approach and there may be a little bit of science to the
madness, but the madness is very disorganized.
It is unfortunate because that is what I was trying to get to earlier in
my question is is there a way that industry systematically approaches this that
could be modeled into what we want to do in pediatrics.
DR. SMITH: Are there
delivery systems that could be engineered that could incorporate, here is what
we have in the delivery system that can be an oral suspension or a sprinkle or
whatever does it. Just press the button
and you have it. We don't have that
right now.
DR. SANTANA: Ms.
Hoffman?
MS. HOFFMAN: I just
had one other comment, I guess, as a parent.
When my daughter came out of BMT, you are given so many medications,
different dosages and different ways to give it to them. But I actually found that to be an advantage,
to have multi different formulations. I
knew I gave the yellow liquid in this and
I gave her this much instead of two blue pills. She had to have--it is a cyclosporine in the
glass syringe at such-and-such a time.
I think it actually helped.
If I had had everything as sprinkle, the probability of having it
correctly given to her I think would go down greatly and this may be something
to keep in mind. You are dealing with
parents that are overwhelmed. We don't
have degrees in pharmacology. Even
literacy in your parents isn't necessarily--it might be Grade 8 level of
literacy.
So you don't read your label and go, okay, I understand
that I need X milligrams of this. You
go, okay, I need two blue pills. Just
keep that in mind that multiple formulations can probably help.
DR. SANTANA: Jerry?
DR. FINKLESTEIN: I
would like to go back to Peter's comment earlier this morning which had to do
with the fact that maybe the best we can do in pediatrics is monitor the white
count. As I am listening to the
discussion this afternoon, pharmacists, in good faith, are putting drugs
together to give to children with a variety of diseases, but we will talk about
children with cancer.
We have no idea of the bioavailability, whether it is given
as a liquid or crushed in tablets. We
use survival as a guiding light and yet we know our infants don't do as
well. Over my career, we have seen the
survival rate of children with cancer improve so now we think 75 to
80 percent of children with cancer will be living for five years.
We are looking at genetics as perhaps the reason that we
are missing the last 10 or 15 percent, but maybe it is bioavailability of
drugs. I don't know if this is
commission of the FDA, but I am taking a message back here that the protocol I
referred to this morning where we use
the white count, where we maximize our dose until we figure out more
sophisticated ways of handling drug dosage, may, in fact, be the way we should
operated in pediatric cancer. And we
really aren't doing this across the board.
DR. SANTANA:
Comments or reactions to Jerry's comments?
DR. ADAMSON: I have
one.
DR. SANTANA: Peter?
DR. ADAMSON: I
think, for maintenance therapy in ALL, that is still the gold standard and I
agree we may never improve upon the gold standard for maintenance therapy
despite what we know. But for much of
the rest of therapy, we don't have the white count to adjust our doses to. And we certainly, even in maintenance
therapy, probably avoid toxicity but not necessarily do what we are supposed to
do and that is maximize response by increasing dose as frequently as we ought
to.
So it works in maintenance therapy and we are lucky. We may never improve upon maintenance therapy
beyond the white count. But it really
doesn't, I think, carry over to the vast number of other agents that we utilize
in pediatric oncology. We don't have a
surrogate like that.
DR. SANTANA: I think
it also begs the question that most of the drugs that we use in oncology and
pediatrics are actually intravenous drugs.
So when we move into the oral use of drugs, we have to demonstrate that
there is a good rationale for doing it orally, that it does provide a different
advantage, whether the advantage is compliance, absorption, end effect.
I think that, to me, is a criterion that needs to be
incorporated when one makes a decision that maybe giving this drug orally is
better. There may be many different
things that make it better. It is just
not the end result that the patient is cured because you could get that by
giving it I.V. if you wanted to, if that is true. That is not true for all drugs.
So I think that also has to be part of the consideration
that every disease and every drug is a little bit different and we always have
the advantage of giving it intravenously because most of them were developed
intravenously.
I am advocating for oral drugs. I am just saying that, when one talks about
oral drugs, one has to have a good rationale why one wants to use it
orally. There has to be a reason for
that.
DR. HIRSCHFELD: I
would like to point out that the context for having this discussion is not
restricted to the off-patent drugs that we talked about this morning but for
all pediatric oncology drugs. Many of
the products that Rick and Rik and I are seeing are now oral products with
different types of targets.
What we would like to see is some type of anticipation
that, if we could have, as a result of this discussion, some principles or some
goals so that when we talk to companies developing these oral cancer
therapeutics, that we could not only ask them if they are interested in
pediatric formulation but that we could give them some specific advice and
maybe even develop, as Dr. Przepiorka pointed out, a potentially useful
guidance document to assist them.
Then we also all know, as the point has been made before
but I will just make it again, one aspect, and that is, if you develop a
pediatric formulation, also geriatric population, handicapped population,
chronically ill people, will benefit as well as people who just would like to
have a choice in the modality of taking their medication.
DR. SANTANA:
Richard?
DR. PAZDUR: I would
like to respond to Jerry's comments because I hear a frustration and I feel
it. It is not unique only to pediatrics
but I could say the same thing in adult medications, that our knowledge of what
is the correct dose to use of an oncology drug is tremendously limited in adult
oncology.
We have bought into more is better, more is better, more is
better and have adapted that. There is
very little in the way of dose-finding studies in oncology. Once a drug is approved at the maximum
tolerated dose, it is almost impossible to go backwards and say, can we use
less of a dose in a particular disease.
Those studies are very difficult to do.
This whole area of what is the correct dose, not only dose
formulation but dose, whether one takes a look at a white count or whatever, is
a very, very difficult one throughout the whole field of oncology.
But I think, you know, what Steve is bringing up, we are
seeing more and more drugs being developed in an oral-dosing formulation. One story I would like to share with you for
a degree, perhaps, of pessimism about a field, if you take a look at the drug
IV 5FU, it took us almost 40 years to come up with a commercially oral form of
that--i.e. capesitabine--to be delivered from when that drug originally came
out in the late 1950s to the approval of capesitabine in the 1990s.
That had a lot to do with looking and understanding the
pharmacology and going back not just to formulation but to the understanding of
the drug in a pro-drug formulation and really creating a new drug.
Giving the drug in an oral fashion also is not necessarily
the same thing as an IV formulation. You
may get better efficacy changing in toxicity profiles, et cetera, and can turn
a relatively marginal drug into a much better drug by continuous exposure. As Steve pointed out, I think a lot of the
pharmaceutical firms are getting away from the fear of developing oral
medications.
There was a tremendous fear in oncology due to the
reimbursement issues regarding oral medications, that this was considered
really a taboo area even to touch. It
was almost the third rail to develop an oral anticancer drug because of
reimbursement and the acceptance of private-practice medical oncologist.
However, I think we are getting away from that as we learn
more about the drugs and different targeted agents and the obvious need that
these drugs are going to have to be administered on a chronic basis.
So I think several points that I want to bring out. A change in the science that is going to go
toward more oral medications, as Steve
pointed out, and also the fact that it may not even be just a formulation issue
but thinking about kind of tricks to use in presenting the drug to the body as
capesitabine, as a prodrug of the drug 5FU.
DR. SANTANA:
Clinton?
DR. STEWART: So I
would like to maybe pick up on some of the stuff that Rick is saying. You know, with some of the targeted therapies
like the erbB inhibitors like Iressa and some of the other compounds that are
coming out, obviously they are being developed as oral therapies.
So we have been doing some studies with those compounds
and, you know, we talk about the formulation of the compound. One of the things that I would like to see
also come out is maybe the dosage size.
I say that on the one hand. I
will say, on the other hand, we have been very fortunate in the three studies
that I am participating in, that even though we are using adult dosages, we
have been able to come really very close to the protocol-prescribed dosage, but
it would make it so much easier if we had a smaller pill size.
We don't have to change the formulation, but let's get us a
pill size that is smaller. I think that
would really help out a lot. So I think
that is another thing we should give consideration to.
DR. SANTANA: Other
comments? Yes?
DR. FLANAGAN: I
guess I have a question on a simpler level.
For even those drugs that are still given intravenously, do people feel
that there might be a need for the pediatric population to have either a
smaller volume in a vial so there is more room for dilution or to take the
adult volume in concentration and put it in a bigger vial to just make it
easier to handle for diluting or use? Do
people find any difficulties using the adult parenteral products?
DR. SANTANA:
Peter? Comments?
DR. ADAMSON: I think
probably pediatric pharmacists could better address. My sense is that, because the doses we tend
to use intravenously in children tend to be large, it is not a major
issue. I think when you start talking
about infants in vincristine, you may start getting into that type of
issue. But I think that is an issue that
a pediatric-oncology pharmacist could probably more readily answer. But vincristine is the only one that jumps to
mind and I might be wrong on that one as well.
DR. SANTANA: Donna?
DR. PRZEPIORKA:
Actually, the other person who might address that is the geriatric
oncology pharmacist because we ran into a similar situation with adults who are
on multiple medications with multiple interactions which not infrequently
require a reduction in dose.
Unfortunately, the way Medicare reimburses is if you have a
single-use vial and you only use half the dose, Medicare only pays for half the
dose despite the fact that the practice has to throw away the other half of the
dose. So it becomes a real cost issue.
DR. SANTANA: Alice?
MS. ETTINGER: I
think it leave a lot of room for error in some of the formulations, as I guess
you pointed out--someone pointed out in a very nice slide--that there is a lot
of room for error. Getting back to
actinomycin, I mean, if I have ever seen a drug that is downright dangerous in
terms of how it is formulated, I think that that is certainly one. It is tiny, but the smallness is actually
more of its danger in micrograms and milligrams. So I think there is some room there certainly
for different strengths to be manufactured.
DR. SANTANA: Pat?
DR. REYNOLDS: Just
going back to the oral comments from Clinton, I agree completely about the
smaller pill size. I know of at least
one pharmaceutical company that talked to us about potential pediatric
applications and, after talking to us, said, oh; we are going to keep the
smaller pill size. They were about to
toss it out because, by the time they got to that point, they realized that
their MPD didn't justify it in adults.
I think if FDA, in their having their pre-IND discussions
or whatever discussions, would just simply remind them of the potential for
pediatric, they may keep in the hopper those smaller pill sizes they probably
developed anyway. It is not a big cost
and it would, I think, add a lot of flexibility.
DR. SANTANA: Jerry?
DR. FINKLESTEIN: I
would like to answer Dr. Flanagan's question from one clinician's point of
view. In actual fact, it is really the
antibiotics that cause us the greatest problem when we are worried about fluid
intake. Trimethaprim sulfa is one that
comes to mind. The amount of fluid that
it requires is quite a challenge sometimes to pediatrics. I don't think it is the actual anticancer
agents that we run into a problem with on a day-to-day basis when we are
worried about fluid intake in patients that we have to watch this very
carefully and closely.
DR. SANTANA: Good
point. Rik?
DR. LOSTRITO: Thank
you. I just wanted also wanted to
respond to Clinton's comment before about having multiple or smaller
dosages. I think your point is very well
taken and so in Patrick's in response. I
don't want to diminish that. But I can
say that it is not a trivial matter for drug companies to develop these
collateral strengths or smaller strengths, that quite a body of data is needed
to support the marketing of that in terms of definitely stability, perhaps
bioavailability, data.
So it is an offsetting and competing forces of cost versus
utility. But I think your point is well
taken but it is not a trivial matter. It
is something that I am sure most firms put some thought behind before they pick
a strength or two.
DR. HIRSCHFELD: I
would just like a point of information to Dr. Reynolds' aspect, not just in
oncology but in principle across all the FDA, whenever someone comes in with a
new product for development, they are asked, routinely and repeatedly, what
their pediatric plan is.
DR. REYNOLDS: If I
could ask there, I know it is not trivial, but if you are talking about a
half-milligram versus a 1-milligram tablet size, is that really that expensive
an issue?
DR. LOSTRITO: It is
perhaps maybe a little more expensive than you think. Firms have to show that they can manufacture
that strength. They have to provide data
to do that. They have to provide
stability data, shelf-life data, show the packaging presentation. So it is not double the cost to develop a
second strength but then, again, it is not 1 or 2 percent of the total cost,
either. It is somewhere in between.
How significant an expense it is, I couldn't answer but I
do know, looking at the data I see routinely, that it is a fair amount of work.
DR. SANTANA: Thank
you.
DR. SMITH: I would
just second it as a big issue, though.
We have had examples where the capsule or tablet is marketed as a
certain large size but there happen to be smaller sizes that were used during
the development. So those were done for
pediatrics, but then those run out and what is left for further pediatric
evaluation.
So, as more and more drugs are oral and given on a rather
continuous basis, it will become more and more of an issue. When we talk with companies about it, it is
very clear to us that it is not a trivial issue for them. I think it is a very important one to address
and I think it will be hard to address.
DR. SANTANA:
Richard?
DR. PAZDUR: Every
time there is a change, there is a potential for a mistake. I will just share with you a story, and I
won't mention the drug, but a manufacturer from the clinical-trial tablet just
changed the shape of the tablet as well as adding I think it was some dextran
to it. That led to the product being not
bioequivalent to the drug that they studied, that they did their clinical
trials, which really caused a tremendous amount and potentially a delay of
really getting the drug approved for I think it was months, six months or
so. It was relatively trivial. It was shape and, I think, color of the--and
dextran.
DR. LOSTRITO: We
would not have expected the minor changes that were made to have the impact
they did. So you just never know what
small changes can lead to big effects.
DR. SANTANA: Dr.
Boyett?
DR. BOYETT: I would
just like to echo the pill size, especially you may not be able to change it,
but when you are doing phase I trials in pediatric oncology, you really need to
be careful about it because the tradition phase I trials, the pediatric
oncologists use the 3 and 6 rule. So,
oftentimes--in fact, we have got a study in the Pediatric Brain Tumor
Consortium that we would really have fooled ourselves what the maximum
tolerated dose was and what dosing we were giving because of the size of the
pills and the size of the kids. I think
that is not paid attention to very much in pediatrics.
DR. SANTANA: Pat?
DR. REYNOLDS: Just
to return to the problems of how much it would cost to do, I wonder if the
tablets are encouraged to be at least scored, would that not allow you to have
the same formulation and do everything for the adults with one tablet? But, at least if they are scored, ideally, in
four parts but, if not, in two, then at least you would have some
flexibility. It is not as ideal as a
separate particular dosage, but it is better than crushing the thing and trying
to measure it that way.
DR. LOSTRITO: You
bring up a good point. It is a good
compromise.
DR. SANTANA: I think
we are done with our comments and presented session, so I want to go ahead and
try to address the questions that the FDA wants use to help them with.
Committee Discussion of
Questions to Subcommittee
DR. SANTANA: The
first one, actually it is like--that is why I was asking the question earlier,
is there anything out there that we can grab onto. So you are asking us to create a whole new
set of principles here, so we will do our best of trying to answer this
question which is what factors would be considered essential in the development
of a formulation for children with cancer.
So what things would we consider are important when we are thinking
about developing different formulations.
Specifically, they want us to comment on any age, disease
of pharmaceutical-specific considerations.
I think one thing that I heard earlier this morning and again this
afternoon is this whole issue of usage.
So if it is a drug like 6MP, which is going to be used for a long period
of time in a relatively, pediatrically speaking, large population, then, to me,
that would be an impetus of considering whether you push to get a formulation
developed for that particular drug. So
that would be one consideration.
So there it is a little bit the disease but also the
chronicity of the treatment going together in terms of guiding you that this is
an important formulation issue.
Peter?
DR. ADAMSON: I would
just reemphasize what I think Jeff hit upon and that is yes, a liquid
formulation is a step but we really need to start thinking about some of the
newer potential formulation deliveries, rapidly dispersible formulation, as
well as for long-acting medications, other route of delivery that liquid
formulations, in and of themselves, often are too small a step toward a
pediatric formulation.
Jeff, is that fairly paraphrased?
DR. SANTANA: Pat?
DR. REYNOLDS: I
think that we have heard, over and over again, particularly from nurses and
parents here about the need for having different ways of doing this, that the
same way won't work for the same kid all the time and certainly won't work for
different kids.
So I think, when one develops the formulations, I think
having the flexibility to incorporate them into foods to get them into the
child is, perhaps, one important point we should consider. Then I think that means that we are going to
have to study then, in the context of Dr. Hirschfeld's comment, that not all
applesauce is equal, meaning that we need to have, then, a defined set of foods
that it is studied with that we know are going to be safe and effective.
So it complicates the matter, but I don't see any other way
around it.
DR. SANTANA: Let me
see if I follow you. You are suggesting
that there should be like a standard set of foods that should always be
tested? Is that what you are hinting at
and should applesauce always be one of the vehicles that is tested, I guess is
where I am going.
DR. REYNOLDS: Many
years ago, when I talked to Steve Hirschfeld about this, he said, if you are
going to specify peanut butter, make sure you say--I won't say the brand, but
whatever brand, because that is then a uniform product or at least fairly
uniform.
So I think we need to think in those terms but I also think
that if there was in the guidance, Vic, that what you are saying is a standard
list of what should be tested, or potentially testing vehicles and that what
would be considered by FDA to be fairly standard versions of such foods, that
would be very helpful.
DR. SANTANA:
Clinton?
DR. STEWART: I would
like to actually pose a question just to get some feedback that would help me,
actually. When we do our oral studies,
to avoid this issue of food, what we do is we actually ask the child, the
parents to have the child to fast. So we
just get away from that whole issue of food.
But that is not real life. That
is not the way the child is going to be taking the drug. But it gives a real clear understanding of
the bioavailability of the drug.
We don't have the confounding issue of which brand of
peanut butter they had or applesauce, whatever.
But the issue is should there be studies in children like there are in
adults which evaluate the effect of food and, if so, should they be
standardized. If so, how should you
standardize those. Those are my
questions.
DR. SANTANA: Those
are the questions the FDA wants us to ask, to help them with.
DR. PAZDUR: The
adult food-effect studies are very difficult also, having participated in them
to develop oral medication. They
actually require--they have this breakfast--I call it the Breakfast of
Champions. I can't think of any cancer
patient that could actually eat it. It
is, like, three eggs, two pieces of toast, hash browns and four cups of coffee,
or I don't know what it is. But it is an
unrealistic breakfast for even a lumberjack, almost, let alone a 90-pound woman
that has cancer.
So that is very problematic. Here, again, when most people are developing
an oral medication, they generally do try to go to a fasting state because the
first of the problem for most of the sponsors is they really have to show that
the drug works. If they can't show that
the drug works, the drug is dead and you don't want it be to the fact that we messed up because everybody
ate--or the food absorption was erratic.
So you first have to answer, especially in an NDA process
when the drug is first being tested, when they are getting their initial
licensing application, does this really work, what is the most uniform
situation that you could have.
Nevertheless, we firmly support that drugs should be studied and labeled
with the way that the drug will be used.
I think that having pediatric-specific food studies would
be very much important to address this issue.
I couldn't underscore that more.
But we do have problems even in the adult situation here which we really
need to relook at and reexamine.
DR. HIRSCHFELD: I
think, just to clarify the question, the issue about food, not as in Food and
Drug Administration, but food with drug is if the formulation that is being
anticipated is one that is intended to be delivered with food as some kind of
carrier vehicle, then I think standardization would be beneficial.
That is a separate question from the food effects on a drug
which already has some formulation.
DR. STEWART: I'm
sorry; I don't mean to monopolize this, but I realize that we do put drugs on
food for kids to take. But that, in
itself, is problematic because what if the child doesn't eat all the food. Immediately, you have reduced the
bioavailability right there just by virtue of doing that.
Maybe I am stating the obvious, but I think that is really
very problematic, that whole issue of delivering drugs with food.
DR. HIRSCHFELD: It
is not something that is necessarily endorsed or encouraged, but it is
realistic that someone may have a sprinkle or some type of other formulation
where you would deliver it. That would
be the context for soliciting the advice.
DR. SANTANA: In
answering this question, there has to be an element of practicality. I heard a little bit about this earlier in
terms of when sponsors approach you guys, what they can and cannot do based
both on cost and other factors.
So I think maybe thinking this through out loud, maybe the
way to approach sponsors is to say, if this drug is going to be used in a
pediatric population and we are going to first assume that it will be used
across all age groups, then, first, there should be a pediatric
formulation. I am not the one to tell
you whether it should be a suspension, a sprinkle or whatever.
I am not the one to tell you, but one of the criteria would
be that if you think this will be used in children, you have to come up with a
formulation that is ethical to children.
So that would be the first cut, as I see it.
The second cut is if the disease in which this will be
used, obviously, is unbalanced in terms of the ages, so the HIV story is a good
one. Most of those kids cannot take
capsules. So, if the company came to you
and said, we want to develop an HIV drug for adults and our solution for
pediatrics is to develop a capsule. That
is irrational. That is not going to be
practical. It is not going to be used
that way.
You are going to have to develop something in a liquid
formulation or some other vehicle to treat the neonates and to treat the
two-year olds. So I guess what I am
hinting at in terms of trying to answer this question is that there is no
unique answer but there is a stepwise answer depending on, first, that if the
drug potentially is going to be used in children, we should request that a
formulation be derived, that we are not going to tell them what the formulation
is, that they have to, then, consider the impact of that medication across
different pediatric populations and then select the first formulation that they
want to test.
DR. PAZDUR: Let me
just ask you one question. Would you, as
a practicing pediatric oncologist, be willing to delay the development of drugs
in children until a pediatric formulation is made? In other words, if a company comes to us and
says, gee, you know, we are developing this drug in breast cancer and it is a
tablet that you could cut in half, but we are going to take probably two or three
years down the line and, perhaps, not until the NDA gets approved to taking a
look at pediatric formulations here, which is a realistic situation.
DR. SANTANA: But I
thought this committee is on the record of saying that we want parallel
development.
DR. PAZDUR: But that
is what I am saying is if they say, for example--if they say, we are willing to
start our pediatric studies with an adult formulation, a pill, part of a pill
or whatever, would you say that they should delay the development of that initiation
of the pediatric study?
DR. SANTANA: I will
let other people comment.
DR. ADAMSON: There
is a one-word answer which I think is no.
DR. SANTANA: I
agree. I just didn't want to
monopolize--
DR. PAZDUR: But that
is what we face in a real-life situation.
We have very little regulatory power to say, you must do a pediatric
formulation.
DR. STEWART: Do they
have to repeat those studies when they do come up with a pediatric formulation?
DR. HIRSCHFELD: No;
they can do the--
DR. SANTANA: That
will be Questions 2 and 3.
DR. HIRSCHFELD: Yes;
in effect. But, in short, Clinton, there
are mechanisms that, once you have a formulation that has demonstrated efficacy
and safety, then it is just another pathway in order to alter that.
DR. BLUMER: But what
is missing, though, is the carrot to do it.
I think we heard that many of the companies come to you with, perhaps,
the best of intentions and, perhaps, not.
But they at least tell you that they are going to try. It was interesting in the last experience I
had with this where a company said they were going to try and do this for
pediatric clinical trials and then they sort of shrugged their shoulders after
a year.
We went into the lab and made one and said, okay, here is
something, and they got all embarrassed and went out and made their own, of
course. But it happened in very short
order.
It wasn't for an oncology drug, but I think that this
is--without any sort of incentive, I don't think that this is going to be a
fruitful area. You are not going to
misbrand drugs that don't have pediatric formulations. No one here is interested in delaying drug
development until there is one. It is a
Catch 22.
DR. PAZDUR: From a
practical experience, having worked with companies in this area, do you feel
that they give a 100 percent good college try to try and develop these
pediatric formulations, or is it, well, we will kind of get to it mañana,
mañana, mañana, mañana.
DR. BLUMER: It is
very half-hearted. It really is, in
general. One of the things that
impresses me in this whole area of oncology, and I am going through this with
our hospital, is running our quality-assurance group. Our oncology floor has put together--we have
had no major medication errors in oncology in five years.
When I look at the gyrations that the staff has put
together to ensure that there are no medication--I said, this is wrong. Now we have a paradigm where even the
caregivers are reluctant to change because it works. But it takes hours and hours of extra time
and effort to ensure this because they don't have the right tools to do it.
It is just very wrong.
DR. REYNOLDS: I just
want to expand on the resounding no a little bit and say, you know, it seems to
me like this should be an evolving process, though. If somebody brings forward a new
antioncologic, to wait until they get around the pediatric formulation,
obviously, we don't want that delay.
But, secondly, if you try it in the pediatric population with the adult
formulation and you have got good pharmacokinetics yet you didn't get activity,
why would they want to go through the expense, or why would you want to
encourage them to do that expense.
But yet, on the same token, if you took whatever
formulation was available and you saw activity and it was, perhaps, suboptimal,
then that would drive the pediatric formulation. So I think it is an evolution, not a just
cart-and-horse issue.
DR. FINKLESTEIN: I
have a question for Rick. I would like
to piggyback on the geriatric concept that you used. Do you have data in what percentage of the
population are geriatrics that would need a liquid or some other kind of
formulation, either in oncology drugs or drugs in general? I mean gerontology is really increasing as a
field. If, indeed, it is significant,
could we, as pediatricians, piggyback upon your idea?
DR. PAZDUR: I am
probably the wrong person to ask because I am not in geriatric medicine. I think people that probably study this more
would have an example, or have the data that you are looking for. So I don't have the answer to your question.
DR. FINKLESTEIN:
Obviously, I am thinking that they are a very organized group.
DR. PAZDUR: I
know. You better believe it.
DR. FINKLESTEIN:
Getting them on this bandwagon would not be difficult if, indeed, it would
be a benefit to that patient population.
DR. PAZDUR: Hello,
AARP!
DR. HIRSCHFELD:
Jerry, this has been looked at. I
don't have the data but I know that the data do exist because there are a few
companies and other organizations that have examined this same issue over the
years to say it is not an age-dependent, it is a patient-dependent, question
about having the alternative formulations.
The reason we are trying to bring it up here in the
pediatric context, aside from that we feel the need, is that we have some
regulatory tools. We can do it through
the incentive program. We can make a
formulation as part of a condition of receiving the exclusivity extension if we
feel that that is required.
And we may have tool, in some pending legislation, to, in
some cases, as I think Dr. Flanagan noted, the Pediatric Rule which was struck
down a year ago, while this committee was meeting, I should add--
DR. SANTANA: We
won't read the paper tomorrow to see what has happened today while we are
meeting; right?
DR. HIRSCHFELD:
--may be enacted into law. Law,
of course, has greater authority than a regulation. Then we would have the leverage to also
compel that, too. But, again, it is
through the vehicle of pediatrics. So
any efforts that are done for other populations, and there are large active
organizations for handicapped patients and geriatrics, et cetera, the same
things we discussed earlier.
But they haven't been adequately motivated, at least to the
moment. So our focus is on the tools
that we would have at hand.
DR. SANTANA: I want
to encourage you, that, as you use those tools, which everyone--you ultimately
wind up selecting from, that a driving principle for this issue of formulations
is practicality. We could sit here for
three hours and say, ideally, this is what we should be doing and this is what
we want, like our Christmas list; right?
But, in practicality, there are some issues that I think
you have to resonate with the FDA as you approach the company so that we do get
some formulations and they are done in parallel as the adult studies are being
developed and not put them in a box where we won't get anything out of them.
DR. PAZDUR: I think
there has to be an element of practicality here. I think there is a difference in asking somebody
to do something and mandating them to do it are two different things. We have very limited power. Remember, even if the Pediatric Rule comes
back, there is a limited amount of extrapolatability here. Even if we use the exclusivity process, one
could say, well, if we put too many barriers in front of people, they may start
backing away from this.
We have really limited experience with that process. So there are a lot of things. It is very complicated issue that we face
frequently behind closed door that people do not see with the negotiations with
the pharmaceutical companies.
DR. SANTANA: Dr.
Boyett?
DR. BOYETT: I was
going to suggest exclusivity as a way to hang the carrot out there. So maybe what you do is you add another month
of exclusivity if you have a pediatric formulation or something like that.
DR. PAZDUR: That has
to be required by law.
DR. SANTANA: We will
work--
DR. HIRSCHFELD:
Right. But ideas like that have
been entertained and the legislation will come up in 2007. Just to tell you another idea that, because
it is harder to do studies in neonates and infants, there was some discussion
about adding some extra--but, all that is theoretical. But who knows? It could be practical in three years.
DR. SANTANA: I think
we have given you all the help we are going to give you with Question No.
1. So I want to move on to Question No.
2; what types of testing or clinical-trial design would you recommend for
establishing the efficacy and safety of a new formulation for an existing oncology
drug that already has efficacy and safety demonstrated in the same population?
Peter?
DR. ADAMSON:
Extremely limited, I think is how I would put it. I think, ideally, you would like to do
bioequivalence studies in adults as a starting point. Again, because these are cancer drugs, you
would have to do it in the adult cancer population which will make it
harder. But, when you can do it adults
and demonstrate bioequivalency, then I think consideration of doing a similar
study in children would be reasonable.
I don't think it is reasonable for us, except in very
limited circumstances, to undertake additional efficacy studies for
bioequivalent formulations. We don't
have those kinds of resources.
DR. SANTANA: That is
otherwise bioequivalent.
DR. ADAMSON: That is
otherwise bioequivalent. I think you
would have to individual because there are some drugs where, if they have a
very different absorption profile, you could predict that you actually have to
look at safety and efficacy, antimetabolites and other cell cycle. But, for others, you might take the knowledge
we know and say, well, to what degree do we have to look at differences in
safety and efficacy given differences in the profiles. So it would have to be, I think,
individualized to some extent on the nature of the drug.
DR. PRZEPIORKA: I
was going to disagree just a little bit and say that if you stick to the letter
of the question, it actually hadn't included pediatric versus adult. It just said what type of testing, the trial
for developing a new formulation.
I would suggest that it would be in the same population,
number one, and, number two, since it has already been shown to be safe and
effective and theoretically had a surrogate endpoint to monitor before waiting
ten years for outcome, use the surrogate endpoint as your outcome rather than
long-term survival.
DR. SMITH: I would
urge caution. If the new formulation is
similar and has bioequivalence, then that is one issue. But just the extreme issue of 6MP being an
example of that that we have been talking about all day, it was an oral
formulation, you give it every day. We
had the great idea--we didn't have the great idea, but there was the great idea
that you could give it intravenously and avoid all the variation and absorption
and all and that that would be a much more effective drug.
So we sponsored several clinical trials to try to prove
that point. You can't give the I.V.
formulation and mimic the same PK profile that you can with the oral and
the I.V. was inferior to the oral. So the new formulation, which had a very
different PK profile, was, in fact, less effective than our good-old oral 6MP.
So I think you really do have to individual and, if it is a
more convenient formulation with the same PK profile, it is one thing. If the PK profile is changing substantially,
then I would be very cautious about just accepting them as equivalent in terms
of their clinical effect.
DR. ADAMSON: I guess
to expand a little bit about that, we all recognize there are only a limited
number of phase III trials we can do in the pediatric cancer population. I think we would hard-pressed to commit one
of those trials to an equivalency study.
There would have to be really overwhelmingly compelling arguments to do
that.
DR. BOYETT: I would
like to follow up on that. Not only--the
phase III trials you typically do are not equivalency trials. So, when you undertake an equivalency trial,
your sample size goes up astronomically to prove there is absolutely no--so you
have got real problems if you think you have got to prove equivalency.
DR. SMITH: Both
points are well taken. It would be very
hard to do equivalence trials. The one
thing you could do, just to provide some confidence, is use a factorial
design. The question you are really most
interested in is some new drug, and, by the way, you are asking in that same
clinical trial a question about two different formulations.
So you don't expect there to be a difference and it is
almost a freebie. So, if there was a
case where you had some reason to want to be cautious, it may be possible to
use it as a second or even a third randomization in a trial that would
otherwise be ongoing.
DR. REYNOLDS:
Malcolm, what about--you are talking about drugs that might have vastly
different pharmacokinetic profiles. But
what about ones that have similar pharmacokinetic profiles. I agree with you, Peter, we only have so many
trials we can do, but I am wondering if they have very similar pharmacokinetic
profiles, couldn't your population-kinetics modeling be plugged into a
phase III study just using the new formulation to replace the old
formulation and validating that PK on a larger set of patients, therefore
killing two birds with one stone.
DR. SANTANA: I kind
of get a sense that Malcolm kind of agreed with that comment.
DR. SMITH: Again, it
depends on how similar is similar. The
further apart you get in the comparability of the two in terms of their PK
profile, the more and more cautious you would want to be about it.
DR. SANTANA: What
about question 3, which is the same question but now with a different
population. What type of testing or
clinical-trial design would you recommend for establishing the efficacy and
safety of a new formulation for an already existing oncology drug that already
has efficacy and safety demonstrated in a different population?
Go ahead, Dr. Boyett.
DR. BOYETT: The
efficacy question, I think, is simple.
You have got to do an efficacy study.
You haven't done it in that particular patient population in drugs that
are disease specific.
DR. SANTANA: Other
comments? So the sense there is that you
at least would have to do some efficacy trials since it is truly a different
population. Any other comments on this
question? Any other comments on the
session this afternoon? If not, I think
we are done unless Dr. Hirschfeld or Dr. Pazdur have some concluding comments.
DR. HIRSCHFELD: I
would like to thank everyone again for a very interesting and what has proven
to be stimulation session. I think we
have identified a number of issues, both in the morning and the afternoon,
which had not been anticipated in our other discussions which is always the
value of seeking advice.
We will make a commitment to move forward on these. I would also like to report back to this
committee that, as a consequence of the last meeting we had in July, that we
have been able to make progress on both those issues, one with regard to the
labeling or relabeling of 6-mercaptopurine.
I know that a representative of Teva Pharmaceuticals came here today and
they have been very interested in following through on that. We will report back to you what that final
label will look like, but the advice was extremely valuable.
Secondly, the advice that the committee provided for
multinational studies has resulted in interest in our European colleagues who
organized a meeting last month to address some of these issues and there will
be follow-through on trying to reduce and then equilibrate the regulatory
burdens for doing multinational studies.
So I wanted to committee to know that its work is not only
appreciated but is acted upon expeditiously.
DR. SANTANA: Thank
you.
DR. PAZDUR: To
follow up Steve's words, only one word, "Ditto." Bye.
DR. SANTANA: I think
Dr. Reynolds has one concluding comment.
DR. REYNOLDS: I just
have one question for either Rick or Steve.
I asked this last time and didn't get an answer.
DR. SANTANA: Try
again, Pat.
DR. REYNOLDS: I
thought I would try one more time. In
the Best Pharmaceuticals for Children Act, the FDA was mandated to give a
report to Congress on availability of drugs on January of 2003. I wondered if that report was going to be
made available to this committee to see if it had been delivered to Congress. It would be a very interesting report for us
to consider. Is that going to be made
available publicly at some point?
DR. HIRSCHFELD: The
anticipation is that it will be made available to this committee and will be
made available public. But we don't have
a date yet as to when that report will be issued.
DR. REYNOLDS: Thank
you.
DR. SANTANA: Thank
you everybody.
[Whereupon, at 3:30 p.m., the meeting was adjourned.]
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