FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

MEETING OF

THE PEDIATRIC SUBCOMMITTEE OF

THE ONCOLOGIC DRUGS ADVISORY COMMITTEE

8:09 a.m

Tuesday, July 15, 2003

Room 1066

CDER Advisory Committee Conference Room

5630 Fishers Lane

Rockville, Maryland 20857

ATTENDEES

CONSULTANTS: (Voting)

VICTOR SANTANA, M.D., Acting Chair

St. Jude Children\'s Hospital

JAMES BOYETT, PH.D.

St. Jude Children\'s Hospital

SUSAN COHN, M.D.

Northwestern University

NANCY KEENE, Patient Representative

(Present Morning Session Only)

HOWARD McLEOD, PHARM.D. (Present Morning Session Only)

Washington University School of Medicine

DAVID POPLACK, M.D.

Baylor College of Medicine

PATRICK C. REYNOLDS, M.D.

Los Angeles Children\'s Hospital

SUSAN SHURIN, M.D.

Case Western Reserve University

NAOMI WINICK, M.D.

Texas Southwestern Medical Center

SUSAN WEINER, M.D., Patient Representative

Children\'s Cause

ONCOLOGIC DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)

JODY PELUSI, F.N.P., PH.D.

North Arizona Hematology & Oncology Associates

GREGORY REAMAN, M.D.

Children\'s Hospital National Medical Center

ATTENDEES (Continued)

GUEST SPEAKERS: (Non-voting)

BARRY ANDERSON, M.D.

National Cancer Institute, NIH

LESLIE BALL, M.D. (Present Afternoon Session Only)

Office of Human Research Protection, DHHS

MALCOLM SMITH, M.D.

Cancer Treatment & Evaluation Program

National Cancer Institute, NIH

RICHARD WEINSHILBOUM, M.D. (Present Morning Session Only)

Department of Molecular Pharmacology

Mayo Clinic

INTERNATIONAL GUESTS: (Non-voting)

MARK BERNSTEIN, M.D.

Canada Pediatric Oncology Phase I Consortium

(Participated by Phone Afternoon Session Only)

JOACHIM BOOS, M.D.

University of Muenster, Germany

HUGH DAVIES, M.D.

United Kingdom Central Office for Research Ethics Committee

URSULA KERN, M.D.

Bundes Institut fur Arzneimittel und Medizinprodukte

BRUCE MORLAND, M.D.

United Kingdom Children\'s Cancer Group

RICCARDO RICCARDI, M.D.

Italian Pediatric Oncology Phase I Consortium

GILLES VASSAL, M.D.

French Pediatric Oncology Phase I Consortium

GUEST INDUSTRY REPRESENTATIVE: (Non-voting)

George Ohye

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

STEVEN HIRSCHFELD, M.D.

LARRY LESKO, PH.D. (Present Morning Session Only)

MURRAY LUMPKIN, M.D. (Present Afternoon Session Only)

DAVE MAYBEE, M.D.

THOMAS H. PEREZ, M.P.H., R.PH., Executive Secretary

VICTOR RACZKOWSKI, M.D. (Present Morning Session Only)

GRANT WILLIAMS, M.D.

ALSO PRESENT:

MARK RUSSO, M.D., PH.D.

C O N T E N T S

MORNING SESSION

Pharmacogenetic Testing for

Thiopurine Methyltransferase (TPMT) Deficiency in

Patients for Whom Treatment with Purinethol

(6-mercaptopurine, 6-MP) is Being Considered

\* \* \*

AGENDA ITEM PAGE

WELCOME

by Dr. Grant Williams 11

CONFLICT OF INTEREST STATEMENT

by Mr. Tom Perez 11

INTRODUCTION OF TOPICS

by Dr. Steven Hirschfeld 14

DESCRIPTION OF CDER OFFICE OF DRUG SAFETY PROGRAMS

by Dr. Victor Raczkowski 23

INTRODUCTION TO THIOPURINE METHYLTRANSFERASE

DEFICIENCY AND TEST

by Dr. Larry Lesko 35

by Dr. Richard Weinshilboum 44

by Dr. Howard McLeod 59

PERSPECTIVE OF THE CHILDREN\'S ONCOLOGY GROUP

ON THE USE OF 6-MERCAPTOPURINE

by Dr. Naomi Winick 86

OPEN PUBLIC HEARING

by Dr. Mark Russo 102

SUBCOMMITTEE DISCUSSION OF PRESENTATIONS 106

QUESTIONS TO THE SUBCOMMITTEE 139

C O N T E N T S (Continued)

AFTERNOON SESSION

Overcoming Challenges in Pediatric Oncology

Product Development: Regulatory Oversight of

Multinational Clinical Studies

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Mr. Tom Perez 180

OVERVIEW OF RESEARCH OVERSIGHT

United States Perspective - by Dr. Leslie Ball 186

United Kingdom Perspective - by Dr. Hugh Davies 200

German Perspective - by Dr. Ursula Kern 221

OPEN PUBLIC HEARING 238

SUBCOMMITTEE DISCUSSION OF PRESENTATIONS AND

QUESTIONS TO THE SUBCOMMITTEE 238

P R O C E E D I N G S

(8:09 a.m.)

DR. SANTANA: Good morning. Let\'s go ahead and get started.

The FDA has asked the Pediatric Oncology Subcommittee today to address
two issues to give them advice on. The morning session will be dedicated
to the issue of pharmacogenetic testing for patients receiving
Purinethol, and in the afternoon session, we\'ll have a general
discussion advising the FDA on how we can overcome challenges in
multinational international studies.

So with that brief introduction, I want to welcome everybody and say
good morning to everybody.

For the purpose of the record, we all need to introduce ourselves. If
you could please, beginning with Ursula over there in the corner, state
your name and your affiliation. Thank you.

DR. KERN: Ursula Kern from the Federal Institute for Drugs and Medical
Devices in Germany. I\'m, as a manager, responsible for our national
advisory committees, among them our pediatric expert group. Thank you.

DR. DAVIES: I\'m from the Central Office of Research Ethics Committees
in the United Kingdom. We have the task of overseeing the research
ethics committees in the United Kingdom and their consideration of
research applications.

DR. MORLAND: Bruce Morland. I\'m chairman of the United Kingdom
Children\'s Cancer Study Group, New Agents Group.

DR. BOOS: Joachim Boos from the University of Muenster and from the
German Pediatric Oncology Society.

DR. VASSAL: Gilles Vassal from Institute Gustave Roussy in France and
the chairman of the European Consortium for Innovative Therapies for
Children with Cancer.

DR. RICCARDI: Riccardo Riccardi from the Catholic University of Rome,
chairman of the Department of Pediatric Oncology, and chairman of the
New Agents Group in the Italian Association for Pediatric and Hematology
Oncology.

MR. OHYE: I\'m George Ohye. I\'m the industry representative. This is my
first meeting, so Dr. Hirschfeld asked me to say a few words about an
industry rep.

The Food and Drug Modernization Act that was signed by President Clinton
during his administration provided for all advisory committees to have
an industry rep. So you\'ll often see an industry rep at advisory
committees. I\'m a retired senior vice president of Johnson & Johnson\'s
Pharmaceutical Research Institute. What FDA has tried to do and industry
has tried to do is get a cadre of retired pharmaceutical folks to serve
as industry reps, thinking that they would be more neutral rather than
representing or being paid by one company.

I\'m happy to be here. I think my role is to provide an industry
perspective. For example, if you have questions on how industry might
develop or review protocols, I might be able to answer some questions on
that. So I\'m happy to be here and good morning, everyone.

DR. SHURIN: I\'m Susan Shurin. I\'m at Case Western Reserve University
in Cleveland, and I represent the Ethics Committee of the Children\'s
Oncology Group.

DR. WINICK: Naomi Winick. I\'m from UT Southwestern in Dallas and I\'m
the vice chair for clinical trials for COG for ALL.

DR. POPLACK: David Poplack, Baylor College of Medicine, Texas
Children\'s Cancer Center.

DR. McLEOD: Howard McLeod. I\'m a clinical pharmacologist at Washington
School of Medicine in St. Louis.

DR. WEINER: I\'m Susan Weiner from the Children\'s Cause. I\'m the
patient/family representative.

MR. PEREZ: Tom Perez, Executive Secretary to this meeting.

DR. SANTANA: Victor Santana from St. Jude\'s Children\'s Research
Hospital in Memphis, Tennessee.

MS. KEENE: Nancy Keene, patient and family representative.

DR. COHN: Susan Cohn and I\'m from Children\'s Memorial Hospital in
Chicago.

DR. REYNOLDS: Pat Reynolds, Children\'s Hospital, Los Angeles.

DR. BOYETT: James Boyett from St. Jude Children\'s Research Hospital,
chair of biostatistics.

DR. REAMAN: Greg Reaman, the Children\'s Oncology Group and the George
Washington University.

DR. PELUSI: Jody Pelusi. I sit as the consumer rep and I\'m an oncology
nurse practitioner.

DR. SMITH: Malcolm Smith, Cancer Therapy Evaluation Program, NCI.

DR. WEINSHILBOUM: Dick Weinshilboum, clinical pharmacologist, Mayo
Medical School, Mayo Clinic.

DR. LESKO: I\'m Larry Lesko from the Office of Clinical Pharmacology and
Biopharmaceutics in CDER, FDA.

DR. MAYBEE: Dave Maybee, FDA, Center for Biologics, representing the
Office for Cell Tissue and Gene Therapy.

DR. HIRSCHFELD: Steven Hirschfeld from the FDA, and I\'m in the Division
of Oncology Drug Products and the Division of Pediatric Drug
Development.

DR. WILLIAMS: I\'m Grant Williams. I\'m the Deputy Director of the
Division of Oncology Drug Products, and I\'m subbing today for Dr.
Pazdur who had to be out of town.

DR. SANTANA: Thank you to everyone and welcome again.

Mark Bernstein is not here this morning, but this afternoon he\'ll be
phoned in as part of the proceedings for this afternoon.

I don\'t know if Dr. Hirschfeld and Dr. Williams want to address the
committee as an introduction?

DR. WILLIAMS: Yes. On behalf of Dr. Pazdur and the FDA, I\'d like to
welcome you all. We are very appreciative to you for taking a day and
what must have been quite a substantial amount of time for our overseas
colleagues to share your knowledge and discussions and recommendations
with us.

I wanted to also recognize Dr. Hirschfeld who has, as always, spent a
great deal of time preparing for this meeting, and Tom Perez who is also
making sure it comes off as it should.

So I want to thank you all and we look forward to these very important
discussions.

MR. PEREZ: Good morning. The following announcement addresses the issue
of conflict of interest with regard to this meeting and is made a part
of the record to preclude even the appearance of such at this meeting.

For the topic this morning, all subcommittee participants have been
screened for conflicts of interest. The reported financial interests
have been evaluated, and it has been determined that the interests
reported by the participants present no potential for a conflict or the
appearance of such at this meeting, with the following exceptions.

Dr. Susan Cohn has been granted waivers under 18 U.S.C., section
208(b)(3) and 21 U.S.C., section 355(n)(4) for owning stock in the
sponsor of Purinethol. The stock is valued between \$5,001 to \$25,000.

Dr. Victor Santana has been granted a waiver under 21 U.S.C., section
355(n)(4) for owning stock in the sponsor of Purinethol. The stock is
valued between \$5,001 to \$25,000. Because the value of the stock falls
within the de minimis exception, 5 C.F.R. 2640.202(a)(2), a 208 waiver
is not required.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building.

With respect to FDA\'s invited guests, there are reported interests that
we believe should be made public to allow the participants to
objectively evaluate their comments.

Richard Weinshilboum would like to disclose that his employer, the Mayo
Foundation, holds a patent related to the human thiopurine
S-methyltransferase. The patent is nonexclusively licensed to
Variagenics, Inc. Mayo received an up-front payment of cash and stock,
with the stock being owned entirely by Mayo, totaling less than
\$100,000, and has a right to earned royalties for products sold by
Variagenics. All of the stock was sold in March 2001 and to date, no
earned royalties have accrued. Under Mayo\'s royalty sharing policy, Dr.
Weinshilboum has personally received \$3,188 and is entitled to share in
any future payments that might be received by Mayo under this license or
any third party license for this technology. Mayo is presently actively
seeking additional licenses for this patent.

We would also like to note that Mr. George Ohye is participating in the
meeting as an acting industry representative, acting on behalf of
regulated industry.

We would like to remind the special government employees of the need to
exclude themselves from discussions involving specific products or firms
for which they have not been screened for conflicts of interest. Their
exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

This afternoon we\'ll have another statement read concerning the
different topic that will be discussed then.

I would like to point out that we have a revised presentation for Dr.
Lesko that was placed on top of your handout. The one inside is the old
one. The one on top is the new one. Thank you.

DR. SANTANA: Thanks, Tom.

Anybody else that wants to disclose anything now publicly?

(No response.)

DR. SANTANA: Okay, thank you. With that, then we\'ll hand it over to Dr.
Hirschfeld to give us a brief introduction to the topics that we will
try to cover today. Steve?

DR. HIRSCHFELD: Good morning, and thank you, Dr. Santana. I would like
to thank my colleagues in Division of Oncology Drug Products and in the
Division of Pediatric Drug Development and the Office of Pharmaceutical
Sciences for what has been a very interesting and I hope productive
collaboration in establishing the agenda for this meeting and planning
the particular questions and the selection of our guests.

I want to also echo a particular welcome to our guests who have traveled
from so far and such great distance to come here to participate in this
advisory committee hearing.

The Pediatric Subcommittee of the Oncologic Drugs Advisory Committee has
met on six previous occasions to address a variety of issues. The first
meeting was in September 2001 where there was a discussion of methods
that may be used to describe and link tumor types.

That was followed by discussions in April 2001 on hematologic tumors and
the Pediatric Rule which was a regulation which described the imperative
for doing pediatric studies if adult studies were submitted to the
agency for review and the indication that existed in the adult
population was also found in the pediatric population.

And there was a subsequent meeting in June 2001 which focused on solid
tumors and central nervous system malignancies and the Pediatric Rule.

In November 2001, there was a meeting which discussed study designs with
a particular emphasis on extrapolation of data from adult populations to
pediatric populations and on doing studies in populations of limited
size, particularly some of the rare tumors that are found in pediatric
oncology.

In January 2002, this committee was incorporated into law in the Best
Pharmaceuticals for Children Act, section 15.

A subsequent meeting in October 2002 discussed the timing of pediatric
clinical studies and the criteria for initiating studies with
investigational agents, which led to the recommendations which were
posted on the internet.

And in March 2003, there was a discussion of pediatric information to be
included in oncology product labeling.

Today\'s theme is risk assessment in pediatric oncology. The first
presentation will be from Dr. Victor Raczkowski who is the Director of
the Office of Drug Safety and will give an FDA general perspective on
risk assessment. That will be followed in the morning session by a
discussion of proposed change in the product package insert for
6-mercaptopurine to include pharmacogenetic screening recommendation and
in the afternoon by a discussion of regulatory and patient protection
procedures and perceived barriers ‑‑ and the perceptions might well be
real, we recognize, but we will discuss them ‑‑ to the implementation of
multinational studies in pediatric oncology.

To help everyone understand the issue that is being addressed this
morning with regard to 6-mercaptopurine, I recognize that Drs. Lesko,
Weinshilboum, and McLeod will give us details, but I wanted to offer
some of the substance of the discussions that we had leading up to this
particular meeting.

6-mercaptopurine was synthesized by Elion and Hitchings to inhibit cell
growth and it was approved by the FDA in a matter of weeks, I might add,
for treatment of acute leukemia in 1953. It has been used as a component
of anti-leukemia therapy in pediatric oncology, particularly in clinical
trials, for the past 50 years.

The current product package insert states in the indications and usage
section that mercaptopurine is indicated for remission induction and
maintenance therapy of acute lymphatic leukemia. And the product package
insert uses the terms lymphatic, lymphocytic, and lymphoblastic to refer
to the same set of diseases.

There is a caution at the head of the product package insert, which
states that mercaptopurine is a potent drug. It should not be used
unless a diagnosis of acute lymphatic leukemia has been adequately
established and the responsible physician is knowledgeable in assessing
response to chemotherapy.

In the warnings section of the product label, there is a notation ‑‑ and
I won\'t read every word of this ‑‑ but that there are individuals with
an inherited deficiency of the enzyme thiopurine methyltransferase who
may be unusually sensitive to the myelosuppressive effects of
mercaptopurine, and a note that substantial dose reductions may be
required to avoid the development of life-threatening bone marrow
suppression in these patients. There are references in the product label
which amplify some of the comments which are made in that section.

The dosage section states that 6-mercaptopurine is administered orally.
The dosage which will be tolerated and be effective varies from patient
to patient and therefore careful titration is necessary to obtain the
optimum therapeutic effect without incurring excessive, unintended
toxicity. And once a complete hematologic remission is obtained,
maintenance therapy is considered essential. Maintenance doses will vary
from patient to patient.

The estimated number of affected patients with thiopurine
methyltransferase deficiency and acute lymphoblastic leukemia is based
on two sets of data. One is the estimate of how many children in the
United States have acute lymphoblastic leukemia, which if one takes
figures from the National Cancer Institute surveillance epidemiology
response program, there are somewhat over 3,000 children in the United
States who are diagnosed with leukemia and approximately 2,400 have
acute lymphoblastic leukemia.

Based on a frequency of 0.3 percent, or approximately 1 in 300, of the
homozygous deficiency and assuming proportionate representation in the
leukemic population, as in the populations previously studied to derive
this figure, an estimated 8 children in the United States per year would
be affected as homozygous.

Based on the frequency of an estimated 10 percent heterozygous
deficiency and with similar assumptions as above, an estimate 240
children per year would be affected who would be heterozygous.

The question of dose adjustment should be based on data, and the data on
dose adjustment in the literature, both in the United States and
primarily in the United Kingdom, are that for homozygous patients, the
data are somewhat limited and variable. There are a number of
suggestions which are made in individual case reports. And for the
heterozygous reduction, there are one or two retrospective studies but
no data exist from a cooperative group prospective clinical trial on
what dosing regimen is appropriate to use.

And questions regarding the assessment of 6-mercaptopurine metabolism.
Again, these are just questions that were being raised in our internal
discussions. How does one correlate the highly variable absorption of
the oral drug to serum levels, the rapid metabolism in the blood, and
the product label states that the half-life is approximately 20 minutes
in children, and the red cell test for 6-thioguanine nucleotides which
uses living red blood cells, but it may not represent the true tissue
levels.

And some of the questions regarding genetic testing are which mutant
alleles are captured by which tests. Will different tests have different
results? And should testing procedures receive formal FDA approval?

Our decisions are based on evidence, and the applicability of
extrapolation from published reports should be borne in mind. For
instance, can toxicity seen with intravenous preparations of
6-mercaptopurine be applicable to oral preparations? Can complications
of patients that have received one type of therapy, for instance,
intracranial radiation or particular combinations and sequences of
chemotherapy, since there are a variety of regimens available to treat
acute lymphoblastic leukemia, be considered to represent patients that
have not received that particular therapy?

We want to be clear that not at issue is the rationale for
pharmacogenetic testing in general nor the rationale for
individualization of dosing to minimize risk. What we are focused on is
for this product and for the indicated patient population, what should
our recommendation be.

This afternoon we\'ll discuss international cooperation, and at the
recent meeting of the American Association of Cancer Research, the
president of the association, Dr. Susan Band Horowitz said, \"To
proceed, science must cross boundaries.\" Pediatric oncology is a set of
diseases with about 13,000 new cases per year in the United States. To
complete studies in a timely manner and to effectively use limited
resources, international cooperation is necessary. The FDA is issuing
written requests for pediatric oncology studies with time limits to
improve access to investigational drugs and stimulate clinical research.

For international studies to proceed in a timely manner, regulatory
requirements must be consistent. Regulatory requirements that pertain to
study initiation and study monitoring have been perceived as barriers.
And we should note that pediatric oncology studies may or may not be
intended for registration of a marketing claim, but are most often
initiated to define optimum therapy for a particular population.

So what we are seeking are recommendations on how to achieve consistency
and minimize barriers in multinational international studies in
pediatric oncology.

Thank you. And I will now introduce Dr. Victor Raczkowski who is a
pediatrician himself and has had a number of positions within the Food
and Drug Administration and will now comment on risk assessment.

DR. SANTANA: Thank you, Steve. Can I ask you a regulatory question?
Either you or Victor may answer this in his presentation. But the
current warning section for Purinethol in the package insert that
describes the issue of TPMT deficiency, when was that inserted and under
what review was that inserted? Can you clarify that for me?

DR. HIRSCHFELD: I can\'t give you the precise date, but it was within
the last 5 years. It was more than a year ago, that I can attest to. And
it\'s part of an ongoing dialogue between pharmaceutical sponsors and
the FDA to maintain currency in product labeling. In this case, the
pharmaceutical sponsor was GlaxoSmithKline, and if I may, I will just
ask Dr. Peter Ho from GlaxoSmithKline if he has a further comment on
that particular question.

DR. SANTANA: The question is when did this get inserted into the warning
label and under what review process was it inserted. That\'s the
question.

DR. HIRSCHFELD: That\'s all right, Dr. Ho. I didn\'t mean to put on the
spot. I thought if you had some additional information you wished to
add, we\'d give you the opportunity.

DR. SANTANA: Thanks, Steve.

DR. LESKO: Steve, can I add to that? In the label, there are two
references that are related to that statement. One is from 1991 and one
is from 1993.

DR. RACZKOWSKI: Good morning. My name is Victor Raczkowski and I\'m the
Director of the Office of Drug Safety. Dr. Hirschfeld asked me to
address two large issues in risk assessment in the postmarketing and
pre-approval arena, as well as risk management. So my talk will be
focused on broad conceptual issues.

CDER assures that safe and effective drugs are available to the American
people, and here I would just like to note that there are three
components to the CDER mission statement. One is the safety of drugs.
One is the efficacy, and the third is access to drugs or drug
availability.

Now, the mission of the Office of Drug Safety, we evaluate drug risks
and we promote the safe use of drugs by the American people.
Traditionally the Office of Drug Safety has been primarily concerned
with evaluating postmarketing signals generated through the Adverse
Event Reporting System, but more recently, the Office of Drug Safety is
getting increasingly involved in pre-approval risk management plans and
assessment of drugs because the evaluation of safety is a continuum
throughout a product\'s life cycle. And in addition, instead of just
relying on a spontaneous adverse event reporting system, which has
limitations that I\'ll get into, the Office of Drug Safety uses a number
of databases in order to better address and assess drug risks.

Now, all medical products, when they\'re approved, are required to be
safe, but safety does not mean the absence of risk. I don\'t think I
need to emphasize to this group that a safe product is one that has
reasonable risks given the magnitude of the benefit expected and the
alternatives available. For example, if there is a great benefit, such
as improvement in survival, then the risks that may be acceptable are
generally greater for those sorts of drugs than if the benefit is less.
Or similarly, if a drug has therapeutic alternatives which are safer,
then the risks that would be acceptable with that drug would be less.

What I\'d like to do is talk about postmarketing surveillance and some
of the issues associated with this. I think that this group knows the
issues of clinical trials. Clinical trials are generally of limited
size, limited duration, and oftentimes safety signals are not completely
evaluated in the premarketing arena because of some of these
limitations. But postmarketing surveillance also has limitations, and
traditionally, as I said, we\'ve used the Adverse Event Reporting
System, but this is a passive system and it\'s best probably for
evaluating signals or detecting signals.

Now, the traditional role of the FDA has been in risk management to
approve a drug, and labeling it would be the primary risk management
tool that would be used. However, product labeling has variable
effectiveness in terms of its comprehension, in terms of its adherence
by either physicians, other health care providers, or patients. And more
is needed in some cases because there are sometimes unacceptable levels
of morbidity and mortality due to errors, poor quality, and those sorts
of things.

So what there is a need for is a systematic approach to improving safety
and to reducing errors. Risk management encompasses the assessment of
the risk, either control or prevention or mitigation of that risk,
communication of that risk to all affected parties, including health
care providers, as well as patients, and then evaluation of the
effectiveness of any risk management intervention.

Now, FDA also has a role in larger risk management systems.
Traditionally the main interaction that FDA has had has been with
industry in terms of drug approval, but in order for risk management
interventions to be successful, there needs to be broad stakeholder
involvement. These include patients or consumers, health care
professionals, pharmacists, insurers, HMOs, the industry, and government
agencies such as the FDA and others.

Now, in the Office of Drug Safety, we evaluate, as I said before,
primarily postmarketing risks associated with drugs. The reviewing
divisions in the Office of New Drugs continue to evaluate clinical trial
data even after a drug has been approved. We also use drug utilization
databases. My main focus in terms of risk assessment will be on these
first two items, the Adverse Event Reporting System and the drug
utilization databases. Again, I will not go deeply into discussion of
clinical trials or use of other epidemiological tools such as cohort
studies or case-control studies.

But in addition, the agency also has agreements to evaluate safety
signals through cooperative agreement programs, the CERTs program, which
is the Centers for Education and Research on Therapeutics, and through
other collaborations such as with the VA system.

Now, the Adverse Event Reporting System. I think it\'s important to
understand its strengths, that it is a signal detection system in the
postmarketing arena. And it\'s a computerized database which arose
roughly in about 1997. However, it has adverse event reports going back
for over 20 or 30 years.

Now, the adverse event reports are submitted by sponsors when they
become aware of an adverse event, and this is mandatory once the event
is detected. However, health care providers and consumers give voluntary
reports. For example, if you look at the back of the Physicians\' Desk
Reference, you\'ll see that there\'s a MedWatch report where any
physician or health care provider or patient could report an adverse
event to the FDA, and that is voluntary. These adverse event reports
also include medication error reports.

Now, some of the strengths of AERS are that it can identify uncommon
adverse events and can identify adverse events in special populations,
and it provides information on real-world use of drugs. Again, clinical
trials are typically of limited size and the number of patients can
limit the ability to detect adverse events. Clinical trials, in a sense,
are very ideal conditions of use where patients are on protocols and
that may differ from the real-world use, the types of monitoring, the
careful administration of drug, and so forth.

Now, a major limitation of AERS ‑‑ and I think this is important for
folks to understand ‑‑ is that it does not provide rates of adverse
events and there\'s limited information in case reports. For example,
since it is a voluntary reporting system, we do not know the number of
adverse events associated with a drug because of under-reporting. That
represents a small selection of the totality or the universe of adverse
events associated with the drug. Oftentimes the case reports that come
into the Adverse Event Reporting System have limited information. This
again is somewhat different than in clinical trials where there are case
report forms and so forth and there\'s often extensive information
captured about patients.

So to get around some of these limitations, we have a number of data
resource procurements, including the IMS Health Database, and this
allows us to estimate things like the number of prescriptions that are
being used, particularly for out-patient information, demographic
information about patients, information about the providers, the
subspecialty and those sorts of things.

But as I said, the IMS is primarily an out-patient database. So we have
access to several other databases, including Premier, which provides
in-patient information; AdvancePCS, which is longitudinal out-patient
information; and the CHCA, which is the Child Health Corporation of
America, which provides some pediatric in- patient information.

So from these databases we can assess not only adverse events, but we
have an idea of the denominator, the number of patients who were exposed
to the drug, to allow us to, therefore, calculate rates in a more
real-world setting than in clinical trials.

I\'m going to switch gears now and talk briefly about risk management in
some broad outlines.

One definition of risk management that comes from a concept paper that
the agency recently produced in March of this year ‑‑ and there was a
public meeting in April on it ‑‑ is that risk management is a continuing
process throughout a product\'s life cycle, so not just during
development, but it continues into the postmarketing phase, and it\'s on
a continuum. The goal largely is to optimize the benefit-risk profile.
So there are two ways to do that. One is to decrease the risks
associated with the drug or to optimize the benefits.

Any risk management plan should have clear, specified rules and
objectives and should have an evaluation of the effectiveness of the
program. Again, previously FDA has relied very heavily on labeling.
However, there are a number of studies that show that labeling is of
variable effectiveness in terms of physician compliance with the
labeling or those sorts of things.

So one of the major risk management tools, of course, is education and
outreach and things that go beyond the professional labeling or the
package insert. So there are health care professional letters and other
public notices. Many of you may receive them periodically from the
industry.

There can be training programs and continuing education credits that are
provided to health care providers for completing them to learn about
specific issues or risks and how to recognize, manage, and prevent or
mitigate them.

There is also patient-oriented labeling which include medication guides
and patient package inserts.

So education is a major addition to the use of merely professional
labeling.

However, risk management can go much further than just professional
labeling. There can be systems that guide prescribing, dispensing, and
the use of the drug. Many of you may have seen these such as patient
agreements or informed consent before a drug is administered to a
patient. An example of this may be if you look at the Accutane labeling,
patients or whoever is taking Accutane needs to check off that they
understand some of the risks associated with the use of that drug
because it\'s a teratogen.

And there needs to be enrollment of one or more stakeholders in a
special program in some of these cases.

There are practitioner certification programs such as the drug is only
administered to certified professionals or practitioners, and there are
special conditions of dispensing that can be utilized such as special
packaging, limiting supply of a drug, and checking mechanisms to assure
appropriate prescribing.

And if one goes even further, then there are actually restricted access
systems that can be used in risk management. These are basically
designed to enforce compliance with program elements. These may require
registration or enrollment of physicians or pharmacists or patients.
They may include documentation of safe use conditions such as lab tests
before a drug is prescribed. An example of this last point may, for
example, be thalidomide. I\'m sorry. Clozapine is probably a better
example where with thalidomide, patients need to document that they\'ve
had a negative pregnancy test before taking the drug, and with
clozapine, which is an antipsychotic drug, patients need to get a blood
test to evaluate their white counts. So these sorts of things are called
\"no blood, no drug\" sorts of programs.

Finally, of course, if none of these interventions are effective, then
there can be the suspension of marketing either with or without
application withdrawal.

So as the committee deliberates today, I think it\'s important to
consider some of the following things about selecting and developing
tools for managing risks. First is obtaining stakeholder input, and by
stakeholders, that means anybody such as health care providers,
patients, et cetera in terms of their feasibility and acceptance. Look
for consistency with existing or accepted tools that are used, and is
there evidence that these tools actually work, that there has been past
success of monitoring or use of these tools in the same or related
areas. And finally, to assess the variability, validity, and
reproducibility of any intervention that is undertaken.

I would also encourage the committee to consider risk management plan
evaluation. Oftentimes the agency has implemented labeling changes, for
example, and just assumed then that these interventions were being
utilized by health care professionals or patients. But as I mentioned
before, there\'s a fair amount of evidence that this is of variable
effectiveness. So in order to assess the effectiveness of a program and
its tools, ideally one would do some pretesting before implementation of
the risk management plan and then assess the effectiveness periodically
after implementation.

The goal here really is to ensure that any efforts are expended on
effective interventions and that these changes can then be used to guide
adjustments to the risk management programs.

Finally, on the same line, of course, if one is evaluating a risk
management plan or program, one needs to have outcome measures or
metrics. These can be used to measure changes in the absolute levels of
patient health outcomes or a particular adverse event, surrogates of
health outcomes. They can be process measures to evaluate whether
patients are being appropriately counseled, for example, or not. Or one
can use behavioral components such as assessing patients\' or health
care providers\' comprehension, knowledge, and attitudes.

So what I\'ve tried to provide is a very broad overview for
consideration of two major areas in my talk. One, again, was risk
assessment and the second was on risk management. And I\'d be happy to
entertain any questions that people may have.

DR. SANTANA: Thank you, Victor.

Any immediate questions? We\'re going to have a period of discussion for
which certainly, I\'m sure, Victor will be available. Dr. Reynolds.

DR. REYNOLDS: Since you mentioned Accutane and since this is a pediatric
oncology committee, I wonder if you could comment on the insistence that
we get negative pregnancy testing on these patients that are most often
2 years old in the use of Accutane in the pediatric oncology community,
which has put a burden on people that is really probably not necessary,
and if there is some way to change that.

DR. RACZKOWSKI: Well, that\'s a good point. Accutane is approved for its
dermatological indications and as of yet, it does not have a pediatric
or oncology indication. So that is considered to be an off-label use at
this point and is, as you know, under study. So there are some
limitations in our ability to ‑‑ since acne is largely an adolescent or
later type of condition, the labeling reflects the realities of the
indication that it has been approved for. So I guess I would say it\'s
difficult to make labeling changes for an unapproved use.

DR. SANTANA: Can you give me an idea of what the universe is from the
agency perspective in terms of how many times or how frequently do label
changes occur because there are issues that you have identified in your
risk management program for a particular product? Is it a frequent
occurrence that this happens? Is it occasional? It happens infrequently?
What\'s the sense of how this program works in identifying issues?

DR. RACZKOWSKI: I would simply say that in postmarketing, it\'s very,
very common for labeling changes to occur even addition of black boxes
or new contraindications, new warnings, new precautions because again,
when a drug is approved, the entire safety profile of a drug is not
completely understood. So there\'s this ongoing vigilance to monitor the
safety of the drugs.

DR. SANTANA: Jody?

DR. PELUSI: I just want to kind of follow up on that as well. In terms
of your educational piece, trying to get the updated information out, I
think that\'s a very valuable source because many of us may have read
the package insert once and not necessarily do it on a regular basis. So
that whole issue of education from consumers to providers becomes a very
important piece that we can\'t lose sight of.

DR. SANTANA: If there are no other questions or comments, we\'ll proceed
with the morning session. I think we have three speakers lined up, and
I\'ll ask Dr. Lesko to go ahead and give us his presentation.

Thank you, Victor.

DR. LESKO: Well, good morning, everyone. Again, let me add my thanks to
Steve\'s and welcome you to the advisory committee today. I look forward
to your advice and comments on the particular topic that I\'ll be
introducing today.

What I\'m going to do is introduce the topic and frame it in some broad
terms and turn it over to three of our guest speakers to make
presentations from different perspectives.

Let me start by saying that the agency\'s broad goals for pediatric
therapeutics include identifying opportunities to improve the quality of
therapeutics related to the use of already-marketed drugs as well as new
drugs, to update product labels where new data is relevant to the safe
and effective use of the drug, and to place information in product
labels as a mechanism to disseminate important information about the
drug\'s use.

Now, these goals are entirely consistent with label regulations. This is
part of the label regulations from the C.F.R. that evidence is available
to support the safety and effectiveness of the drug only in a selected
subgroup of the larger population with a disease, and that subgroup can
be defined by many different intrinsic or extrinsic factors. The
labeling shall describe the evidence and identify specific tests needed
for selection or monitoring of patients who need the drug. I\'ve
underlined that part of the label that I wanted to highlight.

Turning now to pharmacogenetics, pharmacogenetics in many ways can be
thought of as an intrinsic factor. The genetic makeup of an individual
can increase or decrease blood levels of a drug and subsequent clinical
responses in a way similar to, say, drug interactions or a disease state
the patient might have. But pharmacogenetics can be thought of as the
study of genetically determined variability in drug metabolism and
responses to drugs which can include either adverse events or desired
effects. And variability in a dose-response relationship occurs because
of variations in DNA such as polymorphisms in a single gene, which
we\'ll be talking about today, or a limited set of multiple gene
sequences that subsequently influence enzyme or receptor activity.

Now, integrating pharmacogenetics into therapeutics is an agency-wide
initiative. This is one of the five major planks in the platform that
Dr. McClellan has for the agency, and as he stated in the Washington
Drug Letter following an FDA Science Board meeting, new therapies will
be developed along with genetic or phenotypic tests that can be used to
identify appropriate populations and detect patients who might need
different doses or are prone to certain toxic effects. This reflects the
potential that he and others in the agency feel that pharmacogenetics
can bring to therapeutics.

I wanted to show you an example of what that means in terms of actual
labeling. This is an example of a drug that was approved in the earlier
part of this year, atomoxetine, and it was approved for the treatment of
pediatric attention deficit disorder. It\'s not a TPMT substrate, but
rather it\'s a 2D6 substrate. I\'m using this as an example to
illustrate the various ways in which information about pharmacogenetics
can be incorporated into the label. The evidence to support a priori
testing of 2D6 for atomoxetine was not strong enough to recommend that
in the label, but in the spirit of truth in labeling, we did include
information that was factual and was evident from the trials that were
done on the drug.

CDER, in turn, has focused on both new and approved drugs in terms of
integrating pharmacogenetics into therapeutics. This is a quote from Dr.
Woodcock at a presentation she made to the FDA Science Board where she
focused primarily on genetic contributions to variability and toxicity
and primarily differences in metabolism that are related to
pharmacogenetics. This is, as you\'re probably aware, one of the most
mature areas of pharmacogenetics in terms of translating it into patient
care.

So now we turn to 6‑MP and childhood ALL. As you all know, ALL is a
life-threatening disease and 6‑MP, in turn, can cause life-threatening
toxicities. In many ways it can be thought of as a drug with a narrow
therapeutic index. Dose titration, as the label indicates, defined by
dosing size, duration, and intensity of therapeutics, is a major
determinant of long-term event-free survival, as well as
myelosuppression. It\'s well known that 6‑MP is metabolized to
pharmacologically active thiopurine nucleotides by the enzyme we\'re
talking about today, TPMT, and TPMT activity shows a well-defined
trimodal variation in the general population.

This is some prescription use of 6‑MP from the IMS database, and you can
see the use of 6‑MP in oncology as well as the use of 6‑MP in off-label
indications such as in the GI, and the other bar shows all of the
prescriptions for 6‑MP. We\'re focusing primarily on the approved
indication for ALL.

What about the polymorphism of TPMT? Well, it\'s well documented in
terms of a causal link between the polymorphism and TPMT and the
clinical effects, including toxicity. In your background package, there
were about 8 to 10 references from the literature, and much of the
current literature over the last 10 years has provided evidence in terms
of clinical utility of the test and in terms of various recommendations
for dose adjustments.

Genotypes with reduced, which is 10 percent of the population, or no
activity, which is the 1 in 300, are at a substantially increased risk
of myelosuppression and secondary cancer based on the literature from
the past 10 years.

More recently, pharmacogenetic tests have become available for TPMT
genotype and phenotype. They\'re feasible. They\'re relatively easy in
terms of technology related to DNA analyses, and these tests are fairly
robust in predicting and identifying patients who are of a certain
genotype and they can be used to guide optimal dosing.

Pharmacogenetic tests you\'ll hear more about from Dr. Weinshilboum, but
the TPMT genotype can predict no or very low enzyme activity. There are
three major alleles in TPMT, the \*2, \*3A, and \*3C, that identify
almost all, but not quite, those individuals with no or very low
activity. In turn, those patients experience excess accumulation of RBC
thioguanine and its nucleotides that result in toxicity.

There are available as well TPMT phenotype tests to measure enzyme
activity either directly in the red blood cells or by looking at
thioguanine nucleotides in the red blood cells.

In several academic centers, both genotype and phenotype are used
together, along with clinical outcome monitoring, in terms of total
blood counts. And these are not to suggest that these tests are going to
replace those clinical observations, but rather the tests play a role as
an adjunct to help identify and, in particular circumstances where
multiple drugs may be on board, the drugs that are causing toxicity.

Now, we had prior discussions of TPMT polymorphism in advisory
committees. These were general discussions. We did not ask the committee
to vote or we did not ask for a specific recommendation. The first of
these was in front of this committee, the Pediatric Subcommittee, back
in November of 2001. At that time, you heard from Dr. Mary Relling, one
of the experts on thiopurine pharmacology and TPMT testing. And then
more recently, we discussed this issue in front of the Clinical
Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical
Sciences, and that meeting was reported in the Pink Sheet November 2002.
By and large, the comments from the participants in those meetings were
supportive and the discussion was very valuable.

This is the current package insert, a copy of which you have in your
background package. It shows the warning section. I might point out that
there is another covariate in the warning section, namely allopurinol,
and allopurinol is, again, a covariate which I think of as another
intrinsic or extrinsic factor that can raise exposure to thioguanines,
and there is some mention in the label about the effect and also the
recommendation to reduce the dose.

This is the dosage section, just to remind what\'s in that section,
which brings us around to the questions that we have for you today.

The first question is beyond what you\'ve seen in the package insert,
what additional information should be added to the product label for
6‑MP regarding what we know about pharmacogenetics of the polymorphism.

Some additional information which the current label now lacks is an idea
for the prescribing physician and the patients about the prevalence of
those patients with little or no TPMT activity. These prevalences are
well established in the literature. One might consider additional
statements in the warnings or dosage sections that patients with this
deficiency may be unusually sensitive to toxicity and at greater risk.

Additional information might include a statement that laboratory tests,
phenotype and/or genotype, are now available to determine the TPMT
status of patients if the physician so chooses and some information
regarding the use of these tests.

And finally, perhaps some recommendations for adjustment of doses in
patients identified as having little or no or reduced TPMT activity.

The second goal for today is to get your advice on this question. If
pharmacogenetic information is added to the label, what other testing
information might be added about genotyping or phenotyping for this
activity that might be necessary and appropriate for the product label?

Some additional testing information might include a recommendation for
testing for the status of TPMT activity before initiating therapy. The
recommendation might be for testing for activity within the first week
of initiating therapy before overt signs of toxicity became apparent.
Third might be a recommendation for testing of activity in those
patients that develop severe myelosuppression as a way of better
understanding the cause of that, or perhaps some description of
information testing for the status of activity that this information
could provide. So there\'s a hierarchy of information and different ways
of expressing the information that we know about the pharmacogenetics,
and we\'d like your advice on that.

I\'m going to turn this over to three other presenters this morning. I
want to thank them all for joining us. Dr. Weinshilboum, who has been an
expert in this field for over 20 years, having first identified many of
the polymorphisms in TPMT, will begin. I believe Howard McLeod will
speak next. Howard has hands-on experience with the test in
therapeutics, and finally Dr. Winick from the COG group will give a
perspective on the topic.

So with that, I\'ll turn it back to the chair. Thank you.

DR. SANTANA: Thank you.

Any brief questions?

(No response.)

DR. SANTANA: If not, we\'ll move on to the next speaker.

DR. WEINSHILBOUM: First of all, let me thank Dr. Hirschfeld and Larry
Lesko for inviting me to come here. My daughter is a pediatrician in
North Carolina and the fact that I, as a poor, benighted internist,
would appear before a group of pediatricians is about the only thing
I\'ve ever done that\'s impressed her.

(Laughter.)

DR. WEINSHILBOUM: Larry was quite clear with regard to what my
assignment was. My assignment is to provide the scientific background
for the discussion. Howard will expand on that, as will Naomi, into the
clinical realm, and I\'ve made my credentials fairly clear. I\'m an
internist, not a pediatric hematologist/oncologist. He also said I
should stay on time, and I\'ll do my best to do that too.

This slide takes us back to the beginning. It was mentioned that it is
now 50 years ago since the thiopurine drugs developed by George
Hitchings and Gertrude Elion of what was then Burroughs-Wellcome Company
were developed as cytotoxic agents. Knowing Gertrude Elion, as I did
before she passed away, she said that what they did was rational drug
design of that era. They looked at the endogenous purines and said if
God had wanted us to have a sulfur there, she would have given it to us.

(Laughter.)

DR. WEINSHILBOUM: And that is exactly what she said. Those of you who
knew her, know that\'s what she said. So this was rational drug design
to develop cytotoxic agents which were, in the context of that time,
amazingly successful.

Here is 6-mercaptopurine, 6-thioguanine, and as you know, azathioprine,
or Imuran, is a prodrug that\'s converted to 6-mercaptopurine in vivo.

You\'ve already seen this definition of pharmacogenetics. Larry provided
this. That is the study of the role of inheritance in individual
variation in response to xenobiotics, including the drugs which those of
us who care for patients, write prescriptions for and they take,
thinking we know what we\'re doing. Most of the pharmacogenetic
knowledge that we have today has evolved out of studies of drug
metabolism. However, as Larry just mentioned a few moments ago, all of
these processes of drug absorption, distribution, interaction with the
target, and excretion we now know are subject to the same degree of
common genetic variation frequently of functional significance. But
today our focus is clearly on, as Larry so elegantly put it, a mature
field that is an example from drug metabolism.

Here is a schematic representation of the biotransformation of
thiopurine drugs. Even the Mayo medical students, who I have to teach on
a regular basis, know that xanthine oxidase, a phase I reaction is
involved in the metabolism of these drugs. George Hitchings and Gertrude
Elion knew that an S-methyl metabolite, undoubtedly the product of a
phase II conjugating reaction, was involved because they measured these
metabolites in the urine.

The enzyme, when we began our work now nearly a quarter of a century
ago, which when I say that, causes me some pause ‑‑ when we began our
work, it had only been studied in rodents, in rats and mice, by a man
named Remy who\'s now retired from the Department of Biochemistry at
what is today Wake Forest University Medical School. My daughter did her
pediatric residency there, so I sat in his living room and said, Dr.
Remy, why did you study this enzyme in rats and mice in 1963, and he
said because George Hitchings told me it might be interesting. Is it?
And I told him, yes, there was some interest in it.

This enzyme, when we began our work 25 years ago, had never been
examined in humans, and we asked a series of very simple questions. Is
it conceivable that this phase II pathway might show variation among
individuals? If so, is it possible that those variations might be
genetically mediated? And if so, might that play a role in individual
variations in either therapeutic efficacy or toxicity of the drugs? And
the reason that we\'re all here today is that the answers to those
questions appear to be yes.

So here\'s the reaction which basically is a standard
S-adenosylmethionine-dependent methyltransferase cytosolic, monomeric
enzyme. And I was asked to provide the scientific basis for what we\'re
doing. And being a poor, benighted internist, I actually wanted a
clinical test when we started doing this. So we measured the enzyme in
the red blood cell.

Now, I was at the NIH last week talking about some of this and the study
sections at the NIH said this idiot in Minnesota thinks that red blood
cells are the liver. No, no. We were hoping that what we saw in the red
blood cell might reflect the level of enzyme activity in other tissues,
and I will tell you, in case I forget to, that the answer is, of course,
it does for reasons that will become clear when I come to the molecular
basis for this polymorphism.

Now, here is the first paper that we published on the genetics in 1980,
and I\'ll provide the time line because when Larry shook hands with me
this morning, he said, I\'m glad you\'re hear. I said, after 20 years
I\'m pretty glad I\'m here too, because this paper was published in
1980. This is a frequency distribution of red blood cell TPMT activity
in 298 randomly selected adult blood donors at the Mayo Clinic in
Rochester, Minnesota. That has implications of a practical nature that
I\'ll come to in a minute because that means every one that we looked at
is named Anderson or Yansen. They\'re all northern European
Scandinavians. That\'s important because I will show you in just a few
moments that there are striking ethnic differences in allele types and
frequencies.

So 90 percent of this population has high enzyme activity. 10 percent
has intermediate activity. And this one lady down here had 0 enzyme
activity. Rochester is a weird town in that 30,000 people out of 90,000
work for the Mayo Clinic, so when I go walking at Apache Mall, her
daughter, who is now in her 20s, stops me and says, how\'s my mom\'s
enzyme doing.

But this is exactly what the Hardy-Weinberg theorem would predict for a
genetic single locus with alleles for high and low enzyme activity with
allele frequencies of 94 in 6 percent using sophisticated molecular
techniques developed by a monk at a monastery in what is today Brno,
that is segregation analysis. So you didn\'t need to clone anything back
then to know that this was genetic.

Now, this a more accurate representation, and still not totally
accurate, schematically of thiopurine metabolism. Azathioprine is a
prodrug. It\'s converted to 6-mercaptopurine and 6-mercaptopurine is
itself a prodrug which undergoes metabolic activation to form
6-thioguanine nucleotides. You can either methylate or oxidize the drug.

And I\'m really glad our colleagues from the UK are here because
actually just by happenstance we have an excellent example of the
importance of international cooperation because I met a woman named
Lynne Lennard from Sheffield who has done a tremendous amount of work
with acute lymphoblastic leukemia in the United Kingdom. And she said,
Dick, I can\'t understand why we treat these kids with exactly the same
dose of these drugs and get such variable 6-thioguanine nucleotide
levels. I said, Lynne, is it conceivable that those kids who have this
pathway pump more of the drug down here and they\'re the ones at
increased risk for myelosuppression? So a lot of the data that I\'ll
show you grew directly out of a Minnesota-Sheffield connection, and I
think makes the point that you\'ll be discussing this afternoon
actually.

And here are some of those data. These are data which we published in
Lancet in 1990. Dr. Lennard sent us samples from 95 consecutive children
in the UKALL, United Kingdom Acute Lymphatic Leukemia, UKALL VIII
trials. And we measured the enzyme activity blind to the 6-thioguanine
nucleotide levels. When you got to the 600 to 800 picomoles per 10 to
the 8th red cells ‑‑ and don\'t ask me why she used that number of red
cells ‑‑ these were the kids who began to have myelosuppression, and the
expected inverse relationship between the enzyme activity in the
6-thioguanine nucleotide levels, which has generally been confirmed in
subsequent reports, was observed.

That raises immediate questions. What about that lady whose daughter
stops me when I\'m walking at Apache Mall who had 0 enzyme activity?

Well, Dr. Lennard had samples from individuals treated with \"standard\"
doses of azathioprine for skin disease, for dermatologic disease. I want
to be quite clear which drug I\'m talking about with this group. And you
can see here she sent us those with a group of controls. Now we\'re up
in the thousands of picomoles. All of these patients developed
life-threatening myelosuppression that required prolonged
hospitalization. Notice this patient is 26 days after the drug is
stopped, and he\'s still, in terms of the active metabolite, above any
of the controls.

I used to present these data and say if they\'re confirmed, we can now
predict and potentially prevent the life-threatening myelosuppression. I
don\'t say that anymore because a great deal of work, which I know
Howard will be talking about in more detail and Naomi in a few moments,
has clearly demonstrated that this group down here is at greatly
increased risk. All of these individuals, by the way, had 0 enzyme
activity.

This is not a childhood leukemia example, but it\'s an example that was
published in the Lancet.

These things don\'t get published anymore. They don\'t get published
anymore for two reasons. Let\'s be quite clear. Because the journal
editors say we already know this and because of litigation issues.

So here this is a heart transplant patient in Germany. Here\'s the white
count. Here\'s the azathioprine dose. The white count drops. The drug is
stopped. The white count goes up. The drug is started again. The white
count goes to 0. The drug is started here. The patient expires with
massive sepsis. The blood sample was determined to have 0 TPMT enzyme
activity.

So the bottom line ‑‑ and you\'ll hear a great deal more evidence from
Howard ‑‑ is that genetically low TPMT results in an increased risk for
thiopurine toxicity. That seems quite clear, and I think we\'ve already
heard that from Larry. We\'ll hear more from Howard in a moment.

I should point out that Mary Relling and the group at St. Jude ‑‑ and we
have a lot of representatives around the table ‑‑ have also demonstrated
that this appears to be a risk factor for the occurrence of secondary
neoplasia, and that\'s been confirmed at least once in one of the Nordic
leukemia trials that has been published.

There is less compelling evidence that high TPMT results in decreased
therapeutic effect. And that\'s an interesting concept that hasn\'t come
up in the course of these discussions that I look forward to hearing
more about from some of the subsequent presentations.

Let me just say that the phenotypic test measuring the red cell enzyme
activity has been a standard test at the Mayo Clinic since 1991. We now
do approximately 5,000 of those tests a year in our clinical
laboratories, about half for our own patients. The vast majority,
obviously, are not ALL patients. They\'re patients with inflammatory
bowel disease, dermatologic disease, organ transplant recipients, et
cetera, and about half that are referred in from outside, supplemented
by genotyping also. Clearly the genotyping is available, as is
phenotyping, through commercial organizations, and Howard may want to
talk about that in just a moment.

There are a couple of important issues here that may relate to future
discussions of pharmacogenetics; that is, the ability to work with Dr.
Lennard. So if any of you do see Lynne and work with her, please tell
her that I gave her credit. She\'s been a true pleasure and a great
scientist to work with ‑‑ is the availability of what I\'ve called an
intermediate phenotype. These children are treated with a variety of
drugs that might cause myelosuppression. Having an intermediate
phenotype like the 6-thioguanine nucleotides as an ability to sort out
which might be at risk because of the TPMT deficiency was very helpful.
Of course, the association with clinical trials on a national and
international basis was a tremendous advantage in terms of developing
evidence-based data with regard to this genetic variance.

What I had there was what is pharmacogenetics because I pointed out that
we began with the phenotype. My definition is the convergence of this
kind of genetic information which Mendel would have recognized with the
explosive development of new information with regard to genomics. And
I\'ll just point out that Ron Honchel in our lab in the early 1990s ‑‑
Ron is now at the FDA ‑‑ cloned the cDNA for TPMT, and then Diane
Otterness and Carolyn Szumlanski cloned the gene.

The TPMT gene has 10 exons, 8 of which encode protein. It\'s on the
short arm of chromosome 6. It doesn\'t have a TATA box. It has a
variable number tandem repeat which is GC-rich in the area of the
promoter. That\'s going to be potentially an issue in just a moment, and
I\'ll come back to that.

And the most common variant, which was described virtually
simultaneously at Mayo and at St. Jude in Bill Evans\' lab, has two
nonsynonymous cSNPs, two changes in encoded amino acid. There\'s a
polymorphism in exon 7 and 1 and exon 10. I point that out because that
allele to my knowledge has never been found in anyone from China, Japan,
or Korea. It is the most common variant allele with an allele frequency
of about 4 to 5 percent in caucasians. In East Asians in people like my
wife, who is Chinese American, only this variant in exon 10 has been
observed. And this is going to be an issue that as you begin to think
about how you\'re going to go forward ‑‑ how we, our discipline is going
to move forward ‑‑ I think it\'s going to be an interesting challenge
because I was visiting professor at the National University of
Singapore, and their comment was that to their knowledge ‑‑ remember,
Singapore is 80 percent Chinese ‑‑ is mainly a problem of the caucasian
kids who are referred in. So these are going to be interesting and
difficult issues to deal with. You can very rarely get the so-called
\*3B which is the exon 7 variant alone.

The reason that changing 2 amino acids results in virtually no enzyme
activity and virtually no enzyme protein, as we reported back in the
early 1980s ‑‑ and this is just work from our lab recently that a
graduate student, L. Wang put together. It confirms work from Bill
Evans\' laboratory ‑‑ is that those two changes in amino acid result in
the protein being very rapidly degraded. This is a reticulocyte lysate
system where you can make radioactive protein. The wild type, more
common allele, is quite stable, but the variant is very, very rapidly
degraded. This is a common phenomenon. Actually it\'s the most common
way in which so-called nonsynonymous cSNPs ‑‑ the cell has ways of
surveillance. It doesn\'t like the idea, if you\'ll allow me to be
anthropomorphic for a minute, that that single amino acid has changed.
And that\'s going to be an interesting area that we\'re going to have to
understand better as we move into the future in this field. So that
nonsynonymous cSNPs are common, often functionally significant. Most
often they result in reduced quantity of protein, not changes in the
enzymatic activity. And the mechanism, where it has been examined, is
most often accelerated protein degradation.

This is a frequency distribution. These are data from Dr. Park Ha, a
hematologist/oncologist in Korea. And notice these are 300. So the n is
about the same as those blood donors in Minnesota. Here we get the sort
of anticipated gaussian distribution. We don\'t have the hump here that
we find in most caucasian populations, and nobody down here. Being a
dedicated scientist, Dr. Park Ha brought DNA from these samples to
Minnesota in the month of February and had us genotype these samples,
and none of these individuals with lower activity had the common double
variant in exon 7 and 10. They only had the \*3C, which is the exon 10
variant.

Here are studies done in Chinese from the two places that you would
expect you would study a Chinese population, Aberdeen, Scotland, Howard
McLeod\'s data, and Rochester, Minnesota where, when we moved there, my
wife was one of the few Chinese Americans in town.

(Laughter.)

DR. WEINSHILBOUM: Our samples came from Shanghai. Howard, where did
yours come from?

DR. McLEOD: Guangdu.

DR. WEINSHILBOUM: All right. So we have two different Han Chinese
populations.

And you can see that in the caucasian population in Rochester, it was
about 4 percent of the \*3A and 0 in the Chinese. This is 250 Shanghai
Chinese. But they had a much higher frequency, about 2 percent, for the
exon 10 variant. Howard had almost identical data. So it\'s fascinating.
About 4.5 percent among the caucasians and 0 in the Chinese and about 2
percent for the exon 10 variant.

So this brings me back to sort of where we began. We should also point
out, though, that from 0 up here to where this break is is about 10
units of activity, but even within those samples that have come from
individuals with the same open reading frame, there\'s also about a
10-unit range of activity. And using population genetic techniques, that
variance is due virtually entirely or predominantly to inheritance,
which says what other genetic factors are there that swing you once
you\'re set by your open reading frame at high, low, or intermediate.

And I forgot to point out that there are a large number of rare
variants. We\'ve talked about \*2, \*3. There are a large number of rare
variants. So if we\'re talking about genotyping tests, that\'s an issue.
They\'re very unusual, but they certainly exist. We had one kindred in
Rochester where they were compound heterozygous with the \*3A and a
splice junction variant that ran right down through the family at the
intron 9/exon 10 splice junction of the canonical GTAGs.

So there\'s going to be allelic heterogeneity, one or two that are
common, ethnic variation in allele frequencies as you begin to think
about how you want to approach these issues. And the variable number 10
and repeat has been shown by studies, both done in France and studies
that we\'ve confirmed in Rochester, to help to modulate level of enzyme
activity.

These are reporter gene constructs that have just been recently ‑‑ this
is unpublished data from our laboratory showing that the most common
variable number 10 and repeat ‑‑ these are 17 to 18 base pair GC-rich
repeats. And you can have from 3 to 9 of them. The French and our group
have shown that both in vivo and in vitro, the higher the repeat number,
the lower the enzyme activity. This is not anything unanticipated. Jeff
Drazen reported similar data with regard to ALOX-5 H gene which also has
clinical implications. And this just shows you that the higher the
repeat number ‑‑ 4 and 5 are the more common. This was from a sample of
2,609 samples from our clinical lab that we drew these ‑‑ the lower the
enzyme activity.

So I\'ll just end ‑‑ and I think I\'m reasonably on time ‑‑ with a slide
that comes from the New England Journal article that was right in front
of a nice article that Howard wrote showing in caucasians the frequency
distribution. The most common reason for high, low, or intermediate
relates to the frequency of the double variant exon 7-10, the so-called
\*3A variant.

Having provided the scientific background now, I\'m looking forward to
the presentations that will come next from Howard and from Naomi. Thank
you very much.

DR. SANTANA: Thank you. That was very thorough.

Any brief questions?

(No response.)

DR. SANTANA: If not, Howard, you\'re next.

DR. McLEOD: I want to thank you very much for the opportunity to present
this data and talk a little bit about the last 5 to 10 years\' worth of
information regarding the clinical implications of thiopurine
methyltransferase deficiency and try to pull together the literature in
a way that we can think about how this information should be put into
the package insert.

I think it\'s important to realize that the question that we were asked
to address was not should TPMT testing be mandated in every person who
can spell 6‑MP, but rather should we be informing patients through the
insert about the information that\'s there and should we be providing
information on how this could be used in a little bit more useful
manner.

Now, there\'s a quote that I\'d like to start us off with that for me
puts the issue into perspective, and that is as shown here. \"A surgeon
who uses the wrong side of the scalpel cuts his own fingers and not the
patient; if the same applied to drugs, they would have been investigated
very carefully a long time ago.\" Now, this is supposedly from 1849. I
don\'t read this journal.

(Laughter.)

DR. McLEOD: Joachim, you probably do if it\'s still around.

This quote is very relevant today. Of the anticancer drugs we have
available to us, there are virtually none of them that we truly know the
mechanism of action and therefore have the precise handle on how to use
these medications.

Also, this really turns things around to putting it into the patient\'s
perspective. We are used to talking about the extremes and worrying
about the extremes when patients worry about the mundane. If I had grade
1 diarrhea from a therapy I was taking, I would not be presenting to you
at this particular moment. Yet, grade 1 diarrhea wouldn\'t even hit our
radar screen. It would be grade 3 or 4 or worse that would make us
worry. The same with neutropenia. We don\'t worry about patients that
don\'t have to be hospitalized for that fall in white count, but they
do. So putting it in that context, in the context of risk prevention, we
can start thinking about this test and how it might be useful and ways
that it might not be useful.

Now, Dick showed this data from 1980 that reminds us that there is
variability in TPMT activity. Now, he focused on the three groups that
were present which indeed is a very important issue. There\'s also quite
a lot of variation in enzyme activity across populations, and
understanding this variation, at least in part, is what we\'re
discussing this morning.

There are a number of ways of trying to evaluate that variability. The
enzyme activity was shown in the previous slide and certainly red blood
cells are a good surrogate of TPMT activity measured elsewhere in the
body, for example, the liver, the lung, the platelets, the kidneys, and
also leukemia blast cells in the two studies that have been performed to
date. So red cells do offer an easily assessable surrogate and there are
tests commercially available for measuring enzyme activity.

The benefit of a TPMT test in the red cells is that you\'re measuring
functional catalytic activity. You\'re measuring variability in activity
from any source, genetic or otherwise, and therefore you can take into
account the dynamics of this particular measure.

The down side is that the red cells do have to be handled carefully.
They do have to be shipped to a reference laboratory, as do most of
these tests, and there are nonclinical or nonphysiologic reasons why
enzyme activity could be varied, for example, freeze-thaw, some of the
influences of shipping, things that have nothing to do with the
patient\'s activity.

Measuring the active metabolites, the thioguanine nucleotides that Dick
has shown you, is another way of trying to evaluate this situation, and
that has the benefit of not just taking into account thiopurine
methyltransferase, but also looking at the variation introduced by
xanthine oxidase and any other source of pharmacokinetic variation that
is found in that particular patient and therefore is more of a
downstream measure of this particular class of agents and can be quite
useful. There are very few laboratories offering this test, although it
is commercially available, and also has some of the handling issues that
I mentioned with the red blood enzyme activity assays.

The last one I\'m going to mention is the genotyping for thiopurine
methyltransferase. It has the benefit of there being a few defined
genetic variants that are responsible for the majority of low activity
in the world\'s populations, and I\'ll show you some of that
information, and therefore a small number of tests will give you
information on the majority of patients. DNA is very stable. We can get
DNA from King Tut. Therefore, we can get it from the patients. And this
testing is quite robust.

What DNA does not offer is a dynamic measure of what is happening with
individual patients, and I\'ll demonstrate that. You still have
variability in enzyme activity in patients with a so-called wild type or
normal genotype.

Now, there were several questions that were given to me to be addressed.
Therefore, I\'ll try to make some points regarding those issues.

The first one is really what is the relationship between the TPMT
genotype and the clinical phenotype. Dick has demonstrated to you
already that there is variability in the enzyme and that high levels of
enzyme cause less drug to be shunted down the activation pathway.
Indeed, I\'ll show you that data as well.

When we take the information of genotype that is available to date,
there are three alleles that have been commonly found to be associated
with low enzyme activity. The wild type normal allele is shown at the
top. There\'s a single nucleotide polymorphism at exon 5 and exon 10 and
then the exon 7/exon 10 polymorphisms that have been demonstrated to
occur in the general population. As Dick mentioned, the most common
variant in the caucasian population or the European extraction
population is this so-called \*3A mutation, whereas \*3C is the most
common in continental Africa and Asian populations, both in those
continents and here in the United States. \*2 allele has primarily been
found in the caucasian population at a low rate. And when you take these
three variants in compilation, you\'re able to predict approximately 95
percent of the patients with low enzyme activity.

Now, that number is not a hard number. There are studies that range from
about 85 percent up to 100 percent prediction, and looking at them in
compilation, it\'s around 95 percent. But there has not been a
prospective study in tens of thousands of patients to determine the
genotype/phenotype relationship in toto.

So these three polymorphisms are responsible for low enzyme activity in
all continents of the earth and are the primary basis for low enzyme
activity in all patients throughout the world.

Now, this is data from the late \'90s. It was the first demonstration,
in respect to patients that I came across anyway, looking at the
genotype/phenotype relationship and it makes a couple of interesting
points. This is data from blood donors from the Memphis area. If you
have two variant alleles either as a homozygous state or as a compound
heterozygous state, you will have low or undetectable enzyme activity as
demonstrated here. If you have one defective copy and one normal copy,
you will have intermediate enzyme activity, as demonstrated in this
middle portion. And then those folks that have two normal alleles have
higher enzyme activity.

Now, a couple of points I want to make from this slide. First of all,
what is this individual doing here? This particular individual did not
have one of those three variants that I showed you. It turned out that
they did have, on repeated testing, intermediate enzyme activity and on
further genomic analysis, they had a unique polymorphism that has only
been found in that individual and their family. So there are going to be
patients out there that do not have the three main polymorphisms but yet
do have low or, in this case, intermediate enzyme activity. So the
current testing approach with the three primary variant alleles will
capture most patients but not all patients with low enzyme activity.

Secondly, there\'s a lot of variability in enzyme activity in these
patients that are genetically normal. They have the reference or wild
type sequence. It\'s just a reminder that there\'s a lot that goes on in
humans that is post-genomic. We start with DNA, but there\'s a lot that
happens post-DNA. So a lot of this variability may have dietary
influences, drug influences, influences that we don\'t have any
understanding about whatsoever. Therefore, we should not assume that
understanding the genomics of this enzyme will allow us to predict all
variation in enzyme activity but rather some variation and, as I\'ll
show you, some of the key sources of severe toxicities.

Now, this is some data from a prospective study that was conducted at
St. Jude. I was a fellow there at the time this was started, so I have
painful memories of the Total XII protocol. Many hours of lost sleep
went into the collection of this type of data demonstrating that high
enzyme activity resulted in low active metabolite levels and vice versa.
So it seems to be simple biochemistry. If you don\'t have enough
substrate to active metabolite, you get low levels. If you don\'t have
the enzyme to inactivate the drug, you have more drug shunting down the
activation pathway.

Now, as has been demonstrated previously, the complete deficiencies are
a very rare instance, about 1 in 300 individuals in the caucasian
American population. Therefore, this is only two individuals. So you
have a large error bar there demonstrating a couple of things. First of
all, this is a rare event, and secondly, we don\'t know a lot about rare
events. So fairly consistently these patients do get into trouble, but
we don\'t know the precise amount of trouble they get into, at least in
terms of active metabolite levels.

This relationship is interesting but it has nothing to do with the
question of whether the TPMT genotype is associated with the clinical
phenotype. We\'re all aware of pharmacogenetic influences on
pharmacokinetics that have no pharmacodynamic endpoint. So I want to
emphasize a little bit more some of the data that\'s out there for that.
Of course, Dr. Winick, will bring that home more completely in her
presentation.

This is data that was my first experience that got me interested in the
field of pharmacogenetics. This is a 5-year-old little girl with acute
lymphoblastic leukemia who was started on the Total XII protocol. After
induction therapy, that protocol every 6 weeks gave some consolidation
chemotherapy, as I\'ll show you in a few slides. What is shown up here
is her hemoglobin levels, and what\'s indicated with the asterisks are
the points where she required red blood cell transfusions and in many of
those instances, she also required platelet transfusions because of
anemia and thrombocytopenia. She had to omit some of her high-dose
chemotherapy during that period because of toxicities. The absolute
neutrophil count is shown here. She had multiple episodes of neutropenia
with hospitalization during that point in time. And more importantly, at
the bottom slide here, there should be a red bar all the way across
indicating the number of weeks of therapy she was able to tolerate.
Every time you see blue here, it reflects that she had to skip her
chemotherapy that week or have reduced doses of her 6‑MP.

And it has been demonstrated by Don Finkel many years ago that half-dose
therapy is not just half as good as full-dose therapy for childhood ALL,
but if you have to give half-dose therapy, the outcome is rather dismal.
So there\'s a lot of worry because she was not only having to miss a lot
of mercaptopurine, but was missing a lot of her other chemotherapy
during this first year of her post-induction therapy.

What is demonstrated in this middle bar here is the active metabolite
levels. The range from the other 200-plus kids on the trial is shown in
red. Her levels are shown up here. She had active metabolite levels
approximately 10 times the average of the rest of the children on this
protocol. TPMT activity was measured and she was found to be completely
deficient of enzyme activity.

She was reduced to one-fifteenth of the standard dose. She licked a
tablet every once in a while. What was found is that she still had high
active metabolite levels but in the tolerable range for this protocol.

More importantly, what\'s demonstrated here is her red cell profile and
similar with her platelet profile after the diagnosis and dose reduction
of mercaptopurine. Most importantly, out of the six chemotherapy drugs
she received during this first year of chemotherapy, only the
mercaptopurine dosage was changed. All the other drugs were given at
full doses because the culprit was identified for her extreme toxicity.
She still had episodes of neutropenia from the high-dose chemotherapy
but was able to avoid some of the red cell and platelet toxicities that
she was experiencing.

Now, these sorts of anecdote are not useful at all for deciding our task
today, but are a reflection of why we\'re even having this meeting.
There are these patients out there that are the extremes that have
driven us to worry about this issue and try to predict this phenomenon.

Also, the resource issues for these few kids are exceedingly high and
you may argue that 1 in 300 is not very much, but these kids take up
more than their share, more than 300 times their share, of supportive
care in many of the instances that are published in the literature,
including the child that I described to you.

What is shown in this slide on the y axis, on the left axis anyway, is
the percentage of therapy missed by the child I just mentioned to you
and another child we came across while I was a fellow at St. Jude.
What\'s shown in blue is that these two children missed somewhere
between 35 and 60 percent of the weeks of therapy prior to the diagnosis
of TPMT deficiency, but missed less than 10 percent of the weeks of
therapy after that diagnosis and dose reduction to extremely low doses,
between 6 and 17 percent of the standard doses that we normally would
administer.

What\'s shown on the right axis is the percentage of weeks requiring a
transfusion, and again that same phenomenon of somewhere between 10 and
25 percent of the weeks requiring transfusion down to less than 5
percent of the weeks requiring transfusion after that diagnosis, showing
what can happen by finding out what the culprit is with this therapy and
acting accordingly.

Now, more importantly is what\'s happening in the context of cohort
studies. These extremes are interesting, but this is data from the Total
XII protocol. This cohort of patients were selected only for the
presence of ALL with the biology that is indicated in the protocol. They
were not selected for TPMT deficiency or any other phenomenon. What was
found is, as would be expected, very rare individuals had complete
deficiency. The heterozygotes were about 10 percent of the population.

What was seen is that 100 percent or both of the deficient patients ‑‑
that\'s a more appropriate way to say it rather than 100 percent ‑‑
required substantial dosage reductions very early on in their therapy.
35 percent of the heterozygous patients required substantial dosage
reductions, and 7 percent of the wild type patients.

So for the deficient patients, there was a 14-fold risk, just doing
simple math, of requiring substantial dose reductions. For the
heterozygotes, there\'s about a 5-fold risk, and that\'s in line with
the paper that was provided to you from the St. Jude experience looking
at referred patients with TPMT deficiency in that there was about a
6-fold excess of variant alleles in the patients with extreme toxicity
compared to what you would see in the general population.

So heterozygotes do have a risk. Their risk is lower than the homozygous
variant patients, and qualitatively they get their toxicity at a later
point in time. But to me it\'s a simple gene-environment interaction. If
you have two variant genes and you have environmental exposure,
mercaptopurine administration, you\'re going to get your risk
demonstrated much earlier than if you have one variant gene, high risk
gene, and the same environmental exposure where there will be a
later-occurring event.

Now, this phenomenon has not been demonstrated in all cohort studies.
This is some data from my time in the UK in collaboration with the MRC,
the UKALL group over there, Tim Eden and Brenda Gibson in particular.
There\'s this percentage of weeks with no therapy on the y axis here and
genotype on the x axis. What we found is, as with the previous studies,
the rare homozygous variant patient misses a lot of therapy, and that\'s
no surprise. Even with dosage reduction, there\'s a lot of therapy
missed. What we did not see is any difference between the heterozygous
patients and the homozygous/wild type patients.

And the difference this study and the Total XII study I just mentioned
to you was the intensity in consolidation chemotherapy. This therapy was
not as intense of a therapy and therefore ‑‑ no surprise ‑‑ did not
demonstrate this phenotype. It\'s just a reminder that it\'s
gene-environment interactions we\'re talking about. If there\'s not a
heavy dose of bone marrow toxicity being induced through the therapy,
either mercaptopurine or otherwise, we\'re not going to see dramatic
phenotypes with the heterozygotes. We\'ll come back to that point in the
end in terms of the relevant merit of genotyping to find the
heterozygous population, but not all studies find heterozygotes who are
at the same risk as other studies found.

So one approach is the approach that\'s commonly used now, and that is
just to use the degree of myelosuppression as a way of trying to
accommodate and avoid extreme toxicity. Really the question of
genotyping up front versus genotyping when there\'s a toxicity is one
that we may not resolve today, but I\'ll come back to it at the very
end. But the disadvantage of adjusting for mercaptopurine doses based
only on toxicity are really twofold.

First of all, early on in modern therapy for childhood ALL, we have a
very high incidence of toxicity from a number of different drugs.
Therefore, trying to figure out which of those drugs is the culprit and
adjust accordingly is difficult to do without specific tests. So the
context of 6-mercaptopurine dose adjustments based on neutropenia during
the first year of therapy is a very challenging thing to do with most of
the protocols that are currently utilized.

Secondly, there are some long-term events that have been associated with
low TPMT activity. I\'ll mention that in the next slide. Therefore,
acute myelosuppression is not the only endpoint that we\'re worried
about in this context.

Now, there\'s certainly a lot of success with using this approach. This
is what many people are doing now and reactive medicine is how most
medicine is practiced in all areas, not just in childhood leukemia. The
question that comes to mind, going back to that initial quote, is that
the way we want to go forward. Our goal is usually to try to make
ourselves better, try to do better than we\'re currently doing. So
trying to think about it in that context, reacting to toxicity is okay
if we have no alternative. Preventing toxicity is really what our
patients expect us to do.

Now, low TPMT has been associated with secondary malignancies, and I
want to put a couple of caveats into this data because I think this can
be oversold. There is a higher risk, at least in the Total XI protocol,
of irradiation-induced brain tumors. Now, this phenomenon has been
observed. I do believe the data. But because of this data, there has
been a reaction to the data that now in my mind really avoids this
issue. The issue was concurrent administration of radiation and
mercaptopurine. Most if not all protocols now avoid that particular
interaction. Therefore, I personally don\'t think that the risk of
irradiation-induced brain tumors by TPMT genotype is a big issue
anymore. I think that has been accounted for now or should be, if it\'s
not, and therefore is an avoidable event independent of genotyping or
phenotype analysis.

Several studies, both in the U.S. and in Scandinavia have found this
higher frequency of t-AML in patients with low TPMT activity. Dr. Winick
is going to talk about this particular topic, as I peaked ahead in her
slides, and therefore I\'m not going to talk about it further. But she
will be able to talk about whether this is a major issue or not. It
probably is not a major issue.

Then there have been the small studies suggesting a higher frequency of
skin cancer in patients receiving thiopurine therapy. There have been
single studies. There have not been widespread reports on this issue.

Therefore, I think this issue of secondary malignancies has to be in our
minds and we have to be thinking about that, but it cannot be the main
driver for the decisions that we make today for the use of this
particular testing entity.

I think one important question is, is there a loss of efficacy after
6-mercaptopurine dose reduction in the context of the TPMT genotype? And
the answer is no. Next topic. No. We\'ll talk about that data in more
detail.

The Total XII protocol is shown here. The backbone of all 2-and-a-half
years of therapy was daily 6-mercaptopurine 75 milligrams per meter
squared per day both during the consolidation phase where patients
received either a milligram per meter squared or blood level-determined
dosing of the high-dose methotrexate or teniposide/Ara-C or during the
subsequent maintenance phase. Mercaptopurine was a daily event in these
kids\' lives.

When you look at the outcome data from the Total XII protocol,
separating the patients on whether they had a defective allele ‑‑ 17 of
the 19 are heterozygotes; 2 are homozygous variants ‑‑ the complete
remission experienced was equal to statistically, superior to
graphically the patients with the wild type genotype. So decreasing the
dose of mercaptopurine based on genotype, based on thioguanine
nucleotide levels, both of which were performed in this study, did not
have a detrimental effect in terms of remission rate in these children.
If anything, there was some hint of benefit.

The Total XIIIB protocol has not been published yet. A similar backbone
of therapy with methotrexate/6‑MP, and that data provided by Dr. Mary
Relling at St. Jude demonstrated that the confidence intervals for
relapse ‑‑ I\'m sorry. The cumulative incidence of relapse is shown on
the y axis and years on the x axis, and the heterozygous patients are
shown in the red dashed line. Their relapse rate was equal to
statistically slightly less, in actual visual terms, than that found
with the wild type patients.

So this data from two sequential studies from a single center, St. Jude,
have demonstrated that certainly the patients that get dose reduction
based on genotyping and thioguanine nucleotide levels are not at a
higher risk of relapse. If anything, they have a better outcome than
their colleagues with the wild type genotype.

Now, the last part is how we should use TPMT genotyping. I think the
most important part of the discussion we\'re having today is not what
are the hard guidelines for using the genotyping or phenotyping
analyses. I think those are going to come out over the next few years as
the Children\'s Oncology Group does prospective studies to really hammer
down the utility of these tests.

To me the most important point is getting information, clearer
information into the package insert so we can inform patients in a
better fashion. There are some patients that are already finding this
information via the internet and acting accordingly. It would be much
more appropriate for them to get reasoned information through a package
insert than just to go out there and hunt it from web sites of variable
quality.

The second is that I mentioned that more intensive protocols with more
taxation on bone marrow reserve ‑‑ the genotype has a more dramatic
influence in that context. So pretreatment assessment of TPMT genotype
in my mind is something that we should be striving for in more intensive
protocols. Certainly there are some hints of how to dose on this.

This is data from Mary Relling that was published in the Journal of the
National Cancer Institute in 1999, data from the Total XII protocol.
What was demonstrated from that protocol is that the wild type patients
on average tolerated the full dose, the 75 milligrams per meter squared
of mercaptopurine. The heterozygotes tolerated right about 50 milligrams
per meter squared of mercaptopurine, and the homozygous variant patients
tolerated right about 10 percent, a little bit less than 10 percent of
the normal dose for their mercaptopurine therapy. So based on that
single prospective cohort study we have some hint on where to start with
these doses.

Now, a single prospective cohort study is better than nothing, but it\'s
certainly not ideal and it is not sufficient for our colleagues in the
evidence-based medicine arena, but at least gives some data on where
this could be started. I\'m not advocating that we put doses based on
this into the package insert, but certainly this has provided the basis
for many people\'s decision making off protocol and, of course, is a
subject of many protocols throughout the world.

This means that with prospective TPMT genotyping, patients with a
homozygous deficiency could have dramatic dosage reductions a priori,
cut down to 10 percent or so of the regular dose. The heterozygous
patients could be cut down to 50 to 60 percent of the normal dose, and
the wild type patients would keep on normal doses and be adjusted based
on white cell count. This is not an all-or-none phenomenon. Even those
patients that have dosage adjustments for complete deficiency still will
have variability that has nothing to do with thiopurine
methyltransferase. Therefore, this subject of evaluating levels of
myelosuppression will not go away. It is a pharmacodynamic endpoint and
a valuable tool. So having initial testing, dosage adjustments before
they ever start therapy, so initial therapy being guided, and then
reacting to myelosuppression is one paradigm that\'s put forward.

Another approach is evaluating patients only after they have toxicity,
and that is what is really currently being done at most centers. A few
are doing the prospective approaches, often not in the childhood ALL
context, more often in the adult setting for off-label usage, and that
is driven both by the demands of the patients. They\'re much more
demanding in terms of toxicity. They don\'t want it. They\'re not going
to let you give it to them. And also because of the litigation issue
that has been brought up by Dick previously, that there is a much more
litigious situation when you\'re talking about pemphigus or rheumatoid
arthritis than when you\'re talking about childhood ALL.

But in the context of many centers, when they have a patient with
toxicity, they do need to know which drug is the culprit and TPMT
testing is being used in that context. In that context, patients with
severe toxicity can have dosages being adjusted based on TPMT results.
So the homozygous deficient patients have the extreme dosage reduction,
less significant reduction but still adjusting the dosage for the
heterozygous patients. The complete deficient patients have the dosage
reductions. The patients with no TPMT defect have all of their
myelosuppressive doses adjusted, and the patients with no toxicity keep
being monitored the same way you\'re doing now with white cell count.

So just to reiterate, if you have TPMT deficiency, either homozygous or
heterozygous, you can react with dosage reductions according to what
I\'ve previously shown you. Those without a TPMT deficiency, we do not
know the culprit. It\'s probably not mercaptopurine, but all of the
myelosuppressive drugs will need to be adjusted in that context.

So what we have is a situation where there is a phenotype with a
molecular mechanism, a molecular diagnostic, and some hints on how to
adjust the dose. So at the minimum, the information on frequency, the
presence of a diagnostic should be available to patients in a uniform
fashion. I would argue that we\'re not quite ready to put dosage
adjustments into the package insert, but it certainly needs to be a
focus of the cooperative group studies that are going forward to define
who is the at-risk population and what doses do they need to be on.

The platforms for doing this analysis will change over time. Right now
you may say, well, it is expensive to do that testing for a 1 in 300
yield, and you can make that argument. But we\'re going to be adding
more and more genotypes in other contexts, and so it will be a case
where genotype analysis is being performed for a number of variants,
including TPMT. And therefore there will be information on a number of
different areas of your patient\'s management, infection risk, pain
control, antinausea and vomiting, cytotoxic therapy, that will make the
cost of an individual test much less and provide that with a much higher
utility.

So I think I\'ll close off with another quote that\'s a little bit more
recent than my last one. Gerhard Levy in 1998 mentioned that the
emphasis should not be on the population averages but rather on
providing tools for making drugs effective and safe for individual
patients. I think the context in which we\'re operating now is that we
know that there is an event, in this case a genetic variant, that
predisposes patients to risk of toxicity. Not acting on it at all or at
least not informing patients of its presence is really not adequate and
not optimal medical care. We may not have the ultimate data set to go in
and start changing everyone\'s dose, but we at least need to take this
into account and to start using it accordingly in a prospective fashion.

And I\'ll stop there.

DR. SANTANA: Howard, thank you so much for a very thorough and
informative presentation.

Does anybody have any acute questions? Sue.

DR. COHN: I just have one question, and that is, my understanding is
that the hepatotoxicity that\'s associated with 6‑MP does not appear to
be related to TPMT deficiency. Is that correct?

DR. McLEOD: It appears that that is the case. We have had mixed results
in that context which makes me think that it\'s something else. We have
people with severe hepatotoxicity that are heterozygous or even
homozygous variant, but there are plenty of patients with hepatotoxicity
that are wild type, at least as far as we can tell, with this genotype.
So I think something else is going on.

DR. COHN: That was going to be follow-up question, whether there was any
clue as to what else might be alluding to that particular toxicity with
this drug.

DR. McLEOD: There are candidate genes. We showed the pathways of the
proteins that are involved in this. Certainly we\'re taking a pathway
approach to try to look at all of those genes. What it really comes down
to is we do not have a clue what the other genes are that are modifying
other toxicities like you described there. That would be a very
important issue for both childhood ALL and all the other uses of
thiopurines because that\'s a common event, relatively speaking, and
it\'s also a common source of extra invasive tests in some contexts. But
I do not know. I should say for myself I do not know what the genes are
responsible for that.

DR. SANTANA: Howard, I want to make one point of clarification in your
presentation. I think you made a reference to the association of brain
tumors ‑‑

DR. McLEOD: I said the wrong protocol.

DR. SANTANA: Yes. You mentioned Total XI and for the record I do want to
correct that it\'s Total XII. Would you agree with that statement?

DR. McLEOD: Yes. Thank you very much. On the fly in mid-slide, I
couldn\'t remember which one it was. So thank you for correcting that.

DR. SANTANA: We will correct it in the record.

The second issue is at the end you presented some provocative algorithms
of potentially what could be done to manage patients. I want to make
clear when you were talking about TPMT, were you talking about measuring
of activity through enzymatic red cells or were you advocating genotypic
analysis in those algorithms? Can you clarify that for me?

DR. McLEOD: Yes. Unfortunately, I was letting my bias show through.
While I was at St. Jude, we were using TPMT testing in the activity
level, thioguanine nucleotide measurements, and genotype analysis. In my
personal experience, the presentation of anemia as one of the initial ‑‑
well, anemia, as an initial presentation of ALL, meant that many of the
children were coming in transfused. Measuring TPMT activity in the
transfused children meant measuring someone else\'s red blood cell TPMT
activity. Therefore, there were several of the cases, including the two
I described to you, that initially looked like they had normal activity,
or at least funny-looking activity, that over time, as their own red
cells came into prominence, were clearly deficient.

So I was really referring more to the genotype-based testing that can be
done a priori. It can be done in the context of even red cell
transfusions. It can be done very rapidly, and it can be done at a lot
more centers. So that\'s my personal bias, but it is nothing more than
that.

There are many centers that use red cell TPMT activity assays with high
success. I mentioned some of the reasons why activity assays are better
than genotyping in terms of capturing more of the variability that is
out there. So that\'s my particular bias, but it also has merit.

Thioguanine nucleotides could also be used in that context, but you have
to administer the drug and then measure the metabolites. So, obviously,
you can\'t do that without exposure to the drug.

DR. SANTANA: Thanks for clarifying that.

Any other comments or questions? We\'re going to have plenty of time
also during the discussion period.

(No response.)

DR. SANTANA: Thank you, Howard.

Naomi?

DR. WINICK: Good morning. I would like to begin by thanking Steve and
Dr. Lesko for inviting me. I\'m honored to be a clinician in this
audience.

Secondly, I\'m afraid that my presentation will include many slides that
have already been presented, and I will ask your forgiveness for the
duplication. I will try to be relatively quick, but I will be presenting
this, I think, from a different viewpoint and you may walk away from
this believing that I am, to borrow some of Dr. McLeod\'s words, the
mundane reactionary component of this meeting.

(Laughter.)

DR. WINICK: Just an overview. I come to this presentation with a deep
and abiding respect for how horrible cancer is in children, and leukemia
is one of the horrors. It\'s the most common horror, but there has been
dramatic improvement over the last 30 years. The lowest event-free
survival curve on this slide represents treatment between 1968 and 1970,
certainly within the life span of everyone in this room, and then this
curve represents therapy between 1996 and 2000. So there\'s been
improvement but we still have a long way to go.

These slides I\'m actually going to skip. You all know the history of
6‑MP. I\'m going to go back one, though, to emphasize something that has
been said, which is that the dose intensity of 6‑MP does correlate with
event-free survival. And this is something that Mary published several
years ago.

This has also been presented. Dr. Weinshilboum gave an elegant
presentation of the gene and its variability. I want to point out a case
presentation that was actually the first in the pediatric leukemia
literature, one published again by Bill Evans and Mary describing a
child with severe myelosuppression who had exorbitant TGN concentrations
and was found to be homozygous deficient. That case presentation was
published in the Journal of Pediatrics in 1991, so actually not that
long ago.

So the questions that I was asked to address are going to be illustrated
on this slide. We know that TPMT variation has an impact on clinical
response to the delivery of 6‑MP. We know that this variation is
assessable both by phenotype and genotype. One question that\'s been
posed is whether one can knowledgeably titrate therapy for children with
ALL without a knowledge of the pharmacogenetics. And then lastly, should
TPMT activity ‑‑ and I beg your forgiveness. This should also say
\"and/or genotype\" ‑‑ be determined prospectively in all children with
ALL?

The arguments suggesting that TPMT activity or genotype should be
determined prospectively include the following.

First, this is not a difficult test. 3 to 5 cc\'s of blood in a green
top tube is hardly horrific compared to other things that we put these
children through.

Second, the cost is nothing compared to the cost of cytogenic studies,
immunophenotyping, et cetera.

Potentially by doing this prospectively, we would avoid severe
myelosuppression. However, you\'ve heard from all speakers that severe
myelosuppression is not going to be eliminated by a knowledge of TPMT
genotype and appropriate dose adjustment. We may or may not prevent
second malignancies, and I will have slides later in the presentation
that address this.

And something important that I perhaps have not phrased scientifically
is another reason to do this prospectively is opposed to genotyping for
neurodegenerative diseases, Li-Fraumeni syndrome, et cetera, the results
of this genotype are not likely to cause undue emotional stress.

This is a slide from Mary Relling. Mary was kind enough to send me these
slides. I don\'t think she knew the context in which I was going to
present them. But this is a slide that Howard just showed, showing that
if you know the child\'s genotype, you can prospectively, or at least
you could prospectively, adjust doses.

The arguments that TPMT genotype should not be mandated prospectively
are actually what I will spend the rest of my presentation reviewing.

First, you\'ve all seen the numbers. Too many times you\'re looking at a
very small population that has a homozygous deficiency, and dosing for
the heterozygous population is actually quite similar to that for the
wild type population. I used as an example the coming Children\'s
Oncology Group standard in low-risk trial.

The Children\'s Oncology Group, parenthetically, is an international
cooperative group that will enroll more than 80 percent of all children
in the United States, the majority of children in Australia, children in
parts of Switzerland and other places on single, randomized, phase III
clinical trials for acute lymphoblastic leukemia.

The estimated projected enrollment for this one trial will be
approximately 2,000 children over a 4-year period. If you use the
population calculations that have already been presented, this means
that 7 children among these roughly 2,000 will be homozygous deficient,
and this covers all of the U.S., as I said, most of Australia, and other
places over a 4-year period.

So in the United States, even relatively large institutions ‑‑ and Dr.
Santana, I apologize. St. Jude is not included here, but most large
institutions in the U.S. don\'t see more than 20 to 30 new patients per
year with ALL, and there are some exceptions. There are also obviously
exceptions in the other direction where an institution may see 5 new
patients with ALL per year. So these institutions may not see a TPMT
deficient child ever, and if they do, it may only be once in every
decade.

This is, again, Mary\'s slide. It\'s already been shown, showing that if
you did have the information and did adjust doses appropriately, whether
it was prospectively or following toxicity, that child\'s event-free
survival won\'t be undermined by the dose adjustment.

Now I\'m going to just briefly review the therapy that the Children\'s
Oncology Group has put forth and will put forth for the treatment of
children with leukemia as a means of defending perhaps my statement that
I don\'t know that the testing should be mandated prospectively.

Induction therapy is fairly straightforward. A glucocorticoid is used
and there\'s enormous debate as to whether or not this should be
dexamethasone or prednisone that I won\'t go into. Vincristine is a
standard part of all induction therapies. Asparaginase is almost
standard. Intrathecal therapy is the initiation of treatment that will
prevent the occurrence of CNS leukemia, and for many higher-risk
patients, an anthracycline is included in the induction.

There is then a period of consolidation wherein CNS prophylaxis is
delivered. For standard-risk patients, this is often a relatively simple
period where the dominant therapy is the intrathecal therapy, again
designed to prevent CNS disease. For higher-risk patients, the
Children\'s Oncology Group will incorporate both cyclophosphamide,
cytarabine, intermittent pulses of vincristine and asparaginase, and
there will be randomized questions asked in this section. So I\'ve put
up a backbone. I have not put up a slide with all of the details.

There is then a period of delayed intensification. The UKALL studies, as
well as Children\'s Cancer Group studies, as well as German trials have
all demonstrated that this is a very important part of the treatment of
children with acute lymphoblastic leukemia. And there is an anti-purine
here, but it is almost universally thioguanine, not 6‑MP. And
thioguanine does not seem to be as influenced by TPMT as 6‑MP.

Maintenance therapy is the area where 6‑MP really becomes prominent.
This extends for 2 to 3 years. Most children worldwide receive nightly
oral doses of 6‑MP, weekly oral doses of methotrexate. Intrathecal
therapy is delivered on a variety of schedules, but a common one is
every 12 weeks. Many children receive vincristine/dexamethasone pulses.
This obviously can also be prednisone. This is the first introduction of
6‑MP in any sustained or prolonged sense.

Contrary to what may have been suggested earlier, this therapy is not
particularly myelosuppressive in the vast majority of children who
receive it. Accordingly, it is often not difficult to believe or to
think that it might be the 6‑MP in a TPMT deficient or heterozygous
child that is responsible for myelosuppression if it is severe.

The other thing that\'s very important to note is that all protocols
adjust to a defined absolute neutrophil count. So some of the
modification is instituted regardless as to whether or not genotype or
phenotype is known.

I\'m now changing subjects. Again, this is a slide that Mary Relling
sent me, and this is looking at the incidence of brain tumors in one
particular St. Jude protocol which was unique in that 6‑MP was delivered
concomitantly with cranial radiation. As Dr. McLeod already pointed out,
19 children developed high-grade CNS malignancies. This is essentially
unheard of in other pediatric protocols both at St. Jude and elsewhere.

This is, again, Mary\'s slide demonstrating that those who had TPMT
deficiency were at significantly greater risk than those who had wild
type TPMT of developing these brain tumors.

So the St. Jude\'s group concluded for obvious reasons that there was a
higher risk of radiation-induced brain tumors among children who either
had high thioguanine nucleotide concentrations or TPMT deficiency. This
is an important point in that among the children studied, there were
children with wild type enzyme who simply had very high TGN levels and
also developed the brain tumors. As I said before, there was a unique
combination in that they delivered 6‑MP during radiotherapy and that
will not likely be repeated in the future. As I said, only 3 of the 6
children initially described actually were TPMT deficient.

The more difficult issue is that relating low TPMT activity and the risk
of either secondary myelodysplastic syndromes or treatment-related AML
following thiopurine therapy. Again, Mary\'s data documenting a trend
that was actually not statistically significant towards a higher
incidence of etoposide-induced secondary AML with lower TPMT activity,
all cases described had the 11q23 abnormality which is a hallmark of
etoposide-related AML.

My greater concern, though, is the Nordic trial, and Dr. Weinshilboum
should comment. I believe he was involved in measuring enzyme activity
and looking at the genotype for these patients. This group never gave
etoposide, not a single milligram. And the dose of alkylating agent,
even in the higher-risk patients, didn\'t exceed 3 grams per meter
squared, which by oncologic standards is low. They documented a higher
incidence of treatment-related myelodysplasia and/or AML in patients who
had less enzyme activity. This was defined as less than 14 international
units per ml of red cells. And it was statistically significant. I
can\'t explain this data away.

But I can present it in the context of other studies that have looked at
secondary AML. Again, remember that all of these trials included 6‑MP
because it is truly ubiquitous among therapies for ALL.

Anna Meadows published a review of CCG data. She looked at an
unquestionably impressive number of children, 9,720 who had been treated
with ALL without etoposide, and there was one documented case of
treatment-related AML among these almost 10,000 patients, all of whom
received 6‑MP.

And then a smaller study, but nevertheless impressive, from Dana Farber
was published in 1990 where they found two cases of treatment-related
secondary AML among 752 children who had been treated at their
institutions for ALL. And this is important because even though Dana
Farber\'s protocols never included etoposide, they are very
anthracycline intensive, and as this room knows, anthracyclines may also
have an effect on topo II and may also predispose to secondary AML. It
is also important to note that Boston perhaps to a greater extent than
any other group uses cranial radiation. So another secondary
malignancy-inducing therapy. Nevertheless, they didn\'t see them.

So what I actually am comfortable with ‑‑ and this is Mary\'s slide and,
Dr. Santana, I promise I will call and beg Mary\'s forgiveness. I
actually like Mary\'s slide recommending dosing based on toxicity and
the results of testing. Patients with serious toxicity or suspected
noncompliance, something we haven\'t discussed here, should have doses
adjusted based on the results of testing genotype activity, thioguanine
nucleotide concentrations. I think there are reasonable reasons to do
all of the above. Those with a TPMT deficiency obviously have to have
their doses of 6‑MP decreased dramatically and preferentially over the
doses of other drugs. Those without a defect would not have the doses of
6‑MP preferentially adjusted, and those who don\'t have 6-TGN
concentrations should be evaluated for noncompliance, which is an issue
in and of itself. Those patients without toxicity who achieve ANCs in
the target range as dictated by the protocol would not necessarily have
the testing done and would not necessarily have changes made in their
therapy.

So the availability of testing for TPMT and thioguanine nucleotides
clearly improves the care of children with ALL. I am not here to be
anti-science. However, prospective testing of all children may not be
warranted. It would clearly limit, though it would not eliminate, the
incidence of severe myelosuppression and perhaps the risk of second
malignancy. However, my greater fear is that it will also actually lead
to a decrease in dosing for children with ALL. My reasons for this are
as follows.

Number one, as you\'ve seen, the numbers are small so there will be many
treating physicians who have never seen a heterozygous phenotype before,
who have never seen a homozygous patient or genotype before, and won\'t
necessarily know how to respond and arguably might overreact and cut
doses fairly dramatically.

Second, in the real world, I\'m afraid that prospective testing isn\'t
always done at exactly the time point that the protocol recommends it,
and I have significant fears that a child will arrive at the moment that
they\'re supposed to begin their 6‑MP therapy, that the blood will not
have been sent, and that therapy will be delayed, in my opinion,
somewhat unnecessarily. There has only been one report of a fatality
related to TPMT deficiency. That slide was actually presented earlier.
It was an adult patient who had undergone cardiac transplantation who
was treated with azathioprine.

So, again, in my role as the mundane reactionary pediatric oncologist,
I\'m not arguing that myelosuppression is not a serious toxicity. I am
certainly not arguing that second malignancies are not one of the worst
toxicities that we face. However, in the context of most protocols to
treat children with cancer, 6‑MP is actually the least toxic drug that
we deliver, and the toxicity is far and away some of the more
manageable.

Thanks.

DR. SANTANA: Thanks, Naomi.

I\'m going to ask you the same question I asked Howard, which is in your
presentation of the algorithm that you proposed that should be used, can
you clarify for me if your intent is to use phenotypic activity ‑‑ and
obviously, you\'re adding toxicity ‑‑ in contrast to genotypic typing of
all patients? Am I understanding you correctly?

DR. WINICK: I would not choose one or the other. I think that one of the
great problems that Howard pointed out is ‑‑ with my recommendation that
this be done not mandated prospectively, but perhaps be done in the
context of toxicity ‑‑ what you don\'t want to have is a physician with
a child with severe myelosuppression who then continuously puts off
sending blood for TPMT activity because of the transfusions. So I think
you have to be flexible, and in that circumstance, genotyping would
clearly be the way to go. But it would also be phenomenally useful I
think to the clinician to get TGN nucleotide concentrations because then
you have a functional result to match your genotype result.

DR. SMITH: Naomi, I had two questions. One was would it matter or make a
difference to you if the first exposure to 6‑MP was in a maintenance
like course of therapy versus being part of a more toxic part of
therapy? And I ask that in the standard risk, I think the first exposure
would likely be in some kind of maintenance-like whereas in a high-risk
setting, it might be during reinduction to 6TG. Would that make a
difference to you in terms of how you would approach the testing?

DR. WINICK: The answer to your first question is simple. Again, this was
the slide that Dr. McLeod presented. If you are giving multiple severely
myelosuppressive agents, then there\'s no question that it will be much
harder to pinpoint the 6‑MP. Unquestionably.

For COG, though ‑‑ and this was actually one of the slides that I put up
‑‑ the delayed intensification and reinduction phases use TG, and again,
there is less of an influence of TPMT activity on thio nucleotide
concentrations following the administration of oral thioguanine. So even
for the high-risk patients, the schema that I supplied is valid.

What I thought you were going to say is what about the kids with T-cell
disease because for the T-cell patients, where the protocol is still in
construction phase, if we adopt a Dana Farber-like regimen where
anthracycline is delivered concomitantly with 6‑MP, then it becomes a
bigger issue. The number of children is much smaller. So again, the
arguments about testing prospectively I think are still somewhat
strained.

DR. SANTANA: Dr. Boyett, I think you had a question.

DR. BOYETT: In several of the presentations, yours included, I guess
I\'m a bit troubled by continued emphasis on secondary tumors because
having been involved in a number of these investigations, it\'s unclear
to me that we truly understand the interactions with the drugs or timing
or schedules, et cetera that lead to those. In fact, nobody has
mentioned the paper that Dr. Relling and I just published in Blood that
shows in the Total XIIIA and B trial that associates the exposure to
irradiation and exposure to G-CSF with developing secondary AMLs.

DR. WINICK: I actually agree with what you said. I tried to make that
point, that the study that stands out as most disturbing to me is the
Nordic trial because in the two papers from St. Jude describing second
malignancies, in one there was clearly an interaction between
thioguanine nucleotide concentrations, TPMT activity, and radiation. And
in the other paper from St. Jude, there was a trend that was not
statistically significant describing an AML in patients who also
received etoposide. Second malignancies are clearly multifactorial.

The Nordic trial stands out in not containing obvious, known ‑‑ and
there\'s a great deal that\'s not known ‑‑ agents that lead to secondary
AML. I wish that paper included the cytogenetics of those cases or a
more detailed description of those cases. I\'m afraid it didn\'t, so
it\'s impossible to tell.

DR. BOYETT: Did it include irradiation?

DR. WINICK: No. I take it back. There were a trivial number of patients
who had CNS disease at presentation, but that doesn\'t count.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: Naomi, just a couple of points. One, you made the statement
that the first time children with ALL are really exposed to 6‑MP is in
maintenance, but in fact there are two periods prior, or at least one
period, of interim maintenance before standard maintenance for all risk
groups of patients.

DR. WINICK: You are correct, but as in maintenance therapy, interim
maintenance does not include anthracycline, does not include
cyclophosphamide, does not include other agents that are significantly
myelosuppressive. So I still believe that a clinician is likely to be
able to identify the cause.

DR. REAMAN: Right. That\'s the point I\'m trying to make. You could
actually look in interim maintenance.

The other is that I\'m questioning the statement about the unique
association of 6‑MP administration during cranial radiation in the St.
Jude experience because that was clearly the regimen that has been
utilized in multiple series of CCG trials years ago when cranial
radiation was administered during consolidation. There was daily oral
6‑MP in large numbers of patients.

DR. WINICK: Then I owe you an apology. When I went back, it looked like
dominantly the drugs delivered during radiation were vincristine and
prednisone.

DR. REAMAN: It was 6‑MP daily and then vincristine once a week.

DR. WINICK: Okay.

DR. SANTANA: I think we\'re going to take a break and we\'ll come back
because I think we have plenty of time for discussion. So with
everybody\'s agreement, can we reconvene in 10 minutes so we don\'t fall
too far behind? Thank you.

(Recess.)

DR. SANTANA: Let\'s go ahead and get started.

We now have an opportunity for an open public hearing session, if there
is anybody in the audience who wishes to address the committee. In the
interest of being fair, please state your name and your affiliation. If
anybody in the audience wants to address the committee, this is the time
to do so.

If there is nobody, we did receive a written comment that I am going to
read into the record. We\'re going to have a period of discussion after
the open public hearing session. We\'re going to have a general
discussion.

Yes? Do you want to go to a microphone and state your name and
affiliation?

DR. RUSSO: My name is Dr. Mark Russo. I am with GlaxoSmithKline. I would
appreciate it if the committee could comment on some of the other agents
that are also metabolized by TPMT and give us guidance on suggestions
for label adjustments there as well.

DR. SANTANA: Mark, just for the sake of fairness, can you state any
potential financial involvement or conflicts that you may have in
relation to your question and comments?

DR. RUSSO: I am employed by GlaxoSmithKline. GlaxoSmithKline has in the
past manufactured and distributed 6‑MP, as well as 6-thioguanine and
azathioprine.

DR. SANTANA: Thank you, Mark.

So the question that Mark wants us to address ‑‑ if you allow me, Mark,
we\'ll try to put that on the docket for the general discussion that
will follow in terms of if any of the participants want to comment on
other specific guidelines of target drugs that may be involved in this
pathway too.

I\'m going to go ahead and then read the comments that we received in
writing, and I\'m going to read these for the issue of the public
record. This is a memo sent to the committee by Dr. Peter Adamson who is
the chair of the Developmental Therapeutics Committee of the Children\'s
Oncology Group. It\'s dated Tuesday, July 15, 2003.

\"Comments to the FDA Regarding Pharmacogenetic Testing for Thiopurines.

\"It has been 50 years since Dr. Burchenal published the initial
experience with 6‑MP in patients with leukemia in the journal Blood,
subscript referenced, and thus perhaps it is fitting that a discussion
on whether pharmacogenetic testing should now be incorporated into the
Purinethol label is taking place. Many experts have presented this
morning, so I will only briefly share my view of the potential risk and
benefits of requiring pharmacogenetic testing when utilizing 6‑MP in
children with ALL.

\"There is likely uniform agreement that the one subpopulation that will
benefit from required pharmacogenetic testing are the 1 in 300 children
who are homozygous for TPMT alleles that code for low TPMT enzymatic
activity. Knowledge of their TPMT status would greatly diminish their
risk of profound myelosuppression when treated with standard doses of
6‑MP. However, for patients who are heterozygotes for TPMT alleles that
code for low enzymatic activity, a priori knowledge of their genotype
has not yet been demonstrated to either diminish the frequency of 6‑MP
induced myelosuppression or improve outcome. For children with wild-type
TPMT alleles, knowledge of their genotype presents minimal to no
potential for benefit, as within this largest subpopulation there is a
high degree of intra- and inter-patient variability in 6‑MP drug
disposition and tolerance that results from factors distinct from the
phenotype.

\"There are potential risks associated with a product label requiring
TPMT genotype testing. The first risk may arise when there is a delay in
administering maintenance chemotherapy while awaiting the results of
genetic testing. In an ideal world such delays would not exist, yet
there will undoubtedly be situations in which the realization that a
patient\'s TPMT status is unknown arises only at the time 6‑MP is to be
prescribed. Delays in the administration of 6‑MP and initiation of
maintenance chemotherapy presents a risk to the entire population of
children with leukemia.

\"The second type of risk centers on the potential for misinterpretation
of patients\' genotypes. For example, patients who are heterozygotes
could inappropriately receive inadequate doses of 6‑MP, i.e., doses
similar to those recommended for patients who are homozygous.

\"6‑MP has been routinely administered to children with ALL as the
cornerstone of maintenance chemotherapy for more than 40 years, and
despite our increase in knowledge, adjusting its dose based upon the
WBC, white blood cell count, remains the standard of care. Encouraging
determination of TPMT genotype may clearly benefit 1 in 300 children,
and potentially augment the management of patients who are heterozygous
for these alleles. For the latter group, however, given the large
overlap between the wild type and heterozygote populations in drug
disposition and tolerance, the utility of a priori dose adjustment based
on genotype remains an important research question, and should not yet
be adopted as a standard of care.\"

I don\'t think we have any other public comments. So with that, we\'ll
start our discussion of the presentations. Before we took our break, I
think Nancy had a question she wanted to ask some of the presenters.
Nancy?

MS. KEENE: I just had a couple of questions for Dr. Winick. One is could
you tell me ‑‑ I don\'t know ‑‑ if there\'s any standard mechanism now
within COG for children enrolled on protocols for ALL, a mechanism
that\'s in place to manage risk for children who have just begun
treatment with mercaptopurine? Is there any standardized way to respond
to rapid onset of neutropenia? What\'s done in the group right now?

DR. WINICK: We have recently included I think a fairly detailed
paragraph within the protocol ‑‑ within the open protocols and
obviously, they\'ll be included in the protocols that have yet to open
‑‑ providing the information that\'s been presented here. So it states
very clearly that TPMT deficiency occurs in 1 in 300 children and it
goes on and explains the fact that testing is available and that
depending on the results of this testing and the child\'s degree of
myelosuppression, that significant dose adjustments may be required.

The other thing to note is that all ALL protocols, without exception,
have hopefully very clear instructions as to what to do in the face of
myelosuppression. So step one is always if the absolute neutrophil count
falls below whatever level is dictated by the protocol, all chemotherapy
or all myelosuppressive chemotherapy is withheld immediately. And then
there is an algorithm then. If the level falls to this point, then you
may reinstitute therapy at full dose. If the level falls to this point
but recovers within 7 days, reinstitute therapy at another level. So
they\'re fairly detailed instructions because myelosuppression is the
single biggest problem in association with ALL therapy, 6‑MP being one
of the players.

Did I answer your question?

MS. KEENE: Yes. So it\'s based on the absolute numbers and not the
rapidity of the decline in the numbers.

DR. WINICK: It\'s based on the absolute number and not necessarily how
quickly it falls because remember that, at least with respect to 6‑MP,
the vast majority is delivered in the out-patient setting. So I
wouldn\'t know if a child\'s neutrophil count fell 2 days after I gave
him the drug or 7 days unless that child happened to get sick. So we
don\'t have anything based on rapidity, but we have a great deal that
describes how long it takes to recover because, again, several of the
slides presented today demonstrated that in a child with TPMT
deficiency, it\'s not only that their neutrophil count falls, but it
stays down forever. So duration is addressed.

MS. KEENE: The paragraph that you first described, is that an addendum
to the open protocols right now? Because I skimmed through this morning
1991 and didn\'t see anything on the topic.

DR. WINICK: I can\'t speak to 1991. Malcolm, do you want to?

MS. KEENE: I just skimmed.

DR. SMITH: Yes. I did a word search on TPMT, and the 1991 protocol does
describe for ANC less than 500 ‑‑ so this would be during maintenance ‑‑
discontinue dose until ANC is greater than 1,000. Restart mercaptopurine
at 50 percent of the original dose on the same day that counts recover,
and then increase to 75 percent and 100 percent as tolerated. And then
the instructions are for patients who cannot tolerate greater than or
equal to 50 percent of mercaptopurine dose in maintenance, call Dr.
Karen Lewing in clinical pharmacology at Kansas City for determination
of TPMT enzyme activity. That\'s in the 1991 study. 99-04.

DR. WINICK: 99-04 and 99-05 included a paragraph that\'s somewhat
different in that investigators are not instructed to call a give person
but since the testing is commercial available, they\'re instructed to do
it.

DR. SANTANA: I\'m going to take this opportunity to ask our European
colleagues how do they address this issue in Europe in the ALL trials.
So please feel free to comment.

DR. MORLAND: I think the approach is very similar to the current
practice in the United States in terms of the guidelines and
recommendations for dose alteration of 6-mercaptopurine. They\'re
almost, if not word for word, probably very similar to those that Dr.
Smith just expressed.

Within the UK, we\'re currently undertaking a prospective analysis of
both phenotype and genotype in the current trial, which is actually due
to close later this year, and to link that information with doses
received and morbidity. So I think that over the course of the next
year, once that data is analyzed, we\'ll have a lot more information on
the true impact of this screening.

The one question I was going to ask is throughout all of the
presentations, the one piece of data that does seem to be lacking is the
real morbidity associated with patients who have homozygous deficiency.
There are clearly a number of ad hoc case reports in the literature, but
I don\'t think I\'ve yet got a feel for the true morbidity that these
patients are experiencing. Clearly mortality doesn\'t seem to be an
issue. We\'re very used to running patients on very low neutrophil
counts in many solid tumor protocols without too much concern. I\'m yet
to be persuaded that the morbidity being experienced by these patients
is any more significant than some of the more intensive solid tumor
protocols that we currently expose patients to.

DR. SANTANA: Do any of the ALL doctors want to comment on that?

DR. WINICK: I think you\'re right. I think one of the comments that I
made is that 6‑MP is actually one of the more benign drugs that we use.
Sue should comment on this, but when I think of what children with ALL
go through compared to children with osteogenic sarcoma or
neuroblastoma, there\'s no comparison. Most of these children have ANCs
above 500 for the overwhelming majority of their therapy.

Sue?

DR. COHN: The only thing I was going to say is that if you want to take
a look at it the other way, you also have a very excellent prognosis for
this group of patients. So the last thing you want to do is take
somebody who\'s got this very excellent prognosis and potentially
subject them to a toxicity that could, in fact, be life-threatening. But
I agree. Certainly in my experience in most of these kids, the 6‑MP is
well tolerated.

DR. MORLAND: You could argue the same for patients with B-cell
non-Hodgkin\'s lymphoma who have an excellent outcome who are exposed to
extremely intensive, heavily myelosuppressive chemotherapy with huge
morbidity. I just haven\'t got a feel for whether this is any worse than
that.

DR. SANTANA: Dr. Vassal?

DR. VASSAL: With regard to dose recommendation, I was wondering whether
Naomi would comment on the recent research of the Scandinavian NOPHO ALL
\'92 study by Karl Schmiegelow. This study randomized classical
controlled prospective adjustment of maintenance therapy versus
pharmacokinetically guided adjustment on the basis of 6-thioguanine and
methotrexate on erythrocytes, and they showed in this population that
there was no difference in boys. However, in girls there was a higher
risk in the groups of patients whose maintenance therapy was adjusted on
the basis of a pharmacologic setting. So would you comment on these
because it seems it is important to consider it with regard to the
recommendation that should be done for these patients and their
maintenance therapy?

DR. WINICK: I\'m happy to. Dr. Weinshilboum, do you want to comment
first?

DR. WEINSHILBOUM: Go ahead.

DR. WINICK: I think it\'s one of the saddest papers that I\'ve read
because one would hope that when you make the effort to use
pharmacologic dose adjustment, the outcome would be better. It\'s just
tragically sad.

However, given that reality, I think that in their discussion they
really do a very nice job of explaining what all of us have made
reference to, that this is a multifactorial process. One of the comments
they make that I thought was interesting was they talk about perhaps the
higher TGN levels in the girls led to more immunosuppression and that
then the host versus leukemia was less effect than in the patients with
lower TGN levels. I don\'t know if there\'s any data to support that,
but I thought it was an interesting comment. I think that it just proves
that there\'s a great deal that we don\'t know about what it means.

The other thing that Mary and Bill published that I thought was a
gorgeous paper is that 6‑MP unlike 6-TG is methylated to a significant
extent, and many people, I think, assume that the methylated product is
trash, but in actuality there\'s nothing to say ‑‑ in fact, there\'s a
great deal to say ‑‑ that if the methylated product decreases de novo
purine synthesis by means of feedback inhibition, it is entirely
possible that the methylated product, which would have gone down in
those girls because they increased the TGN concentration, is more
important than we realize.

DR. WEINSHILBOUM: I think that that\'s an important issue. In the
original NOPHO trial that you referred to, the methylated
mercaptopurines were also followed, and clearly there was some
indication in some patients that they contributed to the therapeutic
effect so that the situation is clearly going to be a bit more
complicated than just 6-thioguanine nucleotides. Please don\'t tell
Lynne Lennard I said that, but it will go beyond that.

With regard to your question about the morbidity, obviously my
experience as an internist who is called in from a biochemical/molecular
perspective, but as a physician, it\'s going to be anecdotal. The
morbidity can be quite striking in that without divulging any patient
information in this HIPAA age, I will tell you that some of these
children are hospitalized for months in referral centers. These are the
homozygous low individuals. So the degree of toxicity which these
children can have ‑‑ and once again, I\'m only called in when there is a
train wreck ‑‑ can be quite striking.

My initial comments during my presentation were not entirely facetious
when I said that as a non-pediatric hematologist/oncologist, but an
internist, this is an interesting cross-cultural experience because I
heard Naomi say, well, for the homozygous low individuals, this doesn\'t
explain everything. I\'ve been in medicine for 30 years and nothing
explains everything in medicine. So, with all due respect, Naomi,
that\'s hardly an argument for not taking advantage of new information
as it comes along.

DR. WINICK: And I wasn\'t ‑‑

DR. WEINSHILBOUM: No, no, no. I know, but I heard what you said too.

Having said that, also as someone who works in a cardiovascular arena, I
guess I would generally before I prescribed digitalis, measure the serum
potassium rather than administering the digitalis and letting the
patient develop PAT with 2 to 1 block. That seems a rather arcane way to
diagnose hypokalemia.

I understand that culturally in oncology ‑‑ and my daughter has
explained this to me in words of one syllable that even an internist can
understand ‑‑ that you manage toxicity and that this is a part of what
goes on. I guess I would say that in some arenas, whatever limited
knowledge we have to avoid toxicity might also come into play.

I want to thank all of you. This has been a fascinating experience for
me.

DR. SANTANA: Dr. Boos, you had a comment.

DR. BOOS: Yes, a comment on the morbidity question because I think this
may be a little bit misleading. It\'s a significant difference if we
have to take morbidity into account because we have to apply a clinical
protocol with some expectation of survival or if we can avoid this
toxicity. And the question is can we really avoid it.

My feeling is that for the homozygous, the positive predictive value
seems to be roughly 100 percent, and this in a 1 to 200 relationship is
for preventive medicine aspects extremely good. But the negative
predictive value has never been addressed yet today, and I have several
patients in my memory where we had extreme toxicity and investigated,
all the genomic people of us, and nothing was positive. And we had this
toxicity and I think those were the 5-10 last patients. Nobody had TPMT.

In Germany we have, as in England, prospective evaluation of genome and
phenotyping for TPMT, and the results compare I think. In roughly 1,000
patients now, there have been 4 identified.

We had patients where the white blood cell counts didn\'t drop anyway.
They stayed with 6,000, 7,000, 8,000 neutrophils during maintenance
therapy, and we sent in these TPMTs and everything was normal. The
highest thiopurine level is intracellular. So I think we should have a
little bit of focus on the other side. What do we oversee? What about
the sensitivity of these assays and on the negative predictive value
because the danger to feel safe and not to be safe may be relevant.

DR. SANTANA: Dr. Riccardi.

DR. RICCARDI: First, a general comment. It seems strange that we start
with a discussion on the label because we never read the label.

(Laughter.)

DR. RICCARDI: We know what we are doing. At least we should.

The second point. I use 6‑MP as an example teaching to the students in
pediatric oncology, as an example of variability, other factors like
food or what type of food or when you are taking the drug. So it\'s
really an example in which we are used to looking at white cells as a
very useful test.

The last point I want to make is I understand all these aspects are very
important, but in Italy we have probably two cases a year of such a
situation. Also in view of international cooperation, I think we should
avoid going toward tests that are so specific and that are so expensive
and also could cause, as was said before, some delay and also some fear
from the parents in the situation in which you have a heterozygote
situation.

DR. SANTANA: Dr. McLeod, you had a comment.

DR. McLEOD: Well, that was a long time ago.

(Laughter.)

DR. McLEOD: I think the fears that you identified are not real. Patients
fear neutropenia more than they fear pharmacogenetic testing. I think
one of the things that we ‑‑ and I do mean \"we\" not just everyone but
me ‑‑ are having a hard time getting our head around is a new way of
looking at practicing medicine. I agree with the comment that was made
at this end of the table that in the context of diseases where there is
not a good outcome, it really doesn\'t matter in some ways because we
just try to do the best we can. In the context of patients where we can
do well, we need to try to optimize things. I think this acceptance of
we can manage toxicity has to be removed out of our thinking. It has
served us very well to this day and will continue to serve us well until
we can do better. But when we have an example of where we can avoid a
problem, then I think we need to think about using it.

Now, I agree with the numbers problem. If it\'s only 1 in 200 to 1 in
300, then we have to see whether that\'s cost effective, and no one has
addressed the cost issue today.

But there\'s a fundamental issue because really what we\'re talking
about here is not is TPMT testing good for childhood ALL, but is TPMT
testing good for thiopurines. Where people get in trouble is not just in
the context of childhood ALL therapy where all of you are very good at
managing therapy. It\'s the ‑‑ I forget the term you used, Dick, but the
poor internist, or whatever the term you used, who is not used to
managing, and when a patient gets a white count of 3,000, they start
panicking and want to admit them. You would love a white count of 3,000
in most of your patients. You would be treating them right away,
probably high dose. So that\'s kind of the secret behind the door that
we haven\'t really talked about yet that\'s on the agenda, the
implication that it\'s not just for childhood ALL, but beyond.

But I wanted to make the point that for the next few years people are
going to be treating childhood ALL the way they\'ve been treating it for
quite a while. Look at those curves Naomi showed. It\'s wonderful
progress.

DR. SANTANA: Steve, I think you have a point you want to raise.

DR. HIRSCHFELD: I want to clarify, with all due respect. The issue is
what the product label says, which is acute lymphocytic leukemia, and
it\'s come before the Pediatric Subcommittee because the focus is on
children with ALL, and we cannot be addressing the off-label uses or can
we address other drugs of a similar molecular structure or similar
metabolic pathways.

Which leads me to one question, and I will direct this to Drs. McLeod or
Weinshilboum. Has the natural substrate ever been identified for this
enzyme, or as far as we know, it exists only to torture people who are
getting drugs?

DR. McLEOD: Dick, shall we say no in tandem? As far as I know, there is
a natural substrate for TPMT. It\'s clear from the uremic patients and
from other similar situations that there is something that interacts
with the enzyme, but I am not aware of anyone having identified what it
is yet.

DR. WEINSHILBOUM: That was the study we published years ago where in the
plasma of patients with renal failure, a methyl acceptor substrate or
substrates accumulate. This enzyme is very widely expressed in a variety
of tissues, but if God gave it to us, as Gertrude Elion would say, to
deal with some known substrate, she is the only one who knows the secret
because we don\'t know.

DR. SANTANA: Nancy, I think you had a comment.

MS. KEENE: I have several. I\'m here to speak for the children and their
families, and I want to bring up a couple of points.

First of all, the economics has been alluded to a couple of times, but
not explored. One of the speakers talked about the large amounts of
resources that are absorbed by the homozygous kids, and one thing we
haven\'t addressed is the relative amount of resources that are absorbed
by the heterozygous kids who have multiple episodes of neutropenia.

I\'m probably the only person sitting at the table whose child was a
survivor of ALL and was treated with this drug. After reading the
literature, I think she was heterozygous. It was a horrific experience
to live through and one I hope none of you ever have to experience. When
you go in weekly for blood tests and the medications are being adjusted
on a weekly basis, when you have a child who has got an absolute
neutrophil count of 0 multiple times throughout treatment, and the child
was hospitalized many times for treatment, we\'re going back to
economics now and not the psychological impact, but that\'s absorbing a
huge amount of resources. If these children can be tested for \$100
each, and we\'re talking about 2,500 kids, if someone worked out the
economics of it, it probably would be a lot cheaper to test them.
That\'s one issue.

The other is I always am uncomfortable when people compare morbidity and
say one thing is not quite as bad as something else. I mean, to compare
the leukemia kids to the sarcoma kids and say, well, it\'s not quite as
bad is doing a disservice to what we really should be doing in medicine.
In medicine we should be treating that disease the best way that we can,
and if we have something that can be prevented rather than managed, I
think we have a moral responsibility to do that.

Also, I find it a peculiar argument to say that the two reasons that
were put forth by the written comments and also by one of the presenters
for not knowing this information is because inexperienced doctors will
overreact and under-treat the child and also that delays in treatment
because someone didn\'t do what they were supposed to do at the time,
which is send the blood ahead of the time when maintenance would begin
to start so you would have the information you need in order to begin
treatment for that child at the appropriate time, that is not a very
good argument. Do people make mistakes? Yes. We\'re human beings. We
make mistakes. But what we should do is institutionalize methods so that
these mistakes will be minimized rather than using them as an excuse for
not knowing the information. I think those are two pretty bad arguments
that don\'t sway me.

I\'m going to wrap up. I\'ll probably say something else later because
this is pretty close to my heart, but I would argue for putting on the
label ‑‑ we\'ll get back to this, Steven, after listening to all the
arguments. I think that frequency should be on the label. I think
physicians should know what percentage of children diagnosed with ALL
are homozygous and which ones are heterozygous, and I think that
diagnostics are available in order to evaluate this. It should be on the
label so people know and it won\'t be just people in this room or a
small other cadre of people in the community who know that. Whether or
not appropriate doses should be included, it doesn\'t sound like we have
enough information at this time.

But I\'m also interested to know if COG has planned any prospective
studies like our colleagues in the United Kingdom have so we\'ll really
have more information to go on from a larger data set sometime soon.

DR. SANTANA: I think Dr. Reaman had his hand up, but before I give him
the microphone, I do want to make one clarification in terms of the
issue of timing of testing. We\'re really talking about two different
sets of testing. The genotypic testing can be done at any time point in
the therapy of the patient. The phenotypic testing has to be contingent
upon the patient getting the drug and then measuring the effect in terms
of the phenotype, if you\'re measuring 6-TG levels, thiopurine levels.
So the issue of the a priori testing is going to be a little bit
different for both of those scenarios. I just want to clarify that for
the record.

Greg?

DR. REAMAN: Well, I was just going to address the fact that we have come
to the point where we are in pediatric oncology because of
evidence-based medicine. I\'m not sure that making decisions based on
testing for thiopurine methyltransferase ahead of time, that we\'re at
that point right now. I would agree with you that doing a prospective
evaluation is something that should be considered within the context of
COG ALL trials, however.

MS. KEENE: Is that in process now at all?

DR. REAMAN: It\'s not in process now. It\'s not in process now because
of limited resources. There are only so many questions that we can
afford to ask, and there aren\'t laboratories that are chomping at the
bit to get 1,200 samples a year for some of the testing. But in reality,
I think it\'s something that we should explore.

DR. SANTANA: Jody?

DR. PELUSI: When I was thinking about this topic, I was trying to think
of any other deficiencies that we see and how we label that. The only
one that came to mind to me, again being from the adult population, is
DPD deficiency in 5-FU, and although there\'s not a commercial test out
there, although you can get it done, it\'s not easy to do. The question
becomes looking and trying to balance looking at clinically how we
manage patients as well as if we had that, would it be good. So, again,
when we look at this and I think about that other population, I go back
and I say, well, what\'s really in the label. And the label does say
that it exists and what to look for.

When you begin to look at this particular topic as well and saying that
maintenance and looking at how the counts should be monitored and stuff,
I think again people need to know that they do have choices. I think
that that\'s where it comes into play, this whole issue of informed
providers, informed consumers, and letting everybody know that there is
an option out there if, indeed, it needs to be done.

I have to say that I really like this algorithm that Naomi presented in
terms of you can have a choice in the very beginning if you want the
testing done or not, but at the same time, because of the numbers being
so small, the question is, is the first sign of the myelosuppression in
an abnormal kind of situation ‑‑ is it then perhaps a way to go and
it\'s a known way that that is the next step in looking at it. So
that\'s kind of what I\'m leaning towards at the time. I realize, being
someone who cares for the symptoms and being the one called in for all
the symptoms, they are not benign by any means. But again, the numbers
‑‑ it\'s hard to balance.

So I think we\'re looking at how we do it with DPD deficiency and
monitoring as well gives us that option. At least you have a test that
is available for us.

DR. SANTANA: Dr. Weiner?

DR. WEINER: I have a technical question actually. Sort of two.

One is, how standard is the test itself, and how does that get evaluated
independently of its application?

And second of all, it seems to me that regardless of the status of the
test, if something is warranted in the label that has to do with the
population that should be treated, the label doesn\'t necessarily need
to refer to the specific test. Those are just sort of technicalities to
clarify a little bit more of what we\'re talking about.

DR. SANTANA: I want to invite Howard or others to comment on this issue
of the standardization of testing and how far we are in that that we
feel comfortable with it.

DR. McLEOD: There are three different types of tests that are out there,
as I mentioned and others mentioned as well, measuring TPMT activity in
red cells, measuring the active metabolites, the thioguanine nucleotides
in red cells, and then measuring the polymorphisms that have been shown
to be responsible for low enzyme activity using a DNA-based test, a
polymerase chain reaction followed by various detection methods.

The assays that are out there that are available for clinical use have
had to be certified in two different contexts. One is they have to be
approved under CLIA guidelines which define a level of robustness in
terms of reproducibility and accuracy of the test itself, not the
relationship between the result and a phenotype, but actually the test
itself.

I think all of these tests are also performed in facilities that are
monitored by CAP. What is it? The College of American Pathologists? The
American pathology society, CAP, which evaluates them in terms of their
documentation, in terms of the controls that they use for the assay, and
looks at basic levels of quality assurance and quality control for the
tests. So the commercially available tests have that level of rigor.

The DNA-based tests that are out there have a very low error rate, and
the tests that have been performed to date in that context are virtually
100 percent predictive, as close as you can be to 100 percent, for
saying if there is a mutation, they find it and vice versa, for the
particular polymorphisms they\'re looking for.

Now, I mentioned the caveat that there are polymorphisms that are unique
to different families that will be missed, but in terms of the accuracy
of the test, it\'s between 99.9 and 100 percent and the results have
been published to date.

DR. WEINER: So what is the FDA\'s role in those tests? You made
reference to the literature.

DR. HIRSCHFELD: I was just going to ask for a point of clarification. We
don\'t address in this committee economics. So whether the test costs 75
cents or \$1 million, that\'s not an issue. We deal on whatever the
evidence is for any issue.

But could you just clarify for us which of these tests are commercially
available, which are research tests? There are some tests which pass
through the FDA through the Center for Devices and the data are reviewed
and they become what\'s called an FDA-approved test. Could you tell us
how many of these tests are FDA-approved?

DR. McLEOD: It\'s my understanding that none of the tests that we\'re
talking about have passed through the FDA\'s devices committees and are
FDA-approved. Now, someone may be able to comment further on that, but
that is my understanding currently. The tests that are out there ‑‑ what
was the other part, the first part of your question?

DR. HIRSCHFELD: You mentioned that some of the tests were commercially
available. Could you mention which of the tests, in particular if any of
the genotype tests are commercially available?

DR. McLEOD: Yes. All three of those areas have commercially available
tests. The genotype assays are available through at least two national
organizations, one that is based on the west coast, and I believe Mayo
Central Labs, which is an affiliate of the Mayo Clinic, also offers that
testing. Then there are other laboratories that offer it as an in-house,
so-called \"home brew\" test within their institution, but not available
more widespread. But as far as I know, there are only two companies that
are offering TPMT genotype analysis nationally.

DR. HIRSCHFELD: Just one final point. Have there been comparisons where
the same samples have been sent to different commercial labs to see if
the same results come out from these different commercial labs?

DR. McLEOD: I am not aware if that has been performed. It certainly has
been performed between academic labs, but in the context of clinical
testing, I do not know the answer to that.

DR. SANTANA: I\'m not an expert in clinical labs, but its my
understanding that part of the quality control of clinical labs is that
periodically there are samples shared unknowingly between different labs
and then that becomes part of your quality institution performance. I
don\'t know if it\'s specifically done for this test, but if they are
commercially available, if I understand you correctly, that must be a
part of that process.

DR. HIRSCHFELD: I just didn\'t want us to assume, and I wanted to know
if there were data that told us that one way or another.

DR. SANTANA: If the tests are approved by CLIA, that is a process that
approves automatically periodically. But Dr. Lesko and others may want
to comment.

DR. LESKO: I\'ll just comment on what I know about one of the commercial
laboratories which is on the west coast. They have transferred their
technology to the east coast and have done comparative laboratory
assessments of samples to confirm that the same results were coming out
of each site.

DR. SANTANA: Is it a commercial test?

DR. LESKO: It\'s a commercial test. It\'s commercially available.

Also, just to go beyond that ‑‑ and I\'m not sure how this works
exactly, but there are two well-known commercial laboratories that offer
this test, but if you look on the internet for testing, there are other
laboratories that advertise it, the major clinical laboratories, and
whether they do it in house, for example, a Quest Lab or something like
that, or they send it to these two major labs I\'m not sure. But there
are many other commercial places you can go to get this sample done with
a tube of blood.

DR. SANTANA: For the purpose of clarification, what tests are you
referring to that are commercially available?

DR. LESKO: I\'m referring to the genotype as well as the phenotype test
that we\'ve been talking about. I think both of the labs that offer this
test do both on the same sample either routinely or if requested.

DR. McLEOD: I made the discernment between home brews and the national
labs because there are a limited number of labs that actually are
licensed to do the testing and a lot of others that supply it by other
means. That\'s why I mentioned there are just a couple that are
available. Many institutions do the testing internally but are not
licensed to offer it outside their institution.

DR. SANTANA: Dr. Shurin, you had a comment?

DR. SHURIN: I think this is probably the first of what\'s going to be a
series of discussions about how we\'re going to incorporate
pharmacogenomics, and I think it\'s important that we address this in a
reasonably systematic and appropriate fashion. I lived through two
instances in recent years in which we\'ve introduced tests without
knowing what to do with the answers, and I have to say that I didn\'t
find that to be a pleasant experience with either the HIV testing or
more recently with the PSA testing. It creates considerable amount of
anxiety.

In reading over the background material here, it wasn\'t at all clear to
me that we know how to dose people who are deficient in this enzyme. So
what we\'re looking at is mandating a test with which we don\'t what to
do with the result, and that\'s concerning to me.

I\'m delighted at the group that\'s been brought together because I
think both the involvement of our European colleagues and the fact that
Greg Reaman is head of COG and Malcolm Smith and Barry Anderson is
important. We certainly have several ways we can go about this. What
we\'ve clearly identified is that this an important problem and we need
to do something. Then I guess the question is what do we do. We can
impose some guidelines. We can impose regulations or we can really
mandate and make a legal requirement.

I would wonder if in this specific indication, which is lymphocytic
leukemia, for which the overwhelming majority of the children not only
in this country but worldwide are treated on protocols, if the more
appropriate way to respond to this isn\'t to try to move the priorities
up so that we actually answer the question in a scientific way and have
some idea of what to do with the answer, that that might not be a much
better approach both for the children who have these deficiencies and
for the children who don\'t whose care won\'t be compromised by sort of,
gee, I can\'t give 6‑MP because I don\'t know the result of this test
that I\'ve treated hundreds of other children without knowing the result
of the test. That might be a much more reasonable approach. It might
result in having a much clearer answer much more quickly and actually
protect the patients better.

DR. SANTANA: Dr. Morland?

DR. MORLAND: Just to reinforce that really in the spirit of
international collaboration that we\'ve all been talking about. I think
it\'s vital that any scientific approaches that are made with regard to
future research is done on a truly internationally collaborative basis.
Sure, COG may want to develop a prospective study, but actually just
duplicating studies which have been performed elsewhere is not going to
help anyone. So I think there is a real enthusiasm for doing
international research and clearly there is already a field of
expertise, both here in the States and in Europe, that should be tapped
into to design some more prospective data capture to start addressing
some of these key issues. So I think just a plea that we all work
together rather than doing our own individual things.

DR. WINICK: Can I make a comment, Victor?

DR. SANTANA: Yes, Naomi.

DR. WINICK: Just to address Nancy\'s concerns. I don\'t think that
anyone in this room is against testing. This has nothing to do with
that. It\'s just a question of whether or not you mandate it
prospectively or not. I think that Susan\'s statements and Dr.
Morland\'s were extremely well made. We don\'t want to mandate a test
for which we don\'t know what to do with the results, and what we don\'t
want to do, especially for children who are heterozygous who are going
to be obviously larger in number than homozygotes, we don\'t want to
have investigators lowering the dose and potentially increasing the
likelihood that that child\'s leukemia will recur in the absence of
solid data defending that practice. So no one is against the test. No
one wants to have children suffering needlessly. The question is just
when do you do the test.

DR. SANTANA: Dr. Smith?

DR. SMITH: There are two points of information that I think are critical
for the committee and for FDA to consider. One is the point that was
raised earlier about what is the morbidity. The algorithm that Naomi
described that came from Mary Relling ‑‑ if you followed that algorithm
and what\'s the morbidity, if it\'s 4 months in the hospital and it\'s a
substantial proportion of kids with terrible toxicity, then that changes
the equation. If it\'s neutropenia that resolves when you stop the drug
and you do the test and you appropriately dose thereafter, then it\'s a
different situation. So it would be very helpful, if those data exist,
to try to get a better handle on what the morbidity is when the
homozygotes are treated in a manner similar to the algorithm that\'s
been described.

The other question relates to what Susan was saying. Do we have any
information about benefit to heterozygotes from doing the testing? If
there is no benefit that we can define for testing heterozygotes, then
whatever testing or labeling that\'s done we\'d have to be very clear
about. These results just don\'t apply to heterozygotes, so don\'t even
think about using these data to base your dosing for heterozygous
individuals. So that\'s additional information that\'s needed. How would
we use that information? What are the data that we could build upon to
use information about how to dose heterozygotes?

DR. SANTANA: Yes, David.

DR. POPLACK: I\'d just like to follow up in support of Malcolm\'s
comments and Susan\'s. I think clearly we have new information and all
the information you suggest about the phenotype and the genotype and
percentages of population who may be at risk. All of the relevant
information needs to be included in the label.

But I have significant concerns about the heterozygotes as well, and I
think that the likelihood is that given our lack of evidence-based
information about this population, that there\'s more potential for a
risk to this group of under-treatment by having a result that indicates
that someone is a heterozygote. I think before we go down that slippery
slope, we need to have more data and more information and studies of
that population.

The other point I\'d like to make just generically about this drug is
that if you had to identify a drug in usage in oncology that is least
appropriate for therapeutic drug monitoring, it\'s probably
6-mercaptopurine because of the tremendous variability between patients
and within patients, et cetera. So it is an illusion, to some extent,
that we have the type of control of a dosing and what our dosing
modifications do in individual patients. I think we need to keep that in
mind.

Finally, however, I also believe we need to further study this in other
populations. I don\'t know. I was asking Howard about what do we know
about this, for example, within the Hispanic population. How prevalent
are the various permutations and combinations? I think we treat all
kinds of people with these agents and we have a responsibility to
everyone in this country. I think prospectively we need to do those
types of studies as well.

DR. SANTANA: Dr. Reynolds and then Dr. Reaman.

DR. REYNOLDS: We\'ve heard a recurring theme here and that\'s the
concern that if we mandate some testing, that it\'s going to impact on
the heterozygotes, which I think we don\'t see a lot of clear-cut data
as to what one can do with those. That\'s the reason why I raised
earlier on the question about 13-cis retinoic acid and mandated tests. I
think we need to recognize that if a test is mandated on a label, it\'s
going to get broadly applied, and once you do that, going backwards is
very difficult. It\'s much easier to go forward incrementally than it is
to go forward in a big step and then try and take two steps backwards.
So I just want us to think about the implications of that if we consider
mandating anything.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: I\'m struck by the concern about the heterozygotes. Even
though the homozygotes may be a population for whom there is a definite
benefit by testing, I\'m not aware that there are specific instructions
in the label for how the dose should be modified. So we\'ve heard some
criticism about how as pediatric oncologists, we have modified dose
based on toxicity. For the two homozygote patients that I\'ve managed,
basically we came upon a dose by trial and error, eventually maintaining
their absolute neutrophil count somewhere between 1,000 and 1,500. So
we\'re never really going to get beyond what might be considered the
realm of the mundane practitioner.

And I would certainly agree that we should take every opportunity to
investigate this and to investigate this at an international level and
address differences in populations.

DR. WINICK: Dr. Morland, could you review once more for us the studies
that you referred to that are ongoing in the UK?

DR. MORLAND: I can\'t give you any data, but the studies that have been
undertaken were at the launch of the most recent MRC sponsored leukemia
trial, which is 97. An attempt has been made to obtain samples from all
patients entered into that study both for genotyping and phenotyping,
analyzed centrally at the reference laboratory in Sheffield. So linked
with those studies is obviously the ability to then look at what dose
manipulation has been done for patients with 6-mercaptopurine.

DR. WINICK: I just asked if they were recommending a specific ‑‑

DR. MORLAND: No. There are no recommendations being made on the
analysis. In fact, I think the analysis is still blinded to the
physicians who have been treating patients.

DR. SANTANA: Dr. Boos?

DR. BOOS: This is a bit different in Germany where the homozygous
results will be told to the departments and the dose will then start
with roughly 10 percent.

DR. SANTANA: But that\'s arbitrarily decided, or is that
protocol-mandated?

DR. BOOS: No. It\'s not protocol-mandated.

DR. SANTANA: Dr. Williams.

DR. WILLIAMS: Several of you have mentioned opposition to mandating
something in the labeling, and it wasn\'t really clear to me exactly
what you were talking about. You could be saying don\'t put it in the
labeling because people may consider you have to do it, or you could be
saying that it\'s mandated as part of the dosage and administration, or
it could be one of these programs where you can\'t get the drug unless
you do it. You are opposed to mandating, but it wasn\'t clear to me what
that meant.

DR. SANTANA: My interpretation of that ‑‑ and I certainly didn\'t make
those statements ‑‑ is that the label specifically says if you use this
drug, you should do this test. That was my interpretation of the concept
of mandating.

DR. LESKO: Just to go a step further, that wasn\'t taking into account
putting information in the label that would be more informative. That\'s
different than what you\'re talking about.

DR. SANTANA: That\'s different.

DR. REYNOLDS: Just to address that, what I was thinking about was the
\"no blood, no drug\" concept. Providing information is a whole
different kettle of fish.

DR. SANTANA: I think with that I do want to go ahead and start
addressing the questions. There\'s a long introductory, very well
detailed page to the questions to the committee. I\'m not going to read
that. If Dr. Hirschfeld and Dr. Williams allow me, I\'m going to start
with page 2 in which there are specifically some comments that we want
to address. So I\'ll start with page 2.

It says, what additional information should be included in the product
label with regard to TPMT metabolic activity and the potential for
exposure to excessive bone marrow toxicity in pediatric patients with
acute lymphoblastic leukemia? And they\'re proposing four potential
pieces of information. Am I correct, Steve?

DR. HIRSCHFELD: I don\'t want to say that we are proposing. We just put
as suggestions as to the kind of information that you might want to
include, and those statements aren\'t necessarily mutually exclusive,
nor do any of them have to be included. It was just to give you a
framework to try to answer the question. There are really only two
questions, the one you just articulated and the next one. Your
recommendations do not have to necessarily include any of the language
that\'s proposed.

DR. SANTANA: So, thanks for clarifying that. So in regards to additional
information, one of the points that may be considered is adding
information on the prevalence of pediatric patients in the general
population that have little or no activity or reduced activity. So that
information, it\'s my understanding from the presentations and from what
I know in the literature, is fairly well established, that we do have
some prevalence rates, obviously not studied in 10,000 patients, but
some indication of what this number potentially could be.

Malcolm?

DR. SMITH: Is the data about ethnic variation enough that you would want
to say that persons of Chinese descent have a lower rate of this
abnormality?

DR. SANTANA: Howard, do you want to try to address that?

DR. McLEOD: There is clear data that the frequency of the three
mutations is different between different ethnic groups when studied in
situ, as in in their continent of origin. When we get to the United
States, none of us are homogeneous. I have a Scottish surname but I\'m
equally Irish, German, and mutt. So it starts getting more confusing
when you actually get into the American population where someone may
identify themselves as being Indian but have equal amounts of various
others. It\'s especially important in the African American population
where they certainly have a predominance of the allele that\'s more
common in continental Africa but also have alleles that are seen in
other geographic populations. So indicating that there are ethnic
differences may be appropriate but defining them explicitly would be, I
think, a hard thing to do currently.

DR. SANTANA: Any other comments?

(No response.)

DR. SANTANA: So I sense that the committee has some agreement that there
should be some information about prevalence with the caveat that that is
obviously linked to ethnic subgroups for which we currently don\'t have
a body of information. Does everybody agree with that summary? Okay.

Let\'s try to tackle number 2. An additional statement in the warning
section that children with hereditary deficiency may be unusually
sensitive to the myelosuppressive effects of 6‑MP and at greater risk of
toxicity.

DR. HIRSCHFELD: Just to clarify, the current statement says there are
individuals. It doesn\'t say children. It says there are individuals
with inherent deficiency of the enzyme thiopurine methyltransferase who
may be unusually sensitive to the myelosuppressive effect of
mercaptopurine and prone to developing rapid bone marrow suppression
following the initiation of treatment.

DR. SANTANA: So really, the difference between the two statements is one
of the population. In the current warning label, it\'s a general
statement on patients. Here it refers specifically to children. Did I
pick that up correctly?

DR. HIRSCHFELD: Right.

DR. SANTANA: And hereditary. The label already says hereditary? So the
distinction here is children versus what is currently in the label?

DR. HIRSCHFELD: I\'ll ask Dr. Lesko to comment here.

DR. LESKO: It seems a bit redundant from what\'s currently in the label
to what\'s put here, and I wonder in retrospect if the committee might
consider that statement in the dosage section. In other words, labels
can have redundant information if it\'s deemed pertinent to the safe and
effective use of the drug, and would something like this statement be
reiterated in the dosage section just as a reminder to the prescriber
that this information is important to be aware of.

DR. SANTANA: So not to supersede the current statement that\'s in the
warning section.

DR. LESKO: Right. I don\'t see it as a superseding thing because it\'s
not that different. But we do have labels where information is placed in
several sections of the label if it\'s considered important enough to
the reader of the label.

DR. SANTANA: Can the FDA give us any advice on this issue of where
statements go in the label?

DR. WILLIAMS: I would think the closer you put it to the dosage section,
the closer you are to making an inference that they should adjust the
dose based on that. I think we\'d have to think closely about that.
Certainly if everybody felt strongly that we could adjust dosing, then
it would go right in there as a part of how to dose. Certainly we could
edit the other statement where it is.

DR. SANTANA: The recommendations of dose adjustment are under number 4.
We\'ll get to that in a minute.

Any other comments on this statement? Malcolm?

DR. SMITH: Is the intent here to describe the unusual severe sensitivity
in the homozygous group or to include the moderately sensitive
heterozygous group?

DR. SANTANA: It\'s a good point because this could be interpreted both
for the homozygous and the heterozygous, and we could spend a few
minutes discussing how there\'s lack of data in that subgroup to make
any type of definitive statement. So I think we better be careful with
that word \"hereditary\" to what we\'re specifically referring to, if
we\'re encompassing both or selecting one versus the other.

DR. SMITH: That could be addressed by hereditary complete or near
complete deficiency.

DR. WILLIAMS: And it could be fleshed out a bit to give a little more of
the quantitation associated with the homozygote versus the heterozygote
so that people didn\'t take an inappropriate action.

DR. SANTANA: Greg, you had a comment.

DR. REAMAN: I just have a question about the word \"hereditary\" which
implies direct inheritance, but do we have family studies on all of
these?

DR. WEINSHILBOUM: Yes. The answer is yes.

DR. SANTANA: So it\'s truly hereditary.

DR. WEINSHILBOUM: That\'s what I meant when I referred to Mendel.

DR. HIRSCHFELD: Maybe if we substitute the word \"homozygous\" for
\"hereditary\" in that sentence, it would be more descriptive of the
situation.

DR. SANTANA: That was going to be my comment. I think we do have enough
evidence that it\'s a strong statement that those patients are truly
very sensitive to the myelosuppressive effects. I think practicing
physicians do know what a homozygote is.

DR. WILLIAMS: I would think we would need to think carefully about the
wording because clearly it\'s true for the heterozygotes too. What I can
tell you want to make certain is that people don\'t walk away with a
heterozygous and take an action. So maybe we can come up with some
wording.

DR. SANTANA: Yes. That\'s the point of distinction I think we want to
advise you on that you need to be careful with.

Any other comments? Howard.

DR. McLEOD: I kind of go back and forth on this but I think there is
data saying that the heterozygotes do worse than the wild type patients.
It\'s just that we don\'t believe it to the point where we want to urge
people to act on it. The worry is that we water it down to the point
where people are no longer even informed, and our assumption is that the
package insert will be sort of a role of informing the people that read
it, agreeing with Professor Riccardi\'s comments, that at least it\'s
there and if they didn\'t read it, that was their own fault. Professor
Poplack is making the same comment that we need to inform. So by
removing the heterozygous data altogether, it assumes that there\'s no
literature suggesting that the heterozygotes are at risk, whereas there
is literature. It\'s just that we don\'t believe it enough.

I think we can indicate that heterozygotes may be at risk. There is
litigation going forward in that context. Whether they win or not is a
different story. So we can\'t ignore it. We may not believe it, but we
can\'t ignore it. I guess the point I want to make is that we need to
make sure there\'s enough information in there so that people know that
heterozygotes exist and they can choose to believe what they want as far
as whether anything needs to be done about it.

DR. HIRSCHFELD: I just would want to clarify. The way the phrasing is
now, it says \"unusually sensitive.\" But what we\'re seeking is
recommendations, and we\'ll do the wordsmithing. But we would just want
to get a sense of the overall thinking of the community here so that we
can have some basis on which to proceed.

DR. WILLIAMS: Let me make a suggestion. In the first one, it\'s not
necessarily a warning. If there is more information about some of the
quantitation of the degree of myelosuppression but the lack of evidence
that we know what to do with the heterozygotes and then the more severe
and the homozygote. The warning could clearly relate to the homozygote
perhaps. But providing more information and yet not leading one to the
conclusion that you need to treat heterozygotes, do you think that would
be a reasonable thing?

DR. SANTANA: Yes. I don\'t think we\'re here to write the label. That\'s
not the exercise we\'re having, but I think the sense the committee is
presenting to you is that somehow the public and the practicing
physicians have to be conveyed the message that there is a body of
evidence that is much stronger in one group than there is in the other.
That message has to be transmitted in the statement. I can\'t write the
statement for you, but hopefully you\'ll take that into account.

Dr. Boos and then Dr. Smith.

DR. BOOS: I wonder if it would be helpful in this section to point it
out a little bit the other way around, to say even if the result is wild
type, this does not reduce the risk of toxicity for the patient because
this is in the end the truth. And if there is anybody who thinks, okay,
there is no pediatric formulation at all, therefore I don\'t want to
break the tablets, and my patient is not at risk, or if there\'s one to
say, okay, you are too far away from the hospital, I think it\'s enough
to come in 3 weeks again because you are wild type, this is a risk we
have to address.

DR. SANTANA: Oh, no. I interpreted this as a conditional statement, that
if you have this deficiency, then you are likely to have these effects.
It doesn\'t exclude that other people who don\'t have the deficiency may
also have the toxic effects.

DR. BOOS: Yes, but this is one of the significant misunderstandings of
statistics sometimes. If you say everybody can run into toxicity
depending on the dose, and even the dose calculation, the
bioavailability, the not-available pediatric formulation, all of these
things make the dosage extremely variable. If up to 100 percent may have
toxicity and only 3 percent are homozygotes, then you reduce the risk to
run into toxicity roughly by 6 percent or 3 percent, and this should be
noted here.

DR. SANTANA: If you turn to the first page of this document, do you
think that message is covered under the first point under the dosage
section where it clearly tells you that you do have issues of toxicity
and that you have to then dose based on that variable?

DR. BOOS: For me, all these phrases point out there is a specific risk
and this can be identified. But the other way to see it is to think I\'m
not at risk, therefore I have no risk, and this is wrong and it\'s not
pointed out here anywhere.

DR. SANTANA: Malcolm, did you have a comment?

DR. SMITH: It\'s not that we don\'t believe that there is an association
between heterozygotes and increased myelosuppression. It\'s just that in
terms of how you take that information and translate it into a starting
dose, that\'s the association that we don\'t have. Whereas, for the
homozygotes, I think everyone would agree there\'s a need for dose
modification there.

DR. SANTANA: Yes, Howard.

DR. McLEOD: The same source for the heterozygous dosing recommendations
is where we get our homozygous dosing recommendations except the number
is even smaller. So there\'s the same problem. It\'s just that 100
percent so far of the homozygous deficient patients get into trouble,
where it\'s only about 35 percent or so of the heterozygotes.

DR. SMITH: So over half tolerate the standard dose no differently from
the wild type population.

DR. McLEOD: Exactly.

Dr. Boos\' point is illustrated in the paper that was included in tab 5
of our document. About 35 percent of the patients referred for TPMT
testing with the TPMT-like scenario were wild type, backing up his point
that there\'s a lot of the patients out there that have the extreme
toxicity and don\'t have TPMT for the explanation. So the point you\'re
making, that myelosuppression is not only caused by TPMT in the context
of these kids.

DR. SANTANA: Hopefully the FDA can address that somewhere in the label
in terms of the general statements.

Yes, Nancy.

MS. KEENE: One way to address that issue that you brought up is to say
that there\'s significant variability across all three groups. Identify
the groups, let people know they exist, and then say there\'s
significant variability across all three.

DR. SANTANA: Dr. Boyett.

DR. BOYETT: The existing label seems to address that under dosing. If
you look at those two bullets, it says that it varies from patient to
patient. As long as you don\'t qualify that by saying you\'ve got to be
homozygote or heterozygote, it says from patient to patient.

DR. SANTANA: Let\'s move on to the third point, a statement that
laboratory tests are available to determine TPMT status of pediatric
patients, genotyping or phenotyping, and some information regarding the
use of these tests.

I think the problem I have with this statement is, what is the \"some
information\"? Obviously, it\'s a very open-ended statement. So maybe
the committee can offer you some advice on that.

So I think the point is should there be a statement that there are
laboratory tests available that could help you determine whether your
patient is deficient or not, and then the second point is how that
information can be used. Comments?

DR. POPLACK: I think the first point is fine. The second is ‑‑

DR. SANTANA: That\'s why I separated it.

(Laughter.)

DR. SANTANA: In my own mind, that\'s why I separated it.

Yes?

DR. LESKO: Just as a point of reference, the laboratories that offer
this test do report out the specific alleles and what the alleles mean
in terms of enzyme activity. They don\'t report out what the physician
ought to do with that result. One idea for the label might be to include
what are we talking about in terms of a \*3A or a \*3B. That\'s what we
actually measure in the laboratory, and then relate that to the
phenotype in terms of TPMT activity. That\'s one example of what could
be done here.

DR. SANTANA: I agree with David. In my own mind when I read this, I
separated it into two parts, and personally I have no issue with the
first statement. I think in the spirit of providing information, you
should inform people that there are laboratory tests that can
specifically measure this either phenotypically or genotypically.

I have a little bit more problem with how to use the information because
I\'m not sure that information is totally validated at present from what
I heard in the earlier discussion.

Susan.

DR. SHURIN: One of the other things in the label, not in the paragraph
that\'s given here, is that this should be used only by people who are
experienced in treating leukemia, and if people who are treating
leukemia don\'t know about this, I think it\'s a much bigger problem.

(Laughter.)

DR. SANTANA: Yes, but the problem the FDA has is that once a drug is out
there with the label, it\'s up to the practicing physician to use that
information so we can\'t tell them only practicing oncologists can do
it. So although I share your concern and I agree with it ‑‑

DR. SHURIN: But it sort of says that already. It doesn\'t say practicing
oncologists, but it says persons experienced in the use. I don\'t have
it in front of me exactly what it is, but I remember noticing that was
in the label and it seems to me that that\'s subsumed under that
wording.

DR. SANTANA: Dr. Boos, you had a comment?

DR. BOOS: I\'m not sure if it really helps, but I still have the comment
because if we talk about heterozygotes and homozygotes, we talk about
genotyping and not phenotyping. The problem with the phenotyping is that
there is a continuous scale of results and then you need normal values
for this, and the lab depends on the pre-analytical problems and things
like this. It\'s my feeling this all should, with the current state of
knowledge, be reduced to genotyping because then you have a clear-cut
decision, is it homo or heterozygous.

DR. SANTANA: Is a way to address the issue from the FDA perspective that
you make statements that laboratory tests are available but there\'s no
contingency in the label on how to interpret those tests? You leave that
up to the reference labs and to the information that\'s available.
Because that potentially could be a way of getting out of the latter
part of the statement, that the label does say these tests are
available, you can use them, but the label itself is not going to tell
you how to interpret them. You have to do the cross-referencing to the
current test that you\'re using. We\'re not recommending one test. There
may be a number of tests, but those get cross-referenced to the
specifics of that test in terms of how to interpret and use them.

DR. HIRSCHFELD: The short answer is that\'s a clear possibility.

DR. SANTANA: Because that would be what I would certainly encourage
because I think Dr. Boos\' comment is very real. Based on the different
populations and the tests that are used, it may be difficult to
interpret in subpopulations how to use that information.

DR. WILLIAMS: Perhaps Dr. Lesko can help us look into that, whether or
not there\'s a way you can talk generally about genotypes and generally
about phenotypes and come up with a concise, yet meaningful label.

DR. LESKO: Yes. I was just going through my mind of other labels that
include genetic information and how we worded that. I think we need to
go back and look at that, whether we characterize a genotype by a
well-known phenotype or specifically express the genotype information.
So I think we need to look at some precedent for that on how to express
that.

DR. HIRSCHFELD: I would just ask a clarification, Dr. Santana, and that
is, if you could ask the committee to clarify whether the statement
\"genotyping or phenotyping tests are available,\" or whether there\'s a
recommendation that the statement should only address the genotype
testing.

DR. SANTANA: Dr. Boyett.

DR. BOYETT: I vote for genotype testing.

DR. SANTANA: And why is that, Jim? Why do you specifically restrict it
to that?

DR. BOYETT: Because I think, as Dr. Boos pointed out, it\'s more
interpretable. You\'re not worried about variability. You know exactly
what you\'ve got when you\'ve done it.

DR. SANTANA: Dr. Boos?

DR. BOOS: We didn\'t address two questions today with phenotyping. One
is I remember data from Lynne Lennard in Sheffield where she showed that
phenotypic activity depends on age of erythrocytes, for example. We did
not see any data about inter-patient variability or reproducibility up
to now, and it\'s a gene where we do not really know the physiological
role of this protein and therefore do not know enough about theoretical
aspects of regulation, for example, up and down regulation. I think with
the current knowledge we should just restrict to genotyping.

DR. SANTANA: So your comments are in favor of Dr. Boyett\'s statement,
that it should be restricted to genotyping.

DR. McLEOD: While there is data to address some of the points that
Joachim made, they all point towards genotyping being a more dependable,
reproducible type of assay. With all the caveats that I and others
mentioned as far as the benefits of phenotyping tests in terms of the
stability of the assays across places, genotyping wins today in that
context.

DR. SANTANA: Mr. Ohye?

DR. WINICK: I have two comments. First, in favor ‑‑ oh, I\'m sorry.

DR. SANTANA: That\'s all right. Go ahead, Dr. Ohye.

MR. OHYE: Please. No. I\'m the lay person here. I defer to the
scientists.

DR. SANTANA: Naomi, go ahead.

DR. WINICK: First, the other thing that\'s been mentioned by several
people is that the advantage to genotyping is that the physician can
send that regardless as to transfusion status, and I think that that\'s
an important note to put in the explanatory material.

But I would love to see the phenotyping provided as information,
especially with all this debate about what you do with the patient who
is heterozygous because certainly in that patient, even though there is
phenomenal variability in TGN levels, if that patient, as the first
child that Bill and Mary reported, had a TGN concentration in the many
thousands, it would certainly tend to support the notion in the treating
physician\'s mind ‑‑ I\'m not saying the label should say this ‑‑ that
that patient with heterozygous activity may need a greater dose
reduction than a child with heterozygous activity who has a relatively
low concentration of TGN.

DR. SANTANA: But what I heard earlier, Naomi, in response to your
comment, is that how to manage the toxicity, in terms of dose
modifications for the patients that are heterozygous, is still an area
that we have no clear, uniform guideline. It\'s a protocol mandate or
protocol-driven, and until we get to that ‑‑

DR. WINICK: Right. And I\'m not saying that the label should do that,
but I think that the label should make people aware of the fact that
phenotype data may be useful.

DR. SANTANA: Yes.

DR. LESKO: I\'m somewhat in favor of that because we talked a little bit
about the variability within the wild type group, and some of the data
that shows greater or lesser efficacy in heterozygotes versus the wild
type may somehow be related to the thioguanine nucleotide
concentrations, so that phenotyping would actually give some insight
into why some of the wild types are toxic, that is to say, if they had
high levels related to their metabolic status, or why they were perhaps
not therapeutic. It would also give some insight into compliance if
somebody wanted to use it that way. So there are benefits to having
phenotyping information, at least to say that such information is
available in the label without specific recommendations. I think people
could view that easily as a therapeutic drug monitoring tool that they
can use to address certain clinical questions.

DR. SANTANA: So let me see if I understand both of your comments. A
statement in the label in this section also that says phenotypic testing
or 6-TG levels, thiopurine levels may also provide additional
information in terms of ‑‑ is that what you guys are kind of heading
towards?

DR. WINICK: Absolutely.

DR. SANTANA: But if we leave it very vague, how do we help the
practicing physician? That\'s the problem I have. I know how to do it
because I have a protocol and I can open it up, but remember, there\'s a
whole population of people out there who read this and that\'s what we
have to be sensitive to. We can\'t leave it very vague.

DR. LESKO: I think the advice not to leave it vague is good. I think we
just need to think about the right words to say that. I don\'t know if
we can do that right here on the spot, but that\'s sort of the concept
that I think would be beneficial to include in the label.

DR. WILLIAMS: You might be able to give the benefits of the assays, to
describe the strengths and benefits.

DR. SANTANA: Wow.

DR. WILLIAMS: Certainly as you were talking about, if you\'re
contaminated with red cells, then the DNA assay is the only one you can
use.

DR. HIRSCHFELD: Yes. I\'ll raise a voice of caution. I\'m not sure our
drug labels should go into commentaries on the strengths and weaknesses
of commercially available assays which can be used for the drug under
question or a variety of other assays. I\'ll just raise a caution.

But, Dr. Boyett, I think you were going to make a statement.

DR. BOYETT: My comment is I think we saw some data today that suggested
the variability in activity in the heterozygotes depends upon the
treatments that you\'re getting. Different protocols result in different
types of ‑‑ and so I don\'t know how you could be that in there and
suggest any way people can interpret it because you\'re not going to
know how they\'re being treated.

DR. SANTANA: Dr. Ohye, I don\'t want to ignore you.

MR. OHYE: First of all, it\'s \"Mr.\"

These discussions are almost identical to the labeling discussions that
go on in a corporation when we develop labeling. It\'s not unusual for
us to sometimes consider statements such as \"data suggest, although
more definitive studies are underway or must be done\" when you discuss
issues of labeling of dosing, for example. I\'m getting to the next
question obviously.

I also wanted to mention that this particular package insert has a
number of references. I think the most recent data is 1996, I think if
there\'s a section that cries out to have a reference, it\'s the section
under discussion now. So if there are papers that are on point that
would be instructive to people that will actually seriously research
what goes behind these labeling statements, there should be a
bibliographic reference attached to this section.

DR. HIRSCHFELD: I\'ll just, as a point of information, state it\'s been
certainly the policy in the Oncology Division, which reflects our office
director\'s concept of labeling, that the references should be minimized
and that this label has references because it\'s essentially a legacy
label. But the strategy of trying to clarify or address public health
issues by augmenting the bibliography of the label is not one that\'s
considered a pertinent option.

DR. SANTANA: But I think the comment is pertinent, that if we\'re going
to go down the route of a statement regarding genotyping, that there be
a reference to that which is not currently in the label.

DR. HIRSCHFELD: That\'s well taken.

DR. SANTANA: That was my interpretation of that.

Dr. Vassal.

DR. VASSAL: Should the label mention that current available tests will
identify most of the mutations but not all the mutations since it\'s
what? 85 percent? So the limits of genotyping.

DR. SANTANA: That will be in the reference.

(Laughter.)

DR. SANTANA: Because I think it gets into a lot of detail then and then
the label becomes nonfunctional for the reader.

Let me see if I can recap the summary of this. I think there\'s a
consensus that at least as regards genotyping that there should be a
statement there.

With regards to phenotyping, I\'m not quite sure how I read the
committee on that one yet. I heard comments that some people felt that
there was some information about phenotyping, particularly in
heterozygotes, that would be clinically useful and that information is
available although it hasn\'t been completely validated. I heard
comments that we should restrict ourselves to the genotyping because
that\'s more solid information. So I\'m not sure ‑‑ the committee needs
to help me sort that one out because I\'m not sure I had a clear read on
that latter one.

DR. HIRSCHFELD: I\'ll just ask. We\'ll discount those of us in this
corner who are of the FDA in terms of the advice. Other than Dr. Winick,
Dr. Santana, could you see if there are other individuals who felt there
should be a phenotyping statement?

DR. SANTANA: And if so, I want to hear why you\'re recommending that.
Dr. Reaman?

DR. REAMAN: I think there should be mention of the phenotypic assays as
well. As Mr. Ohye said, the data suggest that this information may be
useful and is currently under investigation. So I think that should be
included.

DR. SANTANA: Does everybody agree with that statement? Okay. That\'s the
recommendation.

And then lastly for that question, should there be recommendations for
adjustment of doses in children identified as having little or no or
reduced TPMT activity? Dr. Reaman, Dr. Shurin?

DR. SHURIN: It wasn\'t clear to me that we knew what to do. So I don\'t
know how you can make recommendations if we don\'t know what to do.

DR. SANTANA: Dr. Reaman?

DR. REAMAN: Other than to exercise extreme caution. But I would be hard
put to say you should begin with a dose of 10 percent. That may be
correct, but I think that warrants further prospective investigation as
well.

DR. SANTANA: Dr. Cohn?

DR. COHN: I was just going to say it could be nebulous and kind of say
it may be necessary to reduce the dose in patients who have this
genotype, but without being specific about what the actual
recommendation is.

DR. REAMAN: And monitor closely, as well.

DR. SANTANA: Howard?

DR. McLEOD: Significant doses have been required is a true statement of
the literature to date, and something like that may make it clear that
something big has to be done. I agree that there is no data saying that
one-tenth is the dose that has worked.

DR. REAMAN: Less than that has worked as well.

DR. McLEOD: Yes, exactly.

DR. SANTANA: So the consensus is there should be a statement not with
specific recommendations but that these patients do require serious
consideration of dose adjustments and ongoing monitoring.

Malcolm.

DR. SMITH: That also has reduced TPMT activity. So is the discussion of
the heterozygotes off the table or is that ‑‑

DR. SANTANA: Good point.

DR. SMITH: And if it is going to include reduced activity, then to
comment that while these patients may eventually require dose reduction,
over half of them are able to tolerate standard doses of 6‑MP.

DR. SANTANA: Dr. Reaman?

DR. REAMAN: I thought we were confining the recommendations to
genotypically demonstrated patients with the absence of TPMT activity.

DR. SANTANA: That was my interpretation too.

DR. REAMAN: So by definition it would exclude, but maybe a statement
needs to be made that there are no specific dose modifications for
heterozygous individuals who may have reduced activity and that that\'s
under investigation.

DR. SMITH: Yes. I think to state that over half of the children will
tolerate standard doses may help to address some of the concerns about
the data being misused for the heterozygous population. There may be a
way to use that type of information.

DR. SANTANA: I think that\'s important information that needs to be
conveyed too, that at least half of them tolerate it well.

Dr. Shurin.

DR. SHURIN: I\'m a little concerned about anything that looks at
anything statistical because it doesn\'t seem to me that we have
remotely enough numbers, including the incidence of any of these things.
So it seems to me it\'s perfectly appropriate for it to stay vague and
not that over half the patients may tolerate it. We don\'t know that.
That\'s been the experience. That\'s what\'s published in the
literature, but it\'s not a population study.

DR. HIRSCHFELD: So just to clarify, the committee would be recommending
a statement for the homozygous condition ‑‑

DR. SANTANA: Right.

DR. HIRSCHFELD: ‑‑ and remain vague or silent with regard to the
heterozygous.

DR. SANTANA: Except there is some dissent on that latter point. There
are some that feel that there is some information that should be
conveyed regarding that. A good proportion of patients who are
heterozygous also tolerate the full dose. I heard that comment at least
being made by one or two individuals.

DR. REAMAN: Instead of remaining silent, maybe there could be a
statement that the recommendation shouldn\'t necessarily be extrapolated
to the heterozygous population. The specific recommendation is made for
homozygotes.

DR. HIRSCHFELD: So a statement that would say no specific dosing
recommendations for heterozygous patients are made, or something to that
‑‑

DR. SMITH: Again, the concern about that is, well, maybe I need to be
safe. I agree, we don\'t know if it\'s 50 percent or 70 percent or 80
percent or 40 percent, but many children who are heterozygous will
tolerate standard doses.

DR. SHURIN: I\'ll endorse \"many.\"

DR. WILLIAMS: Can we say that it hasn\'t been prospectively studied?

DR. BOYETT: You could wait till the English study is ‑‑

(Laughter.)

DR. SANTANA: Dave, do you have a comment?

DR. POPLACK: Well, my assumption is that dose reduction in the face of
toxicity is a standard and is inherent in the label, and that would
occur under any circumstance, including the heterozygous. So by not
having a statement in, we don\'t necessarily remove the fact that they
are going to have dose modification.

DR. HIRSCHFELD: In light of Dr. Poplack\'s statement, is the committee
recommending a specific comment on the heterozygotes or remain silent?

DR. COHN: I would agree with Malcolm\'s statement. I think to remain
silent is potentially a problem because the children may be under-dosed,
and that I think is the concern. If you say many children can tolerate
it and then, as David said, if they get the drug and they become
neutropenic, obviously they\'ll have their dose modified. But I think
what we don\'t want is to have a heterozygote necessarily be started out
at 50 percent of a dose when that may or may not be appropriate for that
particular individual.

DR. HIRSCHFELD: Thank you for that clarification, Dr. Cohn.

DR. SANTANA: Dr. Reaman?

DR. REAMAN: I would agree because I think even though these are
recommendations being made under dose modifications, they may well be
utilized preemptively, and that\'s the situation that we\'re trying to
avoid with the heterozygote patients.

DR. SANTANA: So I think the consensus is there should be some comment
regarding heterozygotes.

Dr. Morland.

DR. MORLAND: I just wondered. One of my anxieties is that an individual
experience of this is going to be very limited. We\'ve already heard
that the average physician may see this once or probably never. It may
be slightly different for the heterozygotes. Is there a possibility of
including in the label specific recommendations that these cases are
discussed with, say, the chairman of the current, ongoing leukemia
protocols?

DR. SANTANA: I don\'t know of any such prior experience, but certainly
we\'ll look to the FDA for guidance. I don\'t think there\'s ever been a
label that specifically says do that. So I think we want to stay away
from that.

Question number 2. If pharmacogenetic information is added to the label,
what other testing information, if any, about genotyping or phenotyping
for TPMT activity in pediatric patients would be considered necessary or
appropriate to include in the product label? Once again, they\'re giving
us a series of comments, not necessarily that we have to agree or
disagree or take them, or potentially we could add others.

So the first one is, a recommendation for testing for the status of TPMT
activity in children before initiating treatment with 6‑MP. If you read
those subsequent ones, they\'re all kind of tied in chronology. You
either do it first before you initiate therapy or the second point is,
within the first week of initiating therapy, and then the third point
is, once they\'ve gotten the drug, if they get severe neutropenia.

Dr. Boyett.

DR. BOYETT: We\'re going to go together.

DR. SANTANA: No. You can only speak once for the record. So one of you
decide. Dr. Boyett.

DR. BOYETT: We vote no for number 1.

DR. SANTANA: Any other comments?

(No response.)

DR. SANTANA: So a consensus that we would not endorse testing before
initiation of therapy.

How about the second point, within the first week of initiating therapy?
Malcolm?

DR. SMITH: Is there a possibility for having a venue of options in the
label? You could argue that there are several defensible ways that this
test could be used for children with ALL. One of the ways is before
treatment. One of the ways is at the first signs of toxicity during the
first time they see 6‑MP and that both of these strategies could be
described and people can have the information and use it as they see fit
or use it as well defined in the label.

DR. SANTANA: I actually kind of like that strategy because it leaves it
up to the practicing physician to decide when he decides to test.

DR. WILLIAMS: The other option, of course, is you don\'t make any
specifications about when you should test, just like we don\'t tell
people how often to check their blood counts, et cetera. That\'s another
possibility.

DR. SANTANA: We don\'t tell them in the product labels people should
have their blood counts checked once a month if they\'re getting X drug?

DR. WILLIAMS: Variably, but we don\'t tell people every test they need
to take to give a drug. We might need to say you need to have your blood
counts checked if that is a particular safety issue, but if this is a
test that will be used variably, one option is not to describe the
issues but just to describe the results as you have in number 4. But
certainly that\'s what we\'re here to ask.

DR. HIRSCHFELD: To clarify, the goal of the label is to provide some
sense of risk management. So the question is, what\'s the risk? And if
you have some mechanism of assessing that risk, what do you do with that
information? So that\'s another way of thinking about what this is
asking. If the sense is that there\'s already sufficient information to
assess the risk, then it becomes moot. If the issue is that there ought
to be more information in the product label about assessing the risk,
then the statement would be if you feel you want to assess the risk,
when should you assess the risk and then what do you do about it.

DR. LESKO: I was just going to bring to the attention of the committee
other laboratory tests in the current label where they talk about
hemoglobin, blood cell count, et cetera. They recommend weekly and then
they go into more detail about strategies to monitor blood count. So
getting back to the first suggestion, there could conceivably be ways to
word using the test in a way analogous to how the current label reads
with regard to the blood counts.

DR. SANTANA: But my interpretation of that would be that you use them
together or you use them separately. So let me give you a couple of
scenarios the way that I would interpret that.

One is you would only order the test if a patient has already received
the drug and has trouble, and in addition to getting additional blood
counts and things like that to monitor the patient, when that scenario
occurs, if the patient becomes neutropenic or severely neutropenic, you
would order the test to either confirm or not confirm your suspicion
that it\'s related. That\'s one possible scenario. Right?

The other scenario is you order on everybody if you\'re too concerned
because, remember, the issue is in the absence of testing the drug on
the patient, how do you know which is the patient that truly is going to
be affected. So that\'s the other scenario. I order it on everybody and
if it comes back negative, it\'s okay. If it comes back positive, then I
have to figure out how I\'m going to dose the patient. But it\'s up to
me to decide in my practice whether I order it on everybody or whether I
order it when the patient has an event that triggers me ordering the
test. To me as a practicing physician, those are the two scenarios.

DR. HIRSCHFELD: I would just comment again philosophically the intent of
the label is to be informative. So if a menu of options are outlined
which represent the full array of logical possibilities, we might pose
the question how informative is that. We already state tests are
available. I think the question being asked here is we\'ve stated that
tests are available. Are we going to make any statements about to use
the test?

DR. WILLIAMS: To follow up on that, I think that there probably could be
two \"should\" statements. I think most appropriate for testing, how to
do it, would be if we could say you should do that. One would be you
should do this in everybody so that you detect the heterozygotes. The
other would be if you have toxicity, you should do this ‑‑ or maybe you
could do this in order to help you weed out what it\'s from. There is a
whole array of different ways you could use the test. That probably, as
Steve was saying, is outside the scope of a drug label.

But I wonder if the committee feels that in either of those cases it
really should be done; that is, you have toxicity, should you do it? Or
should it be done at the first to identify the homozygotes?

DR. HIRSCHFELD: Well, let me try to rephrase and try to parse this out a
little bit. Is there a sense from the committee that the product label
should say all patients should be tested? Parse out that one aspect.

DR. SANTANA: My sense from the discussion this morning is that the
answer is no. There is no strong recommendation that everybody needs to
be tested up front. Does everybody agree with my comment on it?

DR. PELUSI: Victor?

DR. SANTANA: Yes.

DR. PELUSI: If I could. I think somehow we need to make sure, though,
that patients and families know that the test is available, and I don\'t
know in the product labeling if there is a way to ensure that parents
know that that is a test that is available. It\'s the discussion between
the provider and the parents on do they think it\'s appropriate and at
what time and how and why, but I think this is a time when I think
parents really want to know that there is an option there because it\'s
not being done in everyone.

DR. HIRSCHFELD: Right. I think we\'ve agreed that there will be a
statement in the product label to the effect that testing is available.

DR. PELUSI: I just want to make sure that, again, family members know
because many times they don\'t know. They can read the whole thing and
it doesn\'t make a lot of sense. But that\'s just my comment.

DR. SANTANA: Yes. So getting back to the issue, though, if the committee
has a consensus recommendation that we\'re not recommending testing on
everybody ‑‑ I think we\'ve made that very clear ‑‑ then to me the
scenario where we do have to be more explicit is once a patient develops
X event, this is when you should be doing testing and this is how you
would use the information. Obviously the event would be
myelosuppression. And it\'s up to the practicing physician to
incorporate the tests or not do the tests. So the first scenario is out
because we\'re not making a statement that everybody should be tested,
but it should be as an adjunct test in the management of the patient
once this particular side effect occurs.

Susan?

DR. SHURIN: Doing that is defining that this is a test which is
indicated when you have unusual toxicity. So that\'s a clinical
indication. That seems fairly straightforward. So basically some variant
of number 3 would probably be appropriate.

I\'m not sure there is a screening test. The genomic test is awfully
specific. That\'s number 4.

DR. WILLIAMS: Do you feel like the statement should be more of a \"may\"
statement or a \"should\" statement?

DR. SANTANA: Help me with the differences between those.

DR. WILLIAMS: Well, you may do this test if the patient has toxicity.
You may do this test to help weed things out. Or versus you should do
the test.

DR. SHURIN: I would argue that it should be a \"may\" test because
you\'re dealing with patients who are all getting polypharmacy. They\'re
getting multiple myelosuppressive drugs. This is not the only thing that
they\'re getting. The doctor has to look at it as what\'s clinically
indicated.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: I would agree and then maybe just mention that it should be
considered as a potential cause of protracted or prolonged recovery in
myelosuppression.

DR. SANTANA: It should be part of your evaluation in a patient who is
getting this drug and is developing this problem.

DR. McLEOD: I think the critical point is not to box someone in because
there are other drugs that can cause the same thing. The \"should\"
versus \"may\" or \"might\" or whatever it was also has other
connotations in terms of the \"butt in a sling\" test in terms of if you
don\'t do it, you\'re in trouble or not, even if there were clinical
reasons not to.

DR. SANTANA: So I think what we\'re saying, what I gather from the
committee, is that there should be a statement that this should be a
test you should consider in the context of the patient having a
toxicity, particularly myelosuppression, and you decide how to use it.

DR. HIRSCHFELD: Just to get to the fine points, phenotype, genotype, or
it doesn\'t matter?

DR. REAMAN: Let them make the choice.

DR. HIRSCHFELD: Okay. So a statement which says testing for thiopurine
methyltransferase deficiency should be considered for severe toxicity or
something to that effect.

DR. SANTANA: Right.

Dr. Poplack.

DR. POPLACK: I think the terminology \"may be advisable\" might be more
appropriate, and it\'s also used in the existing label.

DR. SANTANA: Right.

I think there was a hand up. Dr. Boos?

DR. BOOS: Yes. I\'m a little bit confused, but we felt that it is not
mandatory to run the test, and we had two suggestions. One is to explain
toxicity and the other was to avoid toxicity. And now we discuss about
explanation of toxicity. My feeling is all these four recommendations
are not necessary because everything has been written down prior and it
depends on the decision of the physician, his relation to the kid, the
prior tolerance of chemotherapy, the combination therapy, the distance
from home to the practice, and things like this, if and when he decides
to run the test. He can do it front line if he feels I cannot allow
toxicity now because it\'s induction therapy including mercaptopurine
and methotrexate and Ara-C, NBB 16 and Total XII and Total XIII or
whatever, and he can do it as the maintenance therapy just if he has
toxicity. I think these four recommendations from my point of view are
not necessary.

DR. HIRSCHFELD: I\'ll just state, as we\'ve often stated before, the FDA
does not regulate the practice of medicine. Our goal is to provide
information for the safe and effective use of drugs which includes some
level of risk management. And given that the top of the label says
\"physicians experienced in the treatment of acute lymphatic leukemia,\"
to quote the nomenclature there, should be the ones giving it, they
would be aware that testing exists and could use it in any way they
wished, just as this drug and many others are used off label. So we
shouldn\'t look at it as practice guidelines, but rather as information
about the drug.

DR. SANTANA: Yes. I would agree with that caveat, that as you well know,
sometimes that does occur. But having said that, we will not continue
the discussion.

Does anybody else have any other comments or advice to the FDA? Dr.
Poplack?

DR. POPLACK: Victor, I\'ll just make one point. If one looks at the
existing label, there\'s very much practice guidelines in there in terms
of when to get certain blood tests. So there\'s a dichotomy which may
reflect historical evolution of writing these documents.

DR. SANTANA: Absolutely.

I don\'t think we have any other advice to give you this morning. So we
will consider this session of the morning concluded.

I think if the FDA agrees, we\'ll get started at 1:15, give people 45
minutes for lunch. We\'ll try to reconvene on time so we can finish on
time this afternoon. Thank you so much.

(Whereupon, at 12:36 p.m., the subcommittee was recessed, to reconvene
at 1:15 p.m., this same day.)

AFTERNOON SESSION

(1:18 p.m.)

DR. SANTANA: So the topic that we will try to address this afternoon is
identifying barriers and overcoming challenges in pediatric oncology
product development, in particular, regulatory oversight over
multinational international studies. We have a series of speakers, and
then we\'ll have an open session for discussion.

There are a couple of formalities that we have to undertake, and so Mr.
Perez will get started.

MR. PEREZ: Thank you. 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 topic of this afternoon\'s session is an issue 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 topic 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
afternoon\'s discussions: Drs. Jody Pelusi, Gregory Reaman, Victor
Santana, James Boyett, C. Patrick Reynolds, Howard McLeod, Susan Cohn,
Susan Weiner.

Because general topics impact so many institutions, it is not prudent to
recite all potential conflicts of interest as they apply to each
participant. FDA acknowledges that there may be potential conflicts of
interest, but because of the general nature of the discussion, these
conflicts are mitigated.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building

With respect to FDA\'s invited guests, there are reported interests that
we believe should be made public to allow participants to objectively
evaluate their comments.

Dr. Richard Weinshilboum previously served as a consultant to Abbott
Labs, Eli Lilly, Johnson & Johnson and he is currently consulting with
Merck. All consulting fees go back to the Mayo Foundation to support
research and education missions.

We would like to note that Mr. George Ohye is participating in the
meeting as an acting industry representative, acting on behalf of
regulated industry. Mr. Ohye owns stock in Abbott, Amgen, Ergo, Gilead,
Johnson & Johnson, Ligand, Lilly, MedImmune, Merck, Omnicare, Pfizer,
Schering-Plough, and various mutual funds that may have drug company
holdings. He also has stock options in NeoRx. Mr. Ohye receives
consulting fees from Johnson & Johnson, NeoRx, Abbott, and Cephalon. Mr.
Ohye\'s wife works for Johnson & Johnson and he receives retirement pay
from Novartis and Johnson & Johnson.

We would like to remind the special government employees of the need to
exclude themselves from discussions involving specific products or firms
for which they have not been screened for conflicts of interest. Their
exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

Thank you.

DR. SANTANA: Does any member of the committee have anything else they
wish to disclose publicly? Yes, go ahead.

MR. OHYE: To complete the record, I also have a beneficial interest in
GlaxoSmithKline because my wife owns some stock in that company.

DR. SANTANA: Thank you for the update.

Dr. Lumpkin, Williams, or Hirschfeld, do you want to make any
introductory comments or do you want to just go ahead and get started
with the introductions of the members of the committee?

DR. HIRSCHFELD: Well, I just think for the record that Dr. Lumpkin\'s
presence should be acknowledged for the afternoon.

DR. SANTANA: We also have Dr. Mark Bernstein on the phone. Are you with
us mark?

DR. BERNSTEIN: Yes.

DR. SANTANA: So we\'re going to start with you. Can you introduce
yourself by name and affiliation?

DR. BERNSTEIN: Sure. I\'m Mark Bernstein at the University of Montreal
and a Children\'s Oncology Group member, and I have been involved with
some of the regulatory issues for Canadian Children\'s Oncology Group
institutions.

DR. SANTANA: Thank you, Mark.

Dr. Ball, do you want to get started from your side?

DR. BALL: Dr. Leslie Ball. I\'m with the Office for Human Research
Protection, Department of Health and Human Services.

DR. KERN: I\'m Ursula Kern from the Federal Institute for Drugs and
Medical Devices in Germany. I\'m responsible for managing our national
advisory committees.

DR. DAVIES: Hugh Davies from the Central Office of Research Ethics
Committee in the United Kingdom.

DR. MORLAND: Bruce Morland representing the United Kingdom Children\'s
Cancer Study Group.

DR. BOOS: Joachim Boos, Department of Pediatric Hematology and Oncology
at the University of Muenster in Germany and the German Pediatric
Oncologist Society.

DR. VASSAL: Gilles Vassal from the Institute Gustave Roussy in France,
Chairman of the European Consortium for Innovative Therapies for
Children with Cancer.

DR. RICCARDI: Riccardo Riccardi from the Catholic University of Rome,
Department of Pediatric Oncology and Hematology, and I also represent
the Italian Association for Cancer in Children.

MR. OHYE: George Ohye, acting industry rep, Naples, Florida.

DR. SHURIN: Susan Shurin, Case Western Reserve University and
Children\'s Oncology Group.

DR. WINICK: Naomi Winick, University of Texas, Southwestern Medical
Center, and the Children\'s Oncology Group.

DR. POPLACK: David Poplack, Texas Children\'s Cancer Center, Baylor
College of Medicine.

DR. WEINER: I\'m Susan Weiner from the Children\'s Cause. I\'m the
patient/family representative. I\'m a member of the Secretary\'s
Advisory Committee on Human Research Protections and also a liaison from
the National Cancer Policy Board to the Institute of Medicine Committee
on Research Involving Children.

MR. PEREZ: Tom Perez, Executive Secretary to this meeting.

DR. SANTANA: Victor Santana from St. Jude Children\'s Research Hospital.

DR. COHN: Susan Cohn from Children\'s Memorial Hospital in Chicago.

DR. REYNOLDS: Pat Reynolds from Children\'s Hospital, Los Angeles.

DR. BOYETT: James Boyett from St. Jude Children\'s Research Hospital,
chairman of biostatistics.

DR. REAMAN: Greg Reaman, Chairman of the Children\'s Oncology Group,
George Washington University and the Children\'s Hospital, D.C.

DR. PELUSI: Jody Pelusi, oncology nurse practitioner, and I sit as the
consumer rep.

DR. SMITH: Malcolm Smith, Cancer Therapy Evaluation Program, NCI.

DR. ANDERSON: Barry Anderson, NCI, CTEP as well.

DR. MAYBEE: Dave Maybee, Center for Biologics, Office of Cell and Gene
Therapy.

DR. HIRSCHFELD: Steven Hirschfeld, FDA, Department of Oncology Drug
Products and Department of Pediatric Drug Development in CDER.

DR. WILLIAMS: Grant Williams, Deputy Director, Division of Oncology Drug
Products.

DR. LUMPKIN: Murray Lumpkin, Principal Associate Commissioner, FDA.

DR. SANTANA: Well, thanks to everyone.

We\'re going to go ahead and get started with the afternoon session. We
have three presentations to cover overview of research oversight, and
I\'ll ask Dr. Ball to get started. Thank you.

DR. BALL: Good afternoon. Dr. Hirschfeld has asked me to speak about the
topic of overcoming some of the challenges in pediatric oncology
development, specifically with regard to international research, and
I\'m going to provide an overview of research oversight, the U.S.
perspective.

First, I wanted to provide you with an overview of what I\'ll be talking
about. First, we all know that there\'s an increased pace and scope of
international research particularly with regard to biomedical research
and also involving children.

I\'m going to provide a framework of U.S. regulatory oversight and
specifically provide you an explanation of the role of OHRP in
relationship to the FDA.

I\'m also going to be discussing some of the regulations that involve
research involving children, as well as international research, and
finally present briefly some of the issues and obstacles.

We\'re here today in part because of the increase in international
clinical trials for new drugs, and this slide depicts the increase. The
y axis is the actual numbers of trials. In yellow are those conducted in
developed countries and in blue are less developed countries, and we see
an increase particularly in the last couple of years in both developed
and less developed countries.

In addition, funding of international research by the U.S. Department of
Health and Human Services has increased. The red line here depicts the
increase in the funding of foreign components of domestic research.

Part of what I think we\'re here to discuss today is the clinical
research balance that everyone struggles with, which is providing a
balance between regulatory oversight and human subject protections on
one hand and scientific advancement and product development on the other
hand.

Now I\'m going to provide a brief overview of the framework of U.S.
regulatory oversight. I think no discussion of regulations is complete
without an obtuse slide and here I present my obtuse slide. This
particular slide presents the framework of human subject protections. In
the center is the common rule, which I\'ll discuss a little bit more in
a moment. Around the spokes of the wheel are the various federal
agencies. Not all of them are Department of Health and Human Services.
There are various other federal agencies that also ascribe to the common
rule. You can see on the far right side is the FDA. FDA is part of HHS,
but they have their own set of regulations that are parallel to the HHS
regulations.

This slide tries to depict where the responsibilities are with regard to
the oversight of human research protections. The first column is OHRP.
OHRP regulations apply to research that is HHS-conducted or supported,
both domestic and international. The regulations that provide these
protections are codified in 45 C.F.R. 46 and there are four subparts,
subpart A which is known as the common rule, and there are also subparts
B, C, and D, subpart D involving children.

With regard to FDA, we all know that FDA regulations apply to research
that involve products regulated by the FDA. Classically there are
certain regulations that are actually called the protection of human
subjects, and that\'s part 50. In addition, 21 C.F.R. 56 involves
regulations that oversee IRB functioning. In addition, there are
additional regulations that the FDA has that provide some protections
for human subjects such as the IND regs at 312. One example might be the
mechanism by which FDA can put certain clinical trials on clinical hold.

This slide is a reminder, because I think sometimes it\'s forgotten
because there are two sets of regs, that FDA is actually part of HHS.
The Secretary is at the top of the pyramid and the FDA is one component,
as well as the other public health service agencies. Where OHRP fits in
is under the Assistant Secretary of Health in the Office of Public
Health and Science.

This slide depicts regulatory oversight as it pertains HHS regulations
and FDA regulations. On the one hand, there are certain trials that are
HHS-funded or supported, and those fall under OHRP\'s purview.
FDA-regulated products fall under FDA purview, but there is an
intersection and overlap between the two, as depicted by the center of
the diagram there. It\'s also important to remember that there are some
studies that are neither HHS-conducted nor funded by the FDA and
therefore not regulated by either agency.

So now I was going to move on to the Office for Human Research
Protection. Its mission is to develop and implement regulations,
policies, and programs for protecting the rights and welfare of human
subjects participating in research that is conducted or supported by the
U.S. Department of Health and Human Services.

Now I\'m specifically going to be talking about some of the regulations
involving children.

First, I wanted to provide you with some historical context and the
evolution of the regulations protecting children. In the \'60s and early
\'70s, there was an increased focus and attention on the part of both
the scientific literature as well as the media with regard to ethical
lapses in the conduct of research. There was a very important article by
Henry Beecher in 1996 in the New England Journal of Medicine that
documented 22 instances of perceived research abuses, some of which
involved children.

As a result of a lot of this attention, in 1974 Congress passed the
National Research Act that created the National Commission. Its charge
included recommendations on research involving children, as well as
research more broadly.

In 1979, the National Commission published the Belmont Report, and I\'ll
talk about that a little bit later.

In 1981, there was a publication of the final rule for 45 C.F.R. 46. It
came upon the foundation provided by the Belmont Report.

In 1983, there was a publication of the final rule for subpart D which
provided additional protections for children involved as research
subjects.

Also in the mix, we add different laws that affected the FDA. In 1997,
the FDA Modernization Act was passed and this provided economic
incentives to conduct pediatric drug studies, specifically market
exclusivity.

In 1998, FDA\'s Pediatric Rule was enacted that provided for the
requirement of assessing the safety and effectiveness of certain drugs
in pediatric subjects. It\'s important to note that last year there was
a court ruling that FDA did not have the authority to issue the
Pediatric Rule and barred the FDA from enforcing this.

In the year 2000, the Children\'s Health Act was passed. This directed
the Secretary of HHS to require that all research involving children
that is conducted, supported, or regulated by HHS, including that
regulated by the FDA, to be in compliance with subpart D. So as a result
of that, to that point FDA did not have separate subpart D regulations,
and in April 2001, they enacted their own interim final rule for subpart
D.

In 2002, the Best Pharmaceuticals for Children Act was passed, and among
other things, it reauthorized pediatric exclusivity incentives for drug
products, and it also provided for the IOM review of research involving
children.

I wanted to touch briefly on the Belmont Report which provides the
foundation for the current HHS regs, as well as the FDA human subject
protection regs. The ethical principles outlined by the Belmont Report
include respect for persons. Specifically, individuals should be treated
as autonomous agents and persons with diminished autonomy are entitled
to special protection.

The second principle was the principal of beneficence, namely the
maximization of benefits and the minimization of possible harms that
might occur as a result of the research.

And justice. It\'s important to remember that justice operates on both
an individual and a societal level. In particular, the National
Commission noted that the selection of subjects deserves scrutiny to
determine whether some classes of subjects are unduly targeted for
research.

So the Belmont Report proceeded to provide an application of those
ethical principles in the form, first, of informed consent. With regard
to children, it\'s important to realize that there are special
provisions that should be made when comprehension is limited.

Secondly, it provided for a full assessment of the risks and benefits.
Specifically when vulnerable populations are involved in research, the
appropriateness of involving them should be demonstrated.

Also, finally, there was discussion of the equitable selection of
subjects. The National Commission addressed this by discussing that
there may be an order of preference in selection of classes of subjects,
for example, using adults in trials before children, and that some
classes of potential subjects may be involved as research subjects, if
at all, only under certain restricted conditions.

So using the Belmont Report as the foundation, 45 C.F.R. 46 codified
this by providing for the informed consent of research subjects, the
independent review of research, and institutional assurances of
compliance.

I wanted to touch a little bit about what an assurance is. Under the
regs, each institution engaged in research, which is covered by this
policy, and which is supported by a federal department or agency shall
provide written assurance that it will comply with requirements set
forth in this policy. So essentially it\'s an agreement between an
institution and OHRP that they will abide by 45 C.F.R. 46. These
assurances are negotiated with and approved by OHRP.

Basically what they do is formalize the institution\'s commitment to the
protection of human subjects, and it\'s important to remember that
filing of an assurance is required by both an awardee, an institution
receiving the money, as well as the collaborating institutions that
might be overseas.

In addition, it also requires the designation of an IRB or independent
ethics committee to review the research.

This slide I included to just depict some of the differences between
OHRP and FDA. With regard to OHRP, we interact primarily with
institutions that oversee research. However, FDA, as you\'re all aware,
interacts primarily with the sponsor of the research.

The common rule, subpart A, provides some additional protections for
children, and I wanted to point out some specific provisions that are
relevant to research involving children. With regard to IRB membership,
if an IRB regularly reviews research that involves children, then the
regs provide that there should be individuals on the IRB that are
knowledgeable about and experienced in working with children.

In addition, there\'s a regulation for providing criteria for IRB
approval that requires that selection of subjects be equitable and that
the IRB should be particularly cognizant of the special problems of
research involving vulnerable subjects, including children.

Subpart D is the part of the regulations that provide specific
protections for children. In this part, it requires that the IRB that is
reviewing such research make specific findings before approving the
research. It must satisfy one of the conditions which are outlined in
subpart D regulations. And generally speaking, as the risk increases in
relationship to the presence or absence of direct benefit, the criteria
for IRB approval under the subpart D category becomes more stringent.

Many people here may be more familiar with these in terms of the numbers
of the FDA regs, but I\'ll be referring to them here for the HHS regs.
45 C.F.R. 46 involves research not involving more than minimal risk.

I think the category that probably most accurately describes most of the
research conducted in pediatric oncology trials is probably a category,
45 C.F.R. 46.405 which is research that involves more than minimal risk
but provides the prospect of direct benefit to the individual subjects.
And if an IRB makes a finding here, they must also make the finding that
the risk in studying children is justified by the anticipated benefit in
that child, that the relationship of the anticipated benefit is at least
as favorable to subjects as that presented by the available alternative,
and finally, that there are adequate provisions made for assent of the
child and permission of their parents or guardian.

Finally, I wanted to touch briefly on some international research
issues. I wanted to emphasize that with regard to the regulatory
requirements for research conducted in international settings that is
HHS-funded or supported, the regulatory requirements are identical to
those requirements for U.S. trials.

I also wanted to point out one particular provision of the regulations,
45 C.F.R. 46.101(h) which states that procedures normally followed in
foreign countries to protect human subjects may differ from those set
forth in this policy, namely 45 C.F.R. 46. If the foreign institution\'s
protections are at least equivalent, the U.S. department or agency head
may approve the substitution of foreign procedures. It\'s important to
realize that HHS has not implemented this provision, but there is a
working group that is involved with advising the Secretary on
implementation of this provision.

So with regard specifically to international assurances, if you go to
the OHRP web site and click on \"assurances\" and scroll down to
\"international assurances,\" you will see that international
assurances, unlike domestic assurances, will require an institution to
state that they will be guided by ethical principles that could include
principles other than the Belmont Report. And under \"international
assurances,\" you can check off Declaration of Helsinki, Belmont Report,
or other appropriate international ethical standards.

In addition, for international assurances, the institution will assure
that they will comply with procedural standards and they can check one
or more of one of these particular procedural standards that have been
developed. It includes ICH-GCP-E-6, as well as the CIOMS ethical
guidelines and some others.

But it is important to emphasize that under the terms of assurances for
the federal-wide assurances, all U.S. federally supported research much
comply with the requirements of any applicable U.S. federal regulatory
agency and that may be FDA regs and that may also be the HHS human
subject protection regs.

Last, I wanted to just discuss some of the issues and obstacles in
regulatory oversight of international research. One of the issues is the
desire to harmonize regulatory requirements wherever possible and that
different requirements of each regulatory agency perhaps can be
minimized to allow for better and easier product development.

In addition, one of the obstacles is the lack of consistent approaches
for study monitoring, reporting of adverse events.

In addition, there is a need to ensure review by IRB/ethics review
committees having knowledge of the local research context. For example,
if an NIH-sponsored research protocol is occurring overseas, it may be
reviewed by the IRB in the U.S. However, they need to provide some
evidence that they have knowledge of the local research context and
when, if at all possible, it makes sense to consider a local IRB review
as well.

For developing countries, it\'s particularly important to begin to
develop host country capacity to conduct and review research. And this
effort is ongoing with regard to the development of IRBs in various
sites around the world by Dr. Melody Lin who is the Deputy Director of
the Office for Human Research Protection and is the head of the Office
for Human Research Protection\'s international activities.

This slide provides some contact information with regard to our OHRP web
site and some information on assurances.

I\'d be happy to answer any questions if there are any. Thank you for
allowing me the opportunity to speak here.

DR. SANTANA: Thank you, Dr. Ball.

Any questions for Dr. Ball? We\'ll have some time, after all the
presentations, to have a general discussion, but any urgent questions?
Dr. Smith?

DR. SMITH: Could you say more about the commission that\'s looking at
the procedures, the setting where procedures normally followed in
foreign countries differ but are sufficiently congruent to allow the
research to continue, what that committee is and what its time line is?

DR. BALL: That particular committee is chaired by Dr. Jim Lavery of the
NIH Fogarty Center, and in fact, he is planning on submitting the report
of this HHS working group to the Acting Director of OHRP this week. So
there will at least be some recommendations by the working group and
then deliberations by OHRP in terms of advising the Secretary on
implementation.

DR. SMITH: Is that a report that will be publicly available or not?

DR. BALL: I\'m not sure at what stage it will be publicly available, but
it will be publicly available. In fact, there is a provision to solicit
input from interested parties.

DR. POPLACK: Leslie, do you know whether they specifically dealt with
the issue of children, research in children?

DR. BALL: I was involved with that activity, and there were discussions
more broadly. I think there were some issues that touched on children
and research, but I can\'t think of anything in particular that was
specific to children.

DR. SANTANA: Thanks again, Leslie.

The second presentation will be Dr. Hugh Davies from the United Kingdom
perspective.

DR. DAVIES: Thank you very much. May I first extend my gratitude to
being invited to talk to this group. I\'ve certainly found the morning
most interesting and illuminating, and I think it\'s probably, putting
the cart before the horse, an excellent example of international
collaboration that I think should be commended and this should be
recorded.

DR. HIRSCHFELD: Dr. Davies, it is recorded.

(Laughter.)

DR. DAVIES: Mindful of Oscar Wilde, who stated that we really have
everything in common with America, apart, of course, from the language
‑‑

(Laughter.)

DR. DAVIES: I\'ll give you some worse ones if you want. I thought I\'d
put some abbreviations up so that if I do lapse into the vernacular, as
I do tend to on occasion, you\'ll hopefully know where I am.

Research ethics committees translate to IRBs, but we have two types. We
have what might be called the local research ethics committee which is
institutionally based ‑‑ I\'ll come on to that ‑‑ and the multi-center
research ethics committee. I suppose if you wanted it to translate
internationally, you might say that these would be state-based, but they
would have a federal role.

Central to the MRECs is something called the Central Office for Research
Ethics Committee, COREC, which I represent. We are charged by the NHS,
Department of Health and NHS, to supervise research ethics committees.
Initially we only had charge of multi-center research ethics committees,
but we know have responsibility for all of them. As I said last night,
if you\'ve ever tried herding cats, you know what our job is like.

The UKCCSG is the United Kingdom Children\'s Cancer Study Group which I
think has particular relevance to this study.

Finally, in terms of vocabulary, GAfREC, the Governance Arrangements for
Research Ethics Committees. That\'s a document that really tries to lay
down how ethics committees should behave, at least in terms of process.

The Department of Health requires that all research falling within
certain categories is reviewed independently to ensure it meets the
required ethical standards. I think that that\'s fairly brief and it\'s
a sort of a philosophy. It\'s not currently really backed up by law, but
it\'s in force in a variety of ways.

The categories of research that require review are patients and users of
our National Health Service, relatives or carers of patients, access to
data, organs, or other bodily material of past and present NHS patients,
and that\'s particularly relevant due to our recent experience, fetal
material and IVF, the recently dead on NHS premises, and the use of NHS
resources.

Reviews undertaken by the research ethics committees ‑‑ and as I said,
these are comparable with the IRBs ‑‑ and their support and management
is overseen by the Central Office for Research Ethics Committees; i.e.,
we manage the budget within certain limits. We have some responsibility
for defining the procedures, and we have a responsibility to try to
define competence and to accredit the ethics committees. That\'s
underway at the moment, the process by which we are doing it. I am
specifically charged with trying to design the training program for
research ethics committee members. There are other people trying to
establish an accreditation process.

I don\'t think details need to bother us much further because I want to
try to move on to more specific issues that might be of relevant
interest to this group.

In deference to my boss, Professor Terry Stacey, he always draws three
circles whenever he comes along. I don\'t know if he\'s been over to
America to draw his three circles, but he doesn\'t use PowerPoint. He
just draws it on acetate and then writes in it. I\'ve moved on a little
bit and I\'m hoping that he\'ll eventually move on the PowerPoint.

(Laughter.)

DR. DAVIES: But nevertheless, it\'s extremely useful. It\'s a clear and
succinct demonstration.

There are three circles really. Policy, which is the remit of
government. That\'s the Department of Health. The NHS has input. It\'s
basically our elected representatives. They charge the Central Office of
Research Ethics Committees to administer the process, and I think the
aim really is to provide a coherent and consistent process. They pass on
the ethical review to the research ethics committees, and as far as
possible, we try to leave them to make their own decisions.

Now, I have a suspicion that the UK member on my right might say, well,
I wish you could actually try to curtail some of the decisions because
they\'re a bit idiosyncratic. Some of them are. What I think we have to
do is we have to balance a permissible variation and we have to allow
that, but we also have to recognize and try to rule out impermissible
variation when committees may make some rather bizarre decisions.

That is the background, and if we look at pediatric oncology, I want to
sort of look at two broad types. The single site studies, which are
probably the phase I/phase II studies, although I recognize that some
may become multi-center, will be reviewed by a local research ethics
committee, or an IRB. The important difference, I suspect, in terms of
differences is that the LREC is actually not an institution or body.
It\'s responsible to what we call a local health authority, which is
outside the trust institution. Nevertheless, a large amount of its
resources, its personnel come through that institution, but it\'s a
means by which we hope that we can try to maintain some independence and
some separation between the reviewing body, which I think has a
principle of being independent, and the research that they\'re
undertaking.

If we look at multi-center research ‑‑ and that\'s more than four sites.
It\'s going to change in the European Directive. In 1997, multi-center
research ethics committees were established. There were 8 when I started
and I think there are 11 now. They\'re based around the country in the
health regions. As I said, you can consider that they might be sort of
state-based. But their opinion will cover the whole country, so that if
you have a study that\'s approved by a multi-center research ethics
committee, that\'s the end of the ethical issue theoretically for the
rest of the country. That study stands approved. In certain
circumstances, that\'s it and then the research can be conducted, and
the local research ethics committees have no further input.

In terms of pediatric oncology, I would argue that there are local
issues. There are local resources used, and therefore the study needs to
be also submitted to the local research ethics committee but for
consideration of local issues only. That\'s quite important.
Unfortunately, some of these ethics committees overstep their boundary
and it\'s a matter of policing it and trying to define and trying to
refer them back to the Health Service guidance for what their role
exactly is. It works in some places extremely well; in other places it
doesn\'t work so well. Like the curate\'s egg, it\'s good in parts;
it\'s bad in other parts.

That\'s the background in terms of pediatric oncology, and maybe what I
want to do is spend some time just describing in more detail the process
that has developed in the United Kingdom. This is a geographical
accident. It\'s a geographical plan. It depends on which way you look at
it. It may be intentional. It may be this has happened.

But the UKCCSG, the Children\'s Cancer Study group is based in Lester,
which is in the middle of England. That is covered by the Trent MREC.
Trent is an area of England. And the Trent Multi-center Research Ethics
Committee over a period of time has built up a relationship with the
UKCCSG. I think it has particular advantages. It means that pediatric
oncology studies tend to go through one ethics committee, and in this
complex and challenging area, I think content expertise is vital. There
is a debate about content expertise and ethics, whether it\'s necessary,
whether it\'s unnecessary, how you achieve it, and where you go for it.
But I would argue ‑‑ and I would be happy to discuss it afterwards ‑‑
that an ethics committee that has content expertise will deliver a more
sensible ethical decision.

I think the other advantage is that the committee is up to speed that
having received one, two, three, four, five ‑‑ I don\'t know how many it
is now ‑‑ they understand the ethos of the UKCCSG. They understand how
it works and they can, therefore, expedite their methodology. And it
simply means that the UKCCSG can say we have this process, we have this
data collection, and they can get that approved, and then if they want
to separate studies, based on the same material, they don\'t have to go
back to square one every time and re-explain the studies to a new ethics
committee. So I hope that it\'s efficient and it saves people time.

The relationship does need careful monitoring. This is called Stacey\'s
devil. I thought in view of the fact that my boss is called Stacey, I\'d
have him on the slide. How close can you sup with the devil?

(Laughter.)

DR. DAVIES: I think that I would argue that it\'s perfectly feasible to
conduct this relationship and maintain high ethical standards. In some
sense I argue that collusion is a state of mind and not a state of
geography and that if you won\'t collude with people a long way away,
you can avoid collusion with people who are very nearby.

But I think it is a relationship that needs careful nurturing, and it\'s
a relationship that needs guarding because it is open to criticism and
if you suddenly find, for example, that members of the committee are
offering independent advice to oncologists, you immediately start seeing
a conflict of interest and that\'s got to be quite carefully monitored.

I have met several of the members of the Trent MREC. I\'ve met the
chairman. It\'s with a slight caution that I would sort of suggest how
they look at pediatric protocols, but I would suggest that they probably
adopt the utilitarian approach rather than a duty-based approach. I.e.,
usually they will look at the benefits and they\'ll look at the risks
and they\'ll see whether the benefits outweigh the risks.

They also follow what I might describe as the various august bodies. And
I was interested to hear Leslie talk because I think that we have
similar ideas but we\'re not sort of tied into legislation. I think we
have a group of august bodies who write down their opinion. They hold
lengthy committee meetings and they deliver it as opinion. That is then
taken on by what we might describe as the policeman of the ethics
system, the ethics committees. They try to interpret those and then
apply them to the applications that they see before them.

They see that some diseases are unique to children and there\'s no way
round that. You can\'t do the research on adults. Physiologically,
pharmacokinetically, behaviorally children are not little adults, and
therefore research is needed on children and not adults.

One thing that Bob Bing, the chairman, was quite keen to point out is
that pragmatically children do better in trials.

They also refer to the guidance from the Royal College of Pediatrics and
Child Health. I\'m not going to go into those, but they essentially say
that research should be encouraged and they reiterate some of the points
of the Trent MREC have made. They define some guidance as to how studies
should be conducted in the pediatric population.

So I think that we\'ve got a model. There are several august bodies, the
Medical Research Council, the Department of Health, the Wellcome
Foundation, the Royal Colleges which I think is equivalent to your
Institute of Medicine ‑‑ I\'m not sure ‑‑ who, through a period of time,
have tried to lay down some ideas. These are incorporated into the MREC
way of working, and they were then trying to look at them, use them when
reviewing a protocol.

When we get on to trial monitoring, I think that we\'re on less clear
ground, and I think that up until recently the trial monitoring of
pediatric oncology studies has been relatively limited. The stipulations
are really laid down in the Government\'s Arrangement for Research
Ethics Committees, and if I read some of them out, they\'re fairly
vague. The researcher is required to notify the committee of any
proposed deviation. No deviation is possible without approval from the
REC. The research sponsor is responsible for ensuring the arrangements
are in place to review significant developments. And then it concludes:
\"Other than by means of these required reports, the REC has no
responsibility for pro-active monitoring of research. The accountability
lies with the host NHS institution.\"

That\'s probably one of the problems or the differences is that the
hospitals ‑‑ I don\'t know what the U.S. system is, but the hospitals
are independent legal entities and therefore carry their own risk and
their indemnity. While they will stipulate you have to get ethics
committee approval, they will want to look at the consequences for the
institution themselves.

Having said that, I think that the European Clinical Trials Directive,
which is due to be subsumed into United Kingdom law in 2004 ‑‑ but
don\'t hold your breath ‑‑ will get a more uniform approach, and that
there will be a more standardized approach across the European Union.

What tends to happen at the moment from my experience is that the
pharmaceutical trials are fairly tightly monitored. They are very
closely monitored. The trials that come through academia are less
closely monitored. Now, very often that\'s quite reasonable because they
carry less risk, and I think the European Clinical Trials Directive
carries the important concept that monitoring needs to be commensurate
with risk, and I think there needs to be some dialogue and negotiation
beforehand to try to define that.

In terms of international collaboration, there are no specific
arrangements that I know of through the research ethics committee, at
least in terms of ethical review. I think it\'s important that the
research ethics committees, the IRBs for the country, will review these
aspects of research projects.

The problems for international studies come down to a slightly
provocative title of ethical imperialism. You\'ll play my way or you
won\'t play with me at all. I think that Europe is likely to be guilty
of this as the EMEA builds up its authority and the FDA or America
likewise.

I think it\'s important to also add the caveat that very often there\'s
a game of Chinese whispers going on and that what the FDA or the EMEA
insists, or whoever it is, is not actually what they\'ve insisted.
What\'s reported to one person is reported to another person is reported
to another person and what comes down ‑‑ what started off as send
reenforcements, we\'re going to advance, as in the famous First World
War Chinese whispers, came as send three and fourpence, we\'re going to
a dance.

(Laughter.)

DR. DAVIES: So we need to be very clear as to what the stipulations,
what the regulations are. From my inspection ‑‑ and I\'ve spent some
time because I\'ve had occasional transatlantic phone calls ‑‑ actually
when you read the regulations or the stipulations from other countries
‑‑ and I\'ve had them from Australia. I\'ve had them from the USA ‑‑
actually they\'ve been misinterpreted. Usually if I\'ve said the ethics
committee is ICH-GCP compliant, the study was conducted according to
that, then there\'s no further issue about it, although they do
occasionally send me very large forms I\'m supposed to fill in and sign
in triplicate. I\'ll do that.

So what conclusions? Well, we\'re in a big of a mess. I think that
there\'s one certainty in this business, and that\'s called change.
I\'ve been on ethics committees now for 15 years and it never stands
still. The European Union Clinical Trials Directive is certainly further
change, and one could think once the European Clinical Trials Directive
is in place, we\'ll all settle down and we\'ll go and sort of sow
carrots or grow broccoli or something. I don\'t believe that\'s the
case. I\'m absolutely certain there will new regulation. There will be
new stipulations. Well, that\'s not difficult for somebody who has
worked in the National Health Service because it\'s always changing.

I think if we look at the differences between the USA and the United
Kingdom ‑‑ I was interested. Leslie and I had a conversation last night.
Many of the philosophical problems are very similar. Many of the
practical problems are very similar. It seems to me that you have a
tighter legal framework and it may be that we will move towards that
through the European Clinical Trials Directive. I hope that we can
balance things out. I think a legal framework will help us enormously
and I think it will help the researchers. But I also believe there\'s no
substitute for reasoning and thinking and argument, debate, and
discussion. But unfortunately, the legal brethren I talk to don\'t like
that very much and they want everything laid out in sort of words of one
syllable. But I hope that we can sort of maintain that balance.

I\'ll conclude. I\'ve only really talked about approval, ethical
approval of research, the research applications. I haven\'t talked about
designing them and I haven\'t talked about data that subsequently
emerges from them. But may I just reiterate that I think a group like
this with a true international flavor is really the way forward to
exchange ideas about how we\'re going to move forward, and I don\'t
understand much about enzymology. I\'m interested in pharmacogenetics.
But it seems to me this is where to thrash out the problems. We have
similar problems, and maybe if we have similar problems, we can achieve
and reach some mutually acceptable arrangements for initiation, review,
and then data analysis of studies.

I\'m also grateful I\'ve had an opportunity to look around Washington
which I rather admire. Thank you very much.

DR. SANTANA: Thank you, Hugh.

I have maybe two minor comments I\'d like you to address. Did I
understand you correctly that this current system in the UK has no
provisions for international research, so if there are studies that are
being conducted between the UK and, let\'s say, France or Australia,
there is no written guidance in that relationship? That\'s the first
comment.

The second comment is, can you expand a little bit on this relationship
between the multi-center IRBs and when things have to go to the local
IRB and who decides that? Are there spelled-out criteria that dictate
when the latter occurs, or is it left to the local IRB to decide that
they also want to review it?

DR. DAVIES: In terms of international collaboration, I think COREC sees
its role to look after its own patch, and if it\'s about ethical review,
the Multi-center Research Ethics Committee will review the ethics of a
study and then locality issues are dealt with by the local research
ethics committees. That doesn\'t mean that the protocol coming from
elsewhere needs to be drastically changed. What I suppose we would say
is you have to fill in our form, which actually is not much more than a
protocol that has just been amended and adapted a bit, and then we will
consider it and we will follow ICH-GCP. We\'re ICH-GCP compliant. We
believe in the Declaration of Helsinki. I don\'t know if we believe in
2000, but we believe in earlier versions. We have difficulties with
that. And the Belmont Report. I think that we have the same views. So I
don\'t see this should be particular problems about that.

What I would like to feel is if a researcher sends a protocol to the
USA, he or she can say that it\'s reviewed there, providing it follows
your regulations and we\'ll accept it, and please send us the data. And
I\'d like to think that similarly if workers in the United States sent
us a protocol, we could review it and then the USA would say, right,
well, the London Multi-Center Research Ethics Committee, which I used to
chair, is ICH-GCP compliant. It\'s met all the regulations that we want
met, and therefore we don\'t have to take it any further. If you want
the chairman of the ethics committee to fill in a long, complicated
form, you\'ll have to speak nicely to him, but I think that the basic
principles should be the same.

In terms of the relationship with the Multi-center Research Ethics
Committee and the local research ethics committee, it\'s been a
difficult one. When we first started ‑‑ I\'ll tell a few anecdotes ‑‑
the local research ethics committees felt that their nose was out of
joint and that these organizations, these larger, sort of national
organizations were sort of usurping their patch, and some were quite
difficult about it. Theoretically once the study is approved by this
Multi-center Research Ethics Committee, it should only go to the local
research ethics committee for locality issues. But if I told you that on
one occasion somebody had to apply to 170 LRECs to do a study, somebody
else had to go back to their funding body to ask for 2,000 pounds for
photocopying money to fill in applications forms, it became
unacceptable.

So in November 2000, I chaired a group to look at how to work this out.
We basically said if you can say that there are no locality issues, then
the MREC makes the decision for the United Kingdom. And no locality
issues means that there\'s no local researcher. The contact with the
local individual is limited.

And we also said that if the local researcher is trained centrally ‑‑
i.e., he has attended a central training program that is sort of
recognized, accredited ‑‑ then there should be locality issues there.
That should not involve the local research ethics committee.

And we also stipulated that if the individual clinician practicing was
undertaking work that could be expected to be within his remit, his
clinical expertise, then there shouldn\'t be any locality issues in
that.

I know that there are difficulties with this, and some ethics committees
accept this. Others have difficulty. The policing is quite difficult. I
think we\'re moving towards a process where we are getting one view for
country, and locality issues, where they arise, are being dealt with by
the local research ethics committees.

DR. SANTANA: Does the legality always become a local issue?

DR. DAVIES: Sorry?

DR. SANTANA: Do the legal aspects of the conduct of the trial, in terms
of indemnity or payment, always become a local issue at that level? Do
all hospitals say we want to review it locally because of the issue of
‑‑

DR. DAVIES: No. The payment of research tends to be a central issue. The
indemnity for the trust or for the local hospital ‑‑ their research
development fund may want to look at it to ensure that it matches their
sort of broad strategy. Also, what they\'re particularly concerned about
usually is resources and to ensure the research doesn\'t absorb
resources that should be going elsewhere.

DR. POPLACK: Just one brief question and that relates to whether there
is an ongoing forum for discussion between you and any analog here in
the United States or elsewhere in Europe about these issues. Because
clearly what you\'ve talked about, the concept of central IRBs, et
cetera is very topical in the States. And I wondered, is there a forum
where you get together with colleagues here or elsewhere in the U.S. to
talk about these issues, the commonality of problems, et cetera, or not?

DR. DAVIES: No, but we would be very keen to, and I think that we would
offer a voice and sort of talk about the problem. Certainly Terry
Stacey, who is my boss, has been out to Australia where they\'re trying
to set up such a system, and I think that it\'s quite a good idea to try
and learn from people\'s mistakes. You don\'t want to reinvent wheels.

In terms of Europe, we\'ve got the European Union, the European
Parliament, and there are one or two bodies, European Forum of Good
Clinical Practice. But I think it\'s an area that is begging for
international collaboration. Ethics committees established themselves in
the UK for some very bizarre reasons and they sort of became individual
fiefdoms that have limited accountability. I don\'t know if that\'s the
same across the world, but it screams out for accountability and some
international agreement.

DR. WEINER: Actually this is a follow-up comment to the title of your
slide, is the United Kingdom being untidy. The United States is actually
quite untidy as well, as we heard this morning with respect to ethnic
and racial backgrounds and language backgrounds as well, which I
understand is also true of the UK. Do the local review boards ‑‑ how
does that get handled? Because that\'s a topic of active discussion and
something that the local review boards are sensitive to. In New York,
there\'s a central IRB which translates the consent form into, as you
can imagine, over 50 languages.

DR. DAVIES: The language in which the patient information sheet is
written is a locality issue, although personally from my experience from
the London MREC, I feel that that\'s not particularly necessary. We have
clinicians who know full well what the issues are, and it can be simply
a matter of ensuring that the sponsor agrees to translate the patient
information sheet into different languages.

If I go back to your first point about what is the relationship, then
there are defined locality issues. It\'s not the definitions. The
definitions are there. It\'s policing and it\'s the interpretation by
the local research ethics committees who sometimes over-interpret their
role and thereafter the policing of that system. What\'s necessary is
for people to say that\'s not your remit. Leave it alone. That sometimes
happens and sometimes doesn\'t happen.

DR. WEINER: So there\'s lay representation on the local committees as
well as the MREC.

DR. DAVIES: Yes.

DR. ANDERSON: Yes. I\'ve been involved with helping the Children\'s
Oncology Group get involved potentially with a multi-center trial
involving institutions in Europe, in England, in the UK. A question
that\'s come up is, so if you do have the trial approved and the trial
is being conducted and an institution was to not follow the consent form
properly or the procedures as it had been approved, who calls them to
task.

DR. DAVIES: I think that you would probably need a sponsor, somebody who
sponsors the project in the country and they would be the person who
would be carrying the responsibility. That\'s in the European Clinical
Trials Directive. I think they would be the person who would be called
to task.

DR. SMITH: Do you see major changes in your system in the UK that
you\'ve described with any new EU regulations, and if so, can you give
us an idea of what those changes might be?

DR. DAVIES: I think that we have strived very hard to follow ICH-GCP,
and therefore, the European Clinical Trials Directive is not hugely
different. That\'s probably not fair. In broad, ethical terms, it\'s not
different. There are a few details that are different in the sense that
multi-center research ethics committees are going to have to review
research that\'s conducted on more than one site, but we\'ve got round
that by redefining the word \"site,\" which is a smart move by my boss.
There will be a legal framework through the European Clinical Trials
Directive, but the legal framework is stipulating really only what\'s in
the ICH-GCP, which we have been following anyway. I\'m contradicting
myself. I don\'t see huge changes but there will be changes, but I
can\'t think of them yet.

DR. SANTANA: Thank you again, Hugh.

I\'m going to invite Dr. Kern to talk about the German perspective.

DR. KERN: Thank you very much. First of all, I would like to thank you
for giving me to opportunity to talk about challenges in pediatric
oncology drug development from the regulatory point of view.

Pooling patients in international multi-center studies is highly
desirable for a number of reasons, among them in order to speed up the
development in pediatric oncology. We\'re talking about a small
population and it makes sense to cooperate internationally. It\'s
furthermore desirable in order to reduce costs, but we learned this
morning that we are not talking about costs here. So let me state
another reason. It\'s about avoiding duplication in clinical studies.
This is a highly ethical issue, you know, no unnecessary exposure.
That\'s why it makes sense to cooperate internationally.

International multi-center studies should have a solid basis in our
common ICH, International Conference on Harmonization, guidelines. We
have been working on this project for years and have a number of
guidelines that we all agreed upon together, and we have come to reach
unified quality standards. That\'s ICH-GCP guidelines, and as Dr. Davies
says, that\'s nothing new. That came into force a couple of years ago
already.

We furthermore have common harmonized ethical standards on the basis of
the Declaration of Helsinki and of the GCP guidelines. We have unified
guidelines, very important, for safety data management requirements in
international studies, and we have unified scientific standards. Let me
just name the statistical guideline and the role of statistical
expertise, or let me, for instance, mention the guideline on choice of
control groups in clinical trials. This altogether should form a solid
basis for our cooperation.

In Europe, national legislation has to be seen in the framework of
European legislation, and that means that national legislation has to
follow the new and legally binding Clinical Directive and the detailed
guidelines of the European Parliament and the Council of the European
Union.

Let me give a short comment on this term of \"detailed guidelines.\" As
you know, when we talk about guidelines, these are normally
recommendations that are not legally binding, but in case you deviate,
you should have good reasons to.

These detailed guidelines of the European Parliament are binding as
well, and they refer to, for instance, the application for an ethics
committee opinion. There are certain rules, which formal requirements to
follow and which information to give. The detailed guidelines,
furthermore, refer to the request to the competent authorities for
authorization of a clinical trial. This also refers to the format of the
application and the content. \"Content\" means what you have to send as
pharmaceutical documentation, the preclinical documentation that has to
be submitted, and the clinical documentation. Furthermore, there\'s the
study protocol and the investigators\' brochure.

This all sounds like a lot of paperwork and it certainly is. However,
when submitting this documentation, this request for authorization, the
applicant is required to really find out what do we know up to now,
what\'s the rationale for the new study, where do we want to go, and
will the benefits of the trial, the possible benefits, the knowledge
derived from the trial outweigh the risks.

Then there are detailed guidelines referring to the adverse reaction
reporting obligations within the trial and more guidance about the
inspection procedures and the qualification of inspectors.

Our national German drug law is being modified right now in order to
comply with the Directive, and I understand that same process is going
on in other European countries. There are always common core
requirements to put it this way. There is certain room for national
particularities and this will have to be regulated as well.

It is the intention of the Directive to prevent repetitive tests,
whether within the community or in third countries. Sorry to have to
call the USA a third country in this respect.

ICH is explicitly mentioned as an appropriate forum for discussion in
order to reach this aim. According to my feeling, these ICH guidelines
are a kind of regulatory oversight that is given in advance because what
does it mean \"regulatory ICH guidelines\"? It doesn\'t mean that we sit
down in an arm chair and fantasize a scenario about how studies might be
and should be, but these regulatory guidelines derive from definite
experiences with new drug applications, drug approval applications that
failed and were turned down and those applications that were approved
and new drugs that were licensed. You can do something right and you can
make mistakes, and all this regulatory experience is put into guidelines
and applicants are well advised to follow these guidelines.

It\'s a further aim of this Clinical Trial Directive to simplify and
harmonize the rules on commencement of trials and to establish
transparent procedures and effective communication between the parties
involved. The parties involved with that ‑‑ that\'s the sponsor, the
monitor, the clinical investigator. That\'s the regulatory authorities
and all this in different countries. You know, we are 15 plus 2
observers right now, and we are going to have 10 more countries within
the European member states within the European Union next year. So this
is a very complicated harmonization process and communication process,
and there will really have to be very transparent rules.

The clinical trials authorization will, as a rule, be implicit on the
basis of the vote, often a positive vote, a positive opinion of an
ethics committee. We talked already about this problem of one single
opinion per member state. Also, in Germany we are still having a system
of local ethics committees and multiple votes, and industry has been
complaining a lot about complicated and time-consuming procedures. This
has to be regulated in another forum. We currently have a working group
of ethics committees and we will see how these things will be regulated
in the new drug law.

This delegation of responsibility for the clinical trial authorization
to ethics committees and their vote makes sense in a way because all the
regulatory authorities are supposed to have the oversight of our
clinical trials. We simply can\'t do everything. It\'s a question of
personnel resources and we have to cooperate with other independent
institutions.

The ethics committees have to judge the suitability of the trial
protocol, the investigators, the recruitment procedures, and the
informed consent. Nevertheless, the competent authority may inform the
sponsor of any grounds for nonacceptance, and we have had examples of
that.

For instance, we had a positive vote for a clinical trial in the field
of neurology, positive opinion by a renowned ethics committee situated
at a German university hospital, but as regulators, when we heard about
this clinical trial, we had some doubts concerning the personal
integrity of the clinical investigator because he had issued positive
opinions about the efficacy of this new drug before any controlled
studies had been made.

So we took a closer look at the study protocol and found out that this
study protocol was really deficient, was basically deficient, and the
clinical trial would never have had a real result, either positive or
negative, because the protocol was inconclusive in itself. So we made an
inspection. The trial had already started, and then we found out that
there were, for instance, no case report forms at all, and finally the
clinical trial was stopped.

Protection of trial subjects includes insurance to cover the liability
of the sponsor and the investigator. Clinical trials on children,
clinical trials in minors are related in this new Directive, and they
require at least some direct benefit for the group of patients
concerned. The ethics committee has to have pediatric expertise to judge
these trials. Exchange of information will include the establishment of
a European database for clinical trials and for adverse reactions.

So this implementation of the European Clinical Trial Directive means a
supreme effort to promote multinational studies, first of all, within
Europe. However, there is considerable resistance and some clinical
investigators feel that this is the death of academic trials.

I\'m showing you a slide that was shown at a recent conference in
Brussels on clinical drug development in children. The speaker addressed
the subject of cooperation and said that there was a joint
responsibility shared by two of the main stakeholders in pediatric
medicine development: the regulatory authorities and the research-based
industry. And the question I\'m asking myself of course is, where is the
clinical investigator, the clinical investigator with the link to the
patient, to the pediatric patient\'s parents, to their hopes, to their
fears, to their expectations? So the problem seems to be that as
regulators we have too closely cooperated with the pharmaceutical
industry and we have forgotten the dialogue with the clinical
investigators.

So what happened on the clinical investigator side, on the other hand,
the investigators initiated development of their own. They felt an
urgent need to apply new medicine and products in children with cancer
and to develop a new treatment regimen. The situation is such that
oncology products are widely used off label in children. Nevertheless,
there\'s a widespread lack of interest on the part of the pharmaceutical
industry to act as a sponsor.

In this situation, pediatric oncologists have taken the initiative and
have developed a system of cooperative study groups with standard
treatment protocols which means, from the regulatory point of view,
systematic off-label use. There are, of course, many financial
constraints for the clinical investigators and the lack of funding,
especially in Germany, lack of public funding, insufficient funding, and
so the situation of the clinical investigators was really bad. The
progress is undeniable. The cure rates improved dramatically. However,
all these research endeavors suffer from the fact that they are not GCP
compliant and they deviate from many regulatory requirements.

So pediatric oncology studies. Do they bypass regulatory oversight? As
you all know, we have the usual terminology concerning clinical trials.
We are used to speaking about clinical trials, phase I, II, III, or IV
if it\'s about an approved drug and within the approved labeling. We are
used to differentiating exploratory or hypothesis finding studies from
confirmatory ones. The vocabulary, the glossary in the field of
pediatric oncology is different. They talk about approval studies as
opposed to therapeutic studies or therapy optimization studies, as if
approval studies were not therapeutic in intent as well. I think this is
a very dysfunctional situation.

The challenge for the future. Can there be supranational networks of
excellence? I called that \"networks of excellence\" because certainly
not every study site will be able to perform GCP-like international
studies. My thesis is that there are definitely no two classes of
studies for which different criteria apply, such as approval studies
versus therapeutic studies. Investigators willing to participate in
multinational studies will have to accept this without feeling
over-regulated. Regulatory oversight includes oversight of compliance
with the EU Clinical Trial Directive.

Conflicts between the clinical investigators\' perspective and the
regulatory perspective are obvious. We heard this morning that
clinicians never read the label.

Practical difficulties can be expected as the implementation means a
modification of current practice and legislation. There are certain
habits on the part of the clinical investigators, and these are not in
line with the new GCP European Directive requirements.

One of the core principles of this challenge that we are supposed to
master is adverse reaction reporting. Detailed guidance is available and
is essential, especially in multi-center studies. One of the key
elements is the institution of an independent data and safety monitoring
committee especially in trials in high mortality disease states, such as
in oncology, and the independent data and safety monitoring committee,
another independent institution that helps regulators to have oversight,
is responsible for continuing review of the risks and expected benefits
of the clinical trial. This has to decide whether, for instance, the
informed consent has to be revised and has to make decisions about
modifications, amendments of the clinical trial, or even premature
termination of the trial. There are, furthermore, key elements such as
adverse event reporting in general, especially expedited reporting and
notification of suspected unexpected serious adverse reactions.

Another key issue is, in my eyes, that the trial protocol should follow
the highest methodological standards. Regulatory oversight should start
with scientific advice whenever possible just because these
nonapprovable decisions often originate from deficiencies of study
protocols and might have noticed earlier, right from the beginning.
This, of course, doesn\'t mean that regulatory scientific advice is to
replace the expertise of the clinical pediatric oncologist, but it\'s
meant to come in addition to that.

At this point of the discussion, the head of our national pediatric
advisory committee, our expert group, usually says, well, well, well,
these are really two different worlds. This is not what I feel. I don\'t
feel that these are two different worlds, but two different ways to look
at the same world, to look from different angles. But if it\'s really
two different worlds, my appeal would be to try and combine the best of
these two worlds.

Thanks.

DR. SANTANA: Thank you, Dr. Kern.

Any questions for Dr. Kern? Dr. Vassal.

DR. VASSAL: Just a few comments. I do agree with you perfectly on the
fact that the approval and therapeutic studies are not the appropriate
name for these studies, and phase I, phase II, phase III, phase IV have
been used during the last 10-15 years in terms of development of
clinical studies in children with cancer. So I do agree very much with
your point.

In addition, with regard to pediatric oncologists thinking that they
might do their clinical trials outside the regulatory frame, just to
mention that in 1988 in France, the first law for GCP was launched, and
pediatric oncology said, oh, no, it\'s not for us. We will not be able
to continue to take care of children within clinical protocols if we do
follow this rule. And the government said, yes, you will go. And
clearly, it did improve the quality of the study. It did improve the
safety of the patients. So clearly, there is no way to me that pediatric
oncologists should do the clinical trials outside a regulatory
framework.

Just with regard to what\'s going on in France, in a few words, it\'s a
little bit more simple than what is going on in the UK. Each clinical
trial has a sponsor, a sponsor responsible for conducting the study,
reporting, monitoring the data, financing the insurance for the
patients, and each study should be submitted to one ethics committee
which is a little bit like the MREC. There are several ethical
committees in France and one is enough to really look at all the items
in terms of ethics. And then all the study goes to AFSSAPS, which is the
French equivalent of the FDA, and should be approved by the French drug
agency before being launched in terms of clinical trials.

Indeed, the main point in terms of clinically driven phase II/phase III
studies is the point of improving monitoring and the point made before
by you on the fact that monitoring maybe adapted to the risk of the
patients in the trial might be a way to really get enough data in terms
of safety, but not too many in heavy works in terms of reporting and
monitoring of all this.

DR. SANTANA: Malcolm.

DR. SMITH: I would just comment from a U.S. perspective that in the
pediatric trials that we sponsor through the Children\'s Oncology Group
and the Pediatric Brain Tumor Consortium, the various rules that we
apply to our adult clinical trials that we sponsor apply equally to the
pediatric clinical trials. So the adverse event reporting guidelines and
expedited, when they need to be, all apply. The same rules concerning
independent data and safety monitoring committees apply. So we try to
make sure that our pediatric clinical trials system is compliant with
all of the rules and regulations whether they be related to OHRP or FDA
or the NIH regulations.

DR. SANTANA: Dr. Reynolds.

DR. REYNOLDS: I just had a question. You said that in Germany in
pediatric oncology trials, however, these studies frequently deviate
from regulatory requirements. Could you give us some examples and then
how do you deal with that? If your deviating from regulatory
requirements, are you giving exceptions or are you just looking the
other way?

DR. KERN: I mean that these studies that are performed according to
common protocols, there\'s no notification procedure. There is no
inspection procedure. There is mostly no study monitoring. All those
elements that are contained in GCP guideline are not executed within
these trials. For instance, an investigator brochure or these
requirements that are laid down in the ICH Directive are not within the
realm of these studies.

DR. HIRSCHFELD: I\'d just like a clarification. On your last slide,
could you clarify whether the German federal government is reviewing all
protocols prior to implementation or whether the review begins and ends
at the ethics committee level?

DR. KERN: No. We are definitely not reviewing all protocols. It would be
impossible for reasons of personnel resources. We generally rely on the
positive opinion unless we have some reason to suspect that something
might be wrong. Then we take the study protocol. As a rule I\'d say if
it is about narcotic drugs and special permission to perform the
clinical trial, we usually review the study protocol ourselves as well.

DR. SANTANA: So what criteria are used to have the government review a
study? I\'m trying to differentiate how that decision is made and what
criteria are specifically used to say it has to have a governmental
review versus it doesn\'t have to.

DR. KERN: There are no criteria. That\'s on a case-by-case basis.

DR. SANTANA: So the investigator voluntarily requests a review or you
guys know about a study and request a review?

DR. KERN: No. The investigators have to contact the ethics committee
first, get a positive opinion, and together with this positive vote,
they notify our regulatory authority.

DR. SANTANA: Okay, and then what triggers the regulatory office to then
say they do want to review the study too?

DR. KERN: As in this example I gave to you, we knew that the
investigator in this case had already issued a personal opinion about
the result of the trial he was just beginning to perform.

DR. HIRSCHFELD: So just to pursue that, the federal government will have
then at least a superficial review of all protocols. That is, there will
be someone who acknowledges a study is about to occur and someone that
will acknowledge that an ethics committee has approved it. And then in
that review process, if there\'s anything else that arouses suspicion or
triggers an inquiry, then it would be at that level that the formal
review would be initiated?

DR. KERN: I\'m sorry. I\'m even unable to say that we do a kind of
superficial review of the study protocol. In first line, we just check
whether there is a positive vote of the ethics committee, and I even
doubt whether a superficial review of the protocol would contribute very
much. My personal experience with the review of study protocols is that
this is a very challenging task, not easy to do, and it\'s
time-consuming, and a superficial review wouldn\'t help. Probably I
would even, for instance, have to consult a colleague from the
statistical department. So it\'s really a challenging task.

DR. SANTANA: Dr. Poplack.

DR. POPLACK: Ursula, I was quite taken by one of your slides in which it
stated that insurance is provided both for the investigator and for the
sponsor. Is that truly the case? So that individual investigators are
not at risk because their insurance is covered by the government.

DR. KERN: It\'s not by the government, but the sponsor has to make an
insurance for the trial subjects and, by an indirect way, the insurance
covers the clinical investigator as well.

DR. SANTANA: Any other comments or questions for Ursula? David.

DR. POPLACK: Just one general comment. I\'m always good at stating the
obvious. But I want to compliment Steven and you, Victor, for having
this be a topic of interest for this committee because it is so
important. As you very astutely pointed out, there\'s a tremendous need
for us to do cooperative trials in pediatric oncology and I would say
probably in other pediatric illnesses as well, although pediatric
oncology is our focus, because of the fact that, ironically, the more
successful we\'ve been, the fewer the numbers of patients that are
available for study despite the fact that we have many, many more agents
to study of potential interest. So it\'s in all of our national
interests, whether you are German or French or Italian or American, to
be able to look now beyond our borders to pursue international studies.
I guess the question is how can this be done efficiently with
appropriate safeguards. So the discussion session should be very
interesting.

DR. SANTANA: Thanks, David.

Any other comments or questions?

(No response.)

DR. SANTANA: We have now an opportunity for an open public hearing. Is
there anybody in the audience that wishes to address the committee?

(No response.)

DR. SANTANA: If nobody does, I do want to ask Dr. Ohye to make a brief
comment about the industry perspective on this issue because many times
sponsors have to go to different countries to conduct research. I
wondered if you could give us a brief synopsis of your experience with
this issue and what you perceive the barriers and the problems are from
the sponsor perspective.

MR. OHYE: First, I\'d like to say I think the barriers are coming down.

With reference to what industry is doing, I think years ago they used to
think in terms of having two programs, a program for the United States
and a program for Europe, and a smaller program even for Japan where
you\'d probably have to have some bridging studies using the data
generated in the United States and in Europe. But it\'s driven by
economics. It\'s easier to do one multinational development program than
separate programs. So I think that\'s a given and that\'s happening.

With reference to how they deal with local standards or cultural
standards with reference to ethical compliance, I think the ICH has gone
a long way to shrink the world and make everybody think almost in one
mind in terms of how to deal with the ethical considerations or, as we
sometimes call it, the duty of care when doing studies in children.

DR. SANTANA: Can I expand a little bit on your comment about how
sometimes sponsors historically have made a distinction between a
development plan in America and a development plan in Europe or another
country? What triggers that decision? Or what\'s behind the separation
or that distinction? Is it purely economics?

MR. OHYE: Quite frankly, the standards were sometimes different, and the
resources that you would use in Europe, for example, you might use some
of the consortiums available in Europe and their protocols might differ
from what the FDA might demand or what you might think the FDA might
demand in terms of control medications, use of placebo, and things like
that. But I think now there is now international thought on what should
go into a development program.

For example, it is acceptable today ‑‑ and I\'ll defer to Dr. Williams
on this ‑‑ to use as a control drug an unapproved drug in the United
States that may be approved in Europe because you know that drug is
widely used and will, no doubt, be approved in the United States. So you
can have a common protocol, and that\'s a lot easier to do today than it
was in years past.

DR. WILLIAMS: There\'s no special requirement that a drug be approved
for a certain ‑‑ are you talking about for a drug that\'s not approved
in the U.S. or a drug that would not be approved for a specific
indication?

MR. OHYE: A drug that may not be approved for a particular indication in
the States be allowed to be used as a control drug in an ongoing trial.

DR. WILLIAMS: I mean, I guess even theoretically you can have a drug
that wasn\'t approved in the U.S. as long as we knew that it wasn\'t
harmful. That\'s correct. The main requirement is a demonstration of
efficacy. It might be important in certain settings where you have a
very good approved drug, but in most settings the main requirement is
just to show a benefit.

DR. SANTANA: Dr. Weiner?

DR. WEINER: Actually this question is for Dr. Ball and for Dr. Reaman.
The Children\'s Oncology Group is an international group. It has, as I
understand it, sites in Switzerland and Australia and New Zealand. Are
there any lessons to be learned from those collaborations that might be
useful in this context?

DR. SANTANA: Mark, you too in Canada.

DR. BERNSTEIN: Thanks, Victor.

DR. BALL: I\'ll defer to Dr. Reaman because I\'m not sure what the
question is with regard to OHRP. You were asking?

DR. WEINER: Well, you have a working group that is presumably addressing
this topic, and I\'m just wondering whether or not your deliberations
have included any of the lessons that presumably come out of the COG
collaboration and how that meshes.

DR. REAMAN: How the Children\'s Oncology Group operates in foreign
sites, because we are supported by the federal government, those foreign
sites have to comply with all U.S. regulations, which includes have a
federal-wide assurance number. So simply stated, the reason they are
able to participate is because they are willing to follow the
regulations which sites in the United States have to follow.

DR. BERNSTEIN: In addition, we have to comply with our national
regulations, which can make life difficult on some occasions.

DR. BALL: With regard to the working group, we did consider more broadly
the issues that have been brought to OHRP with regard to the
difficulties in conducting research and some of the advantages that
might follow from having an equivalent protection determination by the
Secretary for other standards. So I think broadly. We did not
specifically with regard to oncology trials, however.

DR. SANTANA: Mark, I want to follow up on your last comment. You kind of
hinted about additional problems or issues with Canadian review. Can you
comment specifically on what those barriers are, what the differences
are, and what additional hoops you perceive are problematic?

DR. BERNSTEIN: Well, it\'s clear we have additional hoops, and so all of
our trials, in addition, need to be submitted to the health protection
branch, Health Canada, and that means that we need to submit a so-called
clinical trials agreement which includes the protocol, the consent
document, and what has been difficult to date for investigational drugs,
which is either a letter from the pharmaceutical sponsor of cross
reference if there\'s an ongoing study in Canada or chemistry and
manufacturing information. So this has represented for us an additional
barrier to participation in the Children\'s Oncology Group studies,
although, as Greg says, we do meet all of the U.S. regulatory standards.
So this is a subject of ongoing negotiation to try to facilitate our
compliance with all Canadian regulations.

DR. SANTANA: Dr. Reaman?

DR. REAMAN: And just to clarify that the hoops through which people jump
aren\'t only in Canada. Because of bilateral agreements between the
United States and Canada, we have to be sure the we have mechanisms in
place to assure compliance with those Canadian regulations. So as Mark
mentioned, drugs that are not approved for use in Canada for which we
are doing trials in which there\'s participation by Canadian sites, we
have to file a clinical trials agreement. We have to have a mechanism in
place by which we do not enter patients on those trials from Canadian
sites until we have evidence of non-objection from Health Canada. So it
implies a bit of work on our part as well.

DR. BERNSTEIN: Yes. Which brings me back to a question I had. For the
International Committee on Harmonization, is there some sort of target
schedule for when there might actually be regulations in place that all
European and North American authorities would recognize?

DR. SANTANA: Does somebody from the FDA want to address that?

DR. LUMPKIN: I guess there\'s the question, when you say about recognize
‑‑ the example that people have talked about so far, the ICH documents,
indeed are recognized by the Canadian and the U.S. and the European
authorities. I think what you\'re running into is the issue of the
implementation of those. I think what you\'re asking is would there ever
be a time that the Canadian authorities would say, oh, well, never mind.
The Europeans have looked at this, the Americans have looked at this,
we\'re not going to look at it, or vice versa, anywhere around. I think
that\'s going to be the hard one to get over for two reasons.

Number one, at the end of the day, when someone has to take
responsibility for it, there\'s not an international taking of
responsibility. At the end of the day, we here at the FDA are
responsible for what happens within the jurisdiction of the United
States as is Health Canada in Canada and our European colleagues there.

The other thing I think you have to ask yourself is, remember, if that
happens, that means one person gets to say yes or no because if somebody
is competent to say yes, they\'re also competent to say no. And that
means if the first authority says no, we are not going to let this
happen, it\'s over. Nobody else can raise their hand and say, well, wait
a minute. Let\'s think this over again. Maybe it is okay here. And I
think that\'s one of the things that when people start talking about are
all of the government jurisdictions simply going to allow another
government to make the decision for them, you\'ve got to ask your
question, are you willing for one jurisdiction to have the competence to
say yes and no as opposed to just say yes.

So it\'s a bit of a long-winded of answering your question. I think
there are several very complicated issues of responsibility that come
through.

The real thing that we tried in ICH is to say, well, look, we realize
each of us is going to always have responsibility for what happens in
our jurisdiction, but can\'t we get agreement on the technical
requirements because that\'s the big issue. And if we can work through
the technical requirements, then hopefully it will be a yes, yes, yes
kind of thing instead of yes, but or yes, but.

DR. BERNSTEIN: And is there a time frame for that?

DR. LUMPKIN: I think what we\'re trying to find here is what are the
issues that we need to address within some kind of a framework, whether
it\'s ICH or whether it\'s a bilateral agreement or whatever it is. The
ones that have gone through ICH are, indeed, agreed at this point if
they\'ve gone through the ICH process. The issue now is ‑‑ and what
we\'re interested in hearing from you guys ‑‑ the specifics of where are
the problems, what are the issues that are standing in the way that we
need to find some agreement on.

DR. SANTANA: Since you said that, I\'ll start. You mentioned some issues
of technical requirements, and I won\'t address those. And you also
mentioned the issue of defining responsibility and accountability, and I
won\'t get into those.

But I think there are two things that I think when we look at if
international studies are relevant. One is the lack of uniformity in the
review process where different countries look at studies somewhat
differently. A good example would be should a phase I study be a phase I
study in England as it is in Brazil, as it is in America, and would
review process look at the same elements to assure that all those are
the same as it regards the design of the study and the conduct of the
study.

That gets into this issue then of the elements of the clinical study.
Many times when you have studies that are reviewed in South America and
the U.S., different review committees ask for different things in the
paperwork of the study, and I think that creates a lot of barriers for
review committees to have to go back and amend, change studies and you
wind up with clearly a different, on paper, clinical study in South
America as you do in the U.S. So there needs to be some uniformity of
the elements of the clinical study and that everybody is talking the
same language when they\'re talking about elements of the clinical
study.

And then not to monopolize the discussion, I think another issue is the
monitoring of the study. The monitoring of the study should be uniform
across countries. There may be some local context issues that I think we
need to talk about subsequently, but the monitoring of the study has to
be uniform across all countries and it has to be independent of the
country, so as much as possible have monitoring systems that are
independent of the actual individuals who are running the study. I think
that\'s more feasible when you have international studies than when you
have local studies in which usually it\'s the people doing the study who
are monitoring the study.

And then lastly is the issue of resources. There are always financial
impacts. I\'ve been dealing with trying to do a study in another country
in South America through St. Jude, and there are financial issues that
get tied by the country in the South America telling me I can\'t do this
or I cannot do that and who is going to pay for this. So when we\'re
talking about cooperative group studies, there is some element of
financial backing, but the reality is many sponsors and many academic
institutions, when they do international studies, have to look at the
dollar sign and see how much it\'s going to cost in one country versus
the other. So the financial impact of the study is also, I think,
something to me that\'s a barrier when we start thinking about
international studies.

So I just mentioned briefly three or four things that as an investigator
I see are potentially problematic when you\'re trying to do studies
across countries.

Yes.

DR. POPLACK: Just to follow up on the economic issue, even though costs
shouldn\'t be one of our foci, it\'s gratifying, I think, to hear that
for pharmaceutical corporations that the supranational view is the view
of the day, but they can afford to work with existing circumstances as
far as regulations are concerned because they have the financial
resources to deal with these differences. If a trial is initiated by an
academic institution in any of these countries that don\'t have the
resources, then we are much more hampered by not having the resources to
cut through a lot of the bureaucracy. So I think that to some extent one
could argue for the need for change because of the threat that the only
trials one will ever see may end up being trials that are done by
pharmaceutical corporations.

DR. SANTANA: I have another issue that I think to me is a barrier. I
don\'t want anybody leaving the room today thinking that I\'m an expert
in this area, but I\'ve read and I\'ve been here many times that I\'ve
listened to different aspects of international research. When I listened
to our colleagues from Germany and France and England talking ‑‑ and I
think I\'m an educated person ‑‑ it\'s appalling that I\'m not aware of
everything. So I think there\'s a lack of education about what the
different standards are across different countries. The pharmaceutical
industry is very aware of this and they\'re very keen to it, and that\'s
why I think, in part, they develop different clinical development plans
for Europe versus the U.S. because they\'re very versed in the
regulatory aspects and the differences, whereas I think the rest of us
in cooperative groups and academia are not as versed, and I think
there\'s a lack of education of trying to understand the differences,
not the commonality, but the differences between regulatory issues
across countries that would make our lives easier when we want to
propose doing a study. So I think lack of education at the general level
of the investigator is very critical in understanding this.

DR. LUMPKIN: Can I ask, just in follow-up for my education, if you were
to design a trial that would have U.S. sites ‑‑ and say, for example,
since we have experts from the United Kingdom, if you wanted sites in
the United Kingdom, would you work with the Children\'s Cancer Group
that was mentioned earlier? Would that be the mechanism by which this
would occur outside of the pharmaceutical company perspective? It would
be the working of the two children\'s cancer groups together?

DR. SANTANA: I think that\'s potentially a model. It\'s not the only
model, but I think a potential model is if I wanted to do a study either
through COG or as a single institution and I wanted to search other
sites, I could go to the COG if I was a single institution and say, can
we do this together, or I could go to Europe and the UK and say, can we
do this together. That\'s one potential model, but it\'s not the only
model.

Greg, I think you had your hand up and other people on this side.

DR. REAMAN: (Inaudible.)

DR. SANTANA: Dr. Anderson.

DR. ANDERSON: We\'ve talked about ICH guidelines which we recognize the
European countries recognize. So we seem to have a basis there. There
are problems that come up when you have multi-center trials, which we
have to do basically in pediatrics, in multiple sites in Europe, as well
as the U.S., in that when we try to even start to bridge the gap there,
the regulatory assumptions that come with who is following ICH
guidelines differs from the U.S. side versus from the European side such
that the U.S. basically takes the role of saying here are the forms ‑‑ I
think this was referred to earlier ‑‑ that all the institutions within
Europe must fill out if any U.S. institution is to participate or
interact with the European institutions. That, I think, if you want to
talk about a barrier, has caused many studies, I\'d say, to become
non-starters.

At NCI we\'re trying to work through that with several different models
trying to work with what are sort of the OHRP guidelines that are in
place, but it\'s a long road. It\'s not a clear road and I can tell you
it just takes a long, long time. And I don\'t know whether from the
European side the U.S. will face a similar situation on either the ICH
guidelines or on other issues in the near future as well.

DR. SANTANA: Dr. Morland?

DR. MORLAND: I think Barry has made a very important point. The truth is
that we\'ve done this before. We\'ve done a collaborative phase III
study with CCSG and with SIOP in France which was a very successful
collaboration some five, six, seven years ago I guess. I get the sense
that it\'s now more difficult to do that than it was six or seven years
ago. I don\'t know whether Mark might want to comment on some of the
difficulties that have been going on with the discussions around the
proposal for a new multinational osteosarcoma study, but my
understanding is that the regulatory issues rather than the clinical
issues are one of the major barriers to this study being launched.

I think the concern about the perceived bureaucracy that we all have to
deal with is one of these big barriers. It\'s particularly the issue I
think about all of the science in Europe getting FDA approval, whatever
that means. I think it\'s seen as quite a challenge.

I\'m not sure why we can\'t just deal with this nationally in that if
this is a cooperative study, the responsibility for patients in the UK
are the responsibility of the UK; the responsibility for the patients in
the U.S. are the responsibility of the U.S. And why we have to go
through the degree of cross-checking and cross-referencing is to me a
little mind-boggling.

DR. SANTANA: Mark, do you want to comment on that?

DR. BERNSTEIN: Yes, I\'ll comment briefly. Then I\'m afraid I need to
go.

Barry is well aware of these issues and with his help we are ‑‑ there
were two studies that would be worth mentioning because it turns out the
requirements are somewhat different. The Children\'s Oncology Group bone
sarcoma group will be participating in a Euro Ewing\'s study. That study
was already ongoing at the time that we said we would join. So,
therefore, it turns out that the regulatory requirements are somewhat
simpler than for the osteosarcoma study that Bruce referred to where we
have participated in its planning. So again, it turns out that the
regulatory requirements are a little bit stickier for that study.

What we have, I think, successfully done is that as you say, Bruce, each
national group has acquired a federal-wide assurance number, so an FWA,
not an FDA. And each national group will serve as the supervisory body
for the institutions within that country that are participating and will
serve kind of as their guarantor, and actually the Medical Research
Council will serve as the European conduit for that guarantee. I would
say that certainly our colleagues from Germany and COSS have been quite
firm in their adherence to the ICH and GCP guidelines as they are
written. So it is a complicated process to work through, and certainly a
simplification of that process would be very welcome.

DR. HIRSCHFELD: Mark, could you just clarify what you meant by
\"sticky\"? Is it just the volume of having to go through so many
different authorities in sequence and so many IRBs or are there actual
discrepancies and differing requirements?

DR. BERNSTEIN: There were a bit different requirements. For our
participation in Euro Ewing\'s, Muenster, which is the COSS
headquarters, needed to acquire a federal-wide assurance number, but
after that, the requirements were relatively simple for us to join an
ongoing study. It seemed to be a bit more difficult in terms of
guaranteeing that we had a monitoring plan in place for quality
assurance and the institutional monitoring and so on for the localized
osteosarcoma study.

DR. HIRSCHFELD: Could you just be a little more specific in terms of,
again, the differences that you had to overcome getting the de novo
study organized?

DR. BERNSTEIN: For the de novo study, we not only needed each national
group to have a federal-wide assurance number for their principal site,
but we also need to ensure that there is an independent data safety and
monitoring board, which there is in any case for Euro Ewing\'s, but we
needed to guarantee and approve the setup of the data safety and
monitoring board for the osteosarcoma study. We\'re in the process,
because the study is still not open, of planning how institutional
monitoring will go forward in terms of quality assurance in terms of
setting up site audits based in the national groups although, as I said,
for Europe with overall oversight from the MRC.

DR. SANTANA: Mark, clarify something for me. This issue of the
independent monitoring, if the study were done in the U.S. and it did
not include Europe, it still may mandate an independent safety and
monitoring board, or are you mentioning the fact of how the data is
collected across different sites to allow that group to review the
study? Are you addressing both or just one of those?

DR. BERNSTEIN: Well, we\'re doing both.

DR. SANTANA: Is the barrier in both or in one of those?

DR. BERNSTEIN: Well, the data safety and monitoring board was simpler
because all of the European osteosarcoma intergroup and all of the COSS
studies and all of the MRC studies already had a mechanism in place to
set up an independent data safety and monitoring board. So that is in
addition to the Children\'s Oncology Group solid tumor data safety and
monitoring board. So that mechanism was already in place, and so we
simply utilized that mechanism to have such a DSMB setup.

In terms of the monitoring, that was a bit more complicated because as
the German speaker mentioned, site audits and so on aren\'t necessarily
currently in place in Germany although they are moving toward that
system. So what we needed to ensure for the osteosarcoma study is that
such site audits and auditing of data quality would be implemented.

Does that clarify that?

DR. SANTANA: Yes.

Dr. Anderson?

DR. BERNSTEIN: I\'m going to need to go. So thank you for inviting me.

DR. SANTANA: Thank you, Mark.

DR. BERNSTEIN: I enjoyed listening.

DR. HIRSCHFELD: Thank you, Mark.

DR. BERNSTEIN: Thanks, Steve.

DR. ANDERSON: Related to what Mark had said, one of the other major
hurdles for a while was trying to figure out how to bridge. If you just
look at the regulations or guidelines, whether each institution within
each of the countries, such as Germany ‑‑ there are perhaps 80 to 100 of
the institutions that would participate in the study ‑‑ would each have
to get their own FWA, meaning the federal-wide assurance, for COG to be
able to participate with them. And we have worked it such that the
central coordinating center in Muenster has that assurance, as well as
the data center there, as well as each of the other groups in
Scandinavia and in the UK that will participate. They have their own
FWAs in place. A number of individual institutions within each of the
countries already had FWAs in place, but the MRC will be the
coordinating center and the data center through which everything would
come through basically. They will be actually where all the data will go
to, as well as from the U.S. It will go to them.

I think when I had asked about who has the oversight role in the UK if
someone doesn\'t follow the ICH guidelines, the MRC is going to play
that role because when we were having our discussions with the
Europeans, we were trying to figure out who is the OHRP equivalent, who
do you go to to say this institution or this investigator really
shouldn\'t be participating and we need to have them taken out of the
study or invalidate their results or something like that. So the MRC
will play that role.

But it\'s something we had to figure out over time and it\'s not
something that\'s easy to do because there are very few institutions or
bodies within Europe that NCI can work with in this way. The EORTC would
be one. The MRC would be one. There would be few if any others. The only
other route would be that each institution would have to have their own
assurance, and while it\'s only several pages of a form, to get each
institution within a country to fill those out, understand what they\'re
doing just takes a lot of time.

DR. SANTANA: But that was an issue of lack of education of understanding
that there are different ways of getting to the same point. You either
have a center that holds the FWA or you have multiple centers that
independently each holds their FWA. Am I correct?

DR. ANDERSON: Yes.

DR. REAMAN: It went way beyond education.

(Laughter.)

DR. REAMAN: Because this evolves and changes on a regular basis, and
some of it actually relates to who is the coordinating center or who is
actually doing the study. In the case of the Euro Ewing\'s, COG was
joining a study. So the only group that had to have the federal-wide
assurance number was, in fact, the coordinating group and the
coordinating center, which was in Muenster.

DR. ANDERSON: And the data center as well.

DR. REAMAN: And the data center as well.

For de novo studies being developed, early on it was every institution
regardless of where they were had to have a federal-wide assurance
number.

So I\'m not sure that education is really involved here. There\'s just a
changing thought process and decision making.

DR. HIRSCHFELD: Could you just clarify? Was there a requirement for
every country or region to have its own data safety and monitoring
board?

DR. REAMAN: Well, that\'s another issue because there\'s some
discrepancy in what is the role and the responsibility of the data
safety and monitoring board. For our studies, the data safety and
monitoring board is independent, and the data safety and monitoring
board has the responsibility of, for reasons of patient safety,
basically halting accrual to a study. In other places, the data safety
and monitoring board is advisory to the coordinating center or to the
study committee, which I think ‑‑ correct me if I\'m wrong, Barry ‑‑ is
still something that is being discussed and negotiated about how the
osteosarcoma study is going to be done, if it\'s going to be done.

DR. HIRSCHFELD: So one data safety and monitoring board could say, stop
the study and another one could say, we\'ve examined this and our advice
is to continue.

DR. REAMAN: Well, no. What would happen was that the data safety and
monitoring board would say, stop the study, but in one country they
would say, well, the data safety and monitoring board only provides
advice to us, the organizing committee, and we\'re not going to heed
that advice and we\'ll keep the study open.

DR. SANTANA: Dr. Lumpkin, did you have a comment?

DR. LUMPKIN: I just want to make sure that I\'m understanding this
correctly. It sounds like a lot of the issues that you guys are putting
on the table are issues that derive from the fact that these studies
about which you are talking are federally funded. Correct? Therefore,
you\'re falling under the OHRP regulations that require you to have
these federal-wide numbers, et cetera, as opposed to these are FDA
requirements that you\'re falling under.

DR. REAMAN: I think they\'re all OHRP requirements. They\'re not FDA
requirements.

DR. LUMPKIN: I think so too. And I just wanted to make sure that I was
clear on that so that if there were things that we could do or if there
were issues we needed to address on the FDA side, that it was clear what
the FDA issues were. If there are things that are OHRP issues that need
to be addressed, we need to make sure that we\'re clear what those are
just so we know who needs to take what home to deal with. From what I\'m
hearing, it sounds like it\'s primarily this piece of the OHRP
regulations that Dr. Ball was talking about that the committee is trying
to work on to see if there\'s a way that you guys can look at some of
the foreign sites or foreign ways of doing this as equivalent. But
that\'s the main issue that you\'re trying to deal with right now. Is
that correct?

DR. REAMAN: Correct. The only difference would be with respect to some
of the studies that we\'re doing ‑‑ well, all of the studies are being
done in Canadian sites, and the assistance that\'s required sometimes on
the part of the FDA in obtaining the clinical trial agreements in
Canada, particularly when it comes to providing chemical and
manufacturing information. But I think all of the other barriers,
obstacles are really more OHRP than FDA related.

DR. HIRSCHFELD: But what we\'re touching on are studies that are done
with already-marketed drugs.

DR. REAMAN: Correct.

DR. HIRSCHFELD: And we haven\'t even touched on the issue of using
investigational agents in this discussion.

DR. REAMAN: And I think the reason for that is that we\'re having so
much difficulty with already-approved and marketed drugs that no one is
even fathoming going to the next level with IND drugs.

DR. SANTANA: Dr. Reynolds.

DR. REYNOLDS: I want to touch on an issue that Greg just mentioned that
Mark mentioned earlier that I think is an FDA issue because we\'ve been
hammering on OHRP here, and this is an FDA meeting, and that is access
to new agents. In addressing that question to you also, I noticed that
there\'s a report due, I believe, from you all on access to new agents
to Congress. I wondered if we would be able to have a copy of that to
look at. It\'s just a general question because I think it\'s a general
question on the access to new agents issue.

But specifically with respect to access to new agents for the foreign
studies, I know exactly what Mark is talking about. It\'s a phase II he
can\'t get open in Canada ‑‑ he very much wants to ‑‑ because the IND
has been assumed by the NIH and they can\'t get the manufacturing data
out of the company that dropped the IND because they just don\'t seem to
be able to provide it, which is also holding up a phase I study that we
want to do in the U.S.

So the question there is really how can the FDA help that. I think one
thing that could help with the foreign sites in general would be that if
you guys could develop an agreement between at least the major countries
that we interact with on a pediatric oncology basis to where letters of
cross reference or something can go smoothly; in other words, a
reciprocal agreement, that if the FDA in the U.S. has said a drug is
manufactured according to specs and it\'s okay to go here, that they
would just reciprocally agree to that without having to force the
investigators to go out and beat this information out of someone.

DR. HIRSCHFELD: That\'s a point that I think I can just share that
we\'ve seen. We\'re called, I would say, regularly for assistance
because somebody wants to do a study and would like to cross reference
an IND and we cannot acknowledge whether the IND exists or does not
exist. We cannot direct them toward the appropriate party or share the
IND number that they could cross reference, provided that one exists,
because of a number of constraints. And then we watch people ‑‑ and I
would say just speaking personally ‑‑ in a helpless way while they\'re
floundering around writing letters and trying to figure out who holds
the IND and then trying to get permission to cross reference. Then they
may or may not get that permission to cross reference and then come back
to us and say, well, can we do the study anyway if we open up our own
IND? And we\'ve just watched six months go by.

DR. REYNOLDS: Well, see, these are examples of barriers that the agency
could help with. You don\'t have to go talk to OHRP to help with those
problems. You can do it within yourselves.

DR. SANTANA: Dr. Ball?

DR. BALL: Yes. I just wanted to address Dr. Reaman\'s comments. I think
that it is very important to remember that even with any potential
implementation of the equivalent protections provision of the
regulations, it may still require an assurance. So I think that it\'s
very important for our agency to hear exactly where the barriers are
because I\'m told by our assurance division that there are over 5,000
FWAs currently. 20 percent are in sites outside the U.S. and that there
is now an electronic submission mechanism by which you can have an
answer, have an FWA number in as little as five days. I\'m sure there
are barriers, but if we can help identify those and we can try to fine
tune that and work and see if there\'s a way to get around those.

DR. SANTANA: Barry?

DR. ANDERSON: I\'ve been on the OHRP web site. I\'ve helped people who
were trying to put trials together find out does this institution in
Brazil have an FWA. But that all I understand.

The issue comes up whenever the European institution says, why do I need
an FWA for us to collaborate, because they are also sponsoring the
study. The U.S. is putting in some money to support the COG
institutions, but I\'m not supporting the UK institution. I\'m not
supporting the German institution. So what I was saying is that they
have, I think, then the right to say to us, here\'s all the paperwork
you have to fill out now for the German government, for the UK
government, for this or that, which is going to be retaliatory strike,
in a sense, that will stop COG again from being able to collaborate
because it\'s not whether it\'s easy to fill out. It\'s why do I have to
fill out something that comes from the U.S.

DR. BALL: Are they accepting HHS funds in those circumstances?

DR. ANDERSON: I don\'t know how you draw the lines. It\'s a cooperative
trial. So we are accepting in a sense UK and German funds as well. In
both these cases, they\'re not run by the U.S. The European data center
is going to be the main data center. It\'s going to be the coordinating
center for the trial overall. U.S. funds would go into it because COG is
a participant. So essentially COG is the one who is blocked from
participating if the European institutions don\'t obtain an FWA. That\'s
what the reality is.

DR. BALL: I could see that as a difficulty, and I think that there
really does need to be some more dialogue with the OHRP on how that
might be addressed because I think it is a complex problem. But I also
want to emphasize that if a foreign institution is receiving HHS funds,
similar to the FDA regulatory authority regarding FDA-regulated
products, OHRP has the responsibility to oversee the use of funds in
those sites.

DR. SANTANA: Dr. Boos.

DR. BOOS: This is a bit difficult. I once read a draft guidance of the
FDA where it was pointed out that the phase III trial is the standard of
care in pediatric oncology, and this is still true. And it makes an
important difficulty for us because what we discussed today is how to
organize GCP in worldwide trials. At several points we come to
difficulties to decide what is now GCP or what is the problem with GCP,
and this is significantly different if we have, for example, this
French-English group that did several explorative or confirmative phase
II trials in 10 centers, which is quite easy compared to an osteosarcoma
trial with maybe 100 centers in Germany. There is a broad spectrum of
experimentality and organizational problems in the spectrum of clinical
trials between phase I and phase III or even standard of care
organization, what we try to bring under the phrase \"therapeutic
optimization trials.\" Those were those trials where we even couldn\'t
say which was the drug we address questions to.

And the osteosarcoma trial is in this first part. Just the
standardization of what has been done on a routine basis in several
countries in the world, now to bring to one protocol and just to make
quality control of what happens, and at the end it then is a
randomization of an experimental drug in patients in remission with the
question, does it prolong remission, does it reduce recurrence rates or
relapse rates.

What we need there is a very, very detailed discussion, what of GCP is
necessary. GCP is always a frame, but where in this frame do we have to
organize the trial? Do we have to take one sponsor or can we take seven
sponsors for every country? Do we need one data safety committee or do
we need seven data safety committees? How do they have to organize the
exchange? How do we have to initiate the trial sites? Do we need CVs of
every investigator or every sub-investigator, or do we need signature
logs for every involved physician in these hospitals? Or do we need
working procedures for the local pathologists in these hospitals? Or
what else do we need? Do we need double data entry? Or do we need
specifically validated databases? Or how about handling of surgery? Is
the source data the first written note in the surgical protocol, or is
it the letter of the surgeon to the physician on the pediatric ward?
What is the source data? Do we want to sample them in the centers or
not? How do we organize the monitoring? 10 percent of the trial size or
10 percent of the data? And all these things have to be organized.

And this is an enormous amount of work if you compare such a trial with
what has been on a standard basis even in companies because I think
never any company runs trials where up to 95 percent of the specifically
ill patients had been involved. And this is the breaking point because
you in your talk told us that the GCP guidelines were where you worked
on what developed on criticisms of the regulatory capacities to the
pharmaceutical industry and therefore quite a significant different
situation.

We all agree that the principal ideas, data safety and more than this,
patient safety, there\'s no doubt. This is the aim of everybody here,
but how to translate this, how to define the hundreds of guidelines with
respect to these aims is the critical point. From my point of view, we
need a guidance which offers us, really actively offers us, the frame in
what we can decide, that we do not have to discuss every protocol with
every authority and every ethical committee, that we have guidance where
we can say, okay, this is within what we are allowed to decide.

DR. SANTANA: Let me see if I follow you. So your comment is that there
already exists a number of documents out there, GCP, international
harmonization guidance, et cetera. They kind of provide a template or a
framework to kind of generically conduct studies, but what is lacking is
a guidance on the organizational structure of how those studies get
conducted and how you overcome regulatory hurdles, international legal
hurdles.

Let me not put words in your mouth, but that\'s how I understood it,
that we already have a template of how to conduct the study and we have
variances among countries, but in general, most people agree that those
guidance documents we try to follow to some degree. But what\'s lacking
is the organizational framework in which that can be conducted equally
among countries without having to do this discussion every single time
we have a study.

DR. BOOS: We have a guidance how to handle pharmacokinetics in children.
And this is a bit different than in adults. What I wish to have is a
guidance on how to interpret guidelines in the variety of pediatric
oncology situations because there is not one situation. There are
hundreds of situations.

Even if we take the EU Directive, which has been mentioned several
times, it has the phrase \"non-commercial\" clinical trial. This has not
been translated into the German version, unfortunately. But the only
thing which is a compromise there is that the labeling of the
investigational drug is not that strong. We have lots of discussions
with authorities and our inspectors which drug do we have to label as
investigational. This is one of the first things we normally cannot
decide because we prove concepts in many of the trials. Therefore, I
think the discussion has to discriminate between clear-cut drug-related
drug developmental trials, phase I, II, and phase III, and between
trials which clearly are drug-related but have more aspects of quality
control.

DR. SANTANA: Any other comments? Dr. Poplack.

DR. POPLACK: Just a couple of comments. To follow up on Greg\'s point,
the discussion today has focused to a great degree on phase III studies
and the difficulties of carrying out phase III studies, but the need is
for international phase I and phase II studies. I think you\'ve heard
that people are very skittish about even attempting this at this point.
So one has to look at what\'s going to happen if we\'re not able to
circumvent the barriers that exist.

Well, there are many new agents that are \"targeted\" towards unique
targets which make our small pediatric population even smaller, and it
may be that without having the opportunity to go beyond either the
European borders or the U.S. borders, we just won\'t be able to do those
studies.

What will also happen ‑‑ because it\'s happened to date, and I think
this is an ethical challenge ‑‑ is that you\'ll see that phase I and
phase II studies of the same compound will get done in both spheres. So
you take a very precious resource that\'s crying out for new therapies,
and that is kids with cancer, where we end up doing duplication, as
Ursula pointed out.

So some way or another, we have to be able to address this issue, and
whether it means a commission of European and U.S. regulatory
authorities getting together to go through point by point the areas of
potential conflict to find commonality, I\'m not certain what the right
approach is, but the losers in this are going to be the children.

DR. SANTANA: Dr. Shurin.

DR. SHURIN: I think this in many ways sort of an organizational and
administrative challenge because we\'ve already got not only the
clinical practice, at least some common definition with the ICH-GCP, but
the general principles of conduct of research actually we all agree on.
It\'s how to implement it rather than what they are.

It seems to me that the worst thing we could do would be to create an
infrastructure which is very top heavy and very centralized. What you
need is something that delegates the trusts people to assume
responsibility to be accountable. It\'s going to require a tremendous
amount of education and it absolutely, I think, is going to require, as
David mentioned, having some sort of commission to sit down and hammer
out how we need to do these. We don\'t necessarily need to do exactly
everything in the same way other than the fact that adverse event
reporting and the response to adverse event reporting has got to be the
same whether you\'re in Brazil or in Muenster or in San Francisco.

Beyond that, the biggest issue really is allowing the people at the
local area to figure out how they\'re going to solve their particular
problems. I think what Hugh described in terms of the local IRB ‑‑
we\'re not going to sit here ‑‑ Greg will tell you as well ‑‑ and say
that we know how to do this because we already have these problems with
the local IRBs. But there are certain things that are properly
determined at a local level, and there are other things ‑‑ I think we
already sort of know what they are. It\'s really, I think, sort of a
matter of sitting down and doing it.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: Just to follow up on Dr. Ball\'s question ‑‑ and it just
sort of clicked ‑‑ the issue of federal funds going to institutions
outside of the United States and when that happens, the need for
compliance with all U.S. federal regulations. I don\'t know who does the
interpreting here, but in the cases that we\'ve been talking about,
there are no U.S. funds going to any institutions outside of the United
States other than those institutions that are already members of the
Children\'s Oncology Group. But there\'s no money going to any of the
institutions in the UK or to Germany. But the concept is that this is a
trial that is sponsored, conducted by a group supported by federal
funds, and therefore the conduct of that trial has to be in total
compliance with U.S. federal regulations which includes all centers
having federal-wide assurance numbers.

DR. SANTANA: Do you want to respond, Dr. Ball?

DR. BALL: Just that I think that with regard to any ruling of equivalent
protections, while it may well require an assurance, there may be a set
of guidelines from other countries or other bodies that would be deemed
to be equivalent. Therefore, there would not be the requirement that all
human subject protection regs, 45 C.F.R. 46, were followed, which would
allow the countries to use their own standards.

DR. SANTANA: I\'m going to look to the FDA for some guidance here. I
think we\'ve covered a lot in the discussion. I\'m not sure, as I think
through the two questions that you have posed for us, that we need to
address them. I think we\'ve covered most of the issues in enough depth,
that I think you guys have some sense of what our concerns are. Rather
than spending a lot more time rehashing the same subject, I\'d rather,
if the FDA agrees, unless anybody has any other points to make, to end
the discussion at this point.

DR. HIRSCHFELD: I\'ll defer to Dr. Reaman and then come back.

DR. REAMAN: I would also like to just follow up on the point that David
made. I made the comment earlier that we\'ve had so much difficulty
trying to do phase III trials internationally that it has really
precluded our even fantasizing about doing earlier phase studies. But
maybe we should think outside the box and, maybe since the critical
issue is really one of early phase studies, maybe really look at
creating opportunities for how we can do international phase I and phase
II studies and make specific suggestions. Maybe we can do it in such a
way that we don\'t have to be concerned about whether or not a site or a
study is being supported by federal funds. Maybe we could look to
industry in part to support this effort as well. But I would just like
to make that plea, that we not just throw up our hands and say we can\'t
do anything. Maybe we\'re really doing it the wrong way, trying to start
with phase III studies. Maybe we should really be starting with phase I
and phase II studies.

DR. SANTANA: Yes. Maybe a different model is ‑‑

DR. REAMAN: And use this as an opportunity to create that model, or at
least a group that would help create that model.

DR. HIRSCHFELD: Well, thank you, Dr. Reaman, because that was exactly
what I wanted to bring up. We\'re in the position where we\'ve issued
about 30 written requests now in pediatric oncology, and we want to be
sure that when we issue a written request ‑‑ and more than half of these
are for investigational agents ‑‑ that there\'s an opportunity for
someone to actually perform those studies and perform them in a timely
way. There might be some type of a clue in the fact that if a sponsor to
whom the written request is issued does submit a study report, they will
get a financial reward for completing that study report. So this might
be the arena to think about certain types of partnerships.

In answer to Dr. Santana\'s question, are there specific suggestions
that the committee might have of either areas to pursue or unresolved
issues that should be carried forward before we conclude today?

DR. SANTANA: Does anybody want to volunteer some answers for Dr.
Hirschfeld?

DR. HIRSCHFELD: Or recommendations of things that could be done right
now.

DR. SANTANA: Dr. Reynolds.

DR. REYNOLDS: I just want to return one more time to what Greg is
suggesting. We\'re doing new agent trials on an international basis, and
we\'ve got to have the availability, the access of those agents to the
international population. And it\'s really going to take you guys
talking to the FDA equivalents in those other countries to make this
happen without us chasing around trying to get this stuff done. We need
some help there.

DR. SANTANA: Susan.

DR. WEINER: For some reason at these meetings, it always comes to me to
make the moral point, but in this instance it\'s a follow-up to
something that David made. Families want rapid access to new agents, and
it really is a moral imperative for those kids with solid tumors and
those who have poor outcomes.

And we\'ve also heard at these meetings that it can take as long as 10
years for a drug that can become standard therapy in pediatric oncology,
and we also know from the various phase I consortia that it takes about
2 years to complete a phase I trial in pediatrics in the States alone.
So to think that that time could be cut in half is an extraordinary
notion for a family to consider and families that I deal with to be able
to say them.

DR. SANTANA: Dr. Vassal?

DR. VASSAL: Yes, I will fully agree on this proposal by Greg Reaman. I
like the point made before, that these studies should be considered at
the cooperative level and not at the individual level because the risk
is just to pick up in Europe in this way and this place one or two
investigational sites, and this should be done through a really
well-structured cooperative group working together with the same
approach.

DR. SANTANA: But within that model, within the cooperative group, you
could have smaller groups that address some specific issue with phase I
so that ‑‑

DR. VASSAL: Sure. I\'m referring to recent experience considering
pharmaceutical companies wanting to develop phase I and phase II which
we\'re not considering exactly the same way.

DR. SANTANA: No. I was referring to the model that in order to identify
what the hurdles are and to begin to address some of the hurdles, if you
wanted to get into the arena of international phase I studies, you
probably don\'t want to do that in 150 institutions, but within the
cooperative group, you identify some institutions you can collaborate
with and try to resolve the hurdles first ‑‑

DR. VASSAL: Absolutely, but not outside this.

DR. SANTANA: Dr. Morland.

DR. MORLAND: Yes. I couldn\'t agree more. I think probably Gilles and I
have the example of this where eight years ago the UK and French groups
came together in order to start undertaking joint collaborative phase I
and phase II studies, and we recognized that there were some regulatory
differences between the two countries, but broadly speaking the
philosophy of managing patients was absolutely identical. And I guess
that\'s the sense I get round this table today. The thing that fueled
our collaboration was access to a drug and an ability to do a study. So
there\'s nothing like learning by experience.

I think that Greg\'s point was well made in that actually to get on and
do a study as a proof of principle, if nothing else, and that the groups
can collaborate and cut through some of the regulatory issues in the
process is probably the way of driving this forward and actually proving
to us all that we can do it because I think it\'s probably easier than
we think it is going to be.

DR. SANTANA: Dr. Boos.

DR. BOOS: Yes. I\'m sure that today running early clinical trials as may
be mentioned in a written request is multinationally feasible. There\'s
no problem. We did it several times. There are many examples. If there
is financial backing and few institutions are involved, I think this is
possible.

One of the mistakes which often is done I think is that companies then
contact CROs in Europe they are familiar with and not the societies
which have access to the sites. This could probably become better.

With non-commercial trials, with investigator-initiated trials, I\'m
sure that phase II trials would be much easier because then in Germany
we have not the idea to bring everybody into this trial and that the
scientific advice you mentioned before would be helpful as it is really
inflexible response on the needs of GCP which can then be discussed.

And the third thing for phase III, I think Mark Bernstein mentioned the
Ewing\'s sarcoma trial is one where we are involved and is one which has
been done in, I think, currently five or six European countries and
jumped across the Atlantic now, and I think it is an example for what is
possible in these international links. As the experience of the
guidelines comes from industry trials and their problems, I would think
it\'s an enormously important thing ‑‑ and today is the best step in
this direction ‑‑ to look how is the pediatric society organized, what
really is running very good and take these good things and push them and
stabilize them and not put energy in new guidelines, new problems,
strong legal frames which destroy what we still have and does not enable
us to become better in other fields.

DR. SANTANA: Dr. Winick.

DR. WINICK: This may be repetitive but I think that in the context of
doing phase I and phase II trials, multiple countries and institutions
have adverse event report forms that I would guess are relatively
similar. Several people here ‑‑ I\'m sorry Malcolm isn\'t here ‑‑ just
went through the exercise in defining common data elements, and I think
that some of these things with respect to monitoring and making sure
that data exists ‑‑ I understand that process has come to something of a
roadblock, but I think that there are multiple tools already in place
that would truly facilitate international phase I and phase II trials.

DR. SANTANA: Yes, that\'s a good point. There are already a lot of items
that have been defined very well through some of the NCI mechanisms that
I think, if we adopt those and agree that everybody will use the same,
really will improve this process.

Dr. Shurin.

DR. SHURIN: You\'re looking at next steps, and it seems to me the next
step really ought to be for a small group of people to sit down and
enunciate what needs to be in place and then look for what works the
best. I don\'t think that would take long. I think you could probably
get a small group of people together for maybe two days and actually
make that happen.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: I think the specific next step really ought to be to decide
that there should be an international consortium to do pediatric phase I
and phase II studies in childhood cancer. So I would propose that as
being the next step and then following, as Susan suggested, putting
together a small working group to make that happen. Each of us already
has a consortium, and I don\'t think we\'re talking about doing these
studies in 500 institutions. We\'re talking about maybe 20 or 30
institutions in the U.S., 5 or 10 in the UK and in France and Germany.
So I would suggest the next step really is a recommendation maybe from
this committee that there should be an international consortium for
early phase studies in childhood cancer.

DR. SANTANA: Greg, who do you think will take ownership of that?

DR. REAMAN: The international consortium and I would hope that the FDA
would also take some ownership. I mean, this is our recommendation to
them. They invited us to this meeting. And I would hope, as they\'ve
invited federal regulatory representatives from abroad, that they would
continue to do the same and play a role in mediating the regulatory
challenges that we would face.

DR. SANTANA: Dr. Riccardi.

DR. RICCARDI: I think what we are looking for is for uniformity and high
quality and to be able to produce a certain number of studies. So,
however, I think that in this sense, at least from Europe\'s side, I
think the organization that has been built by the French and the English
group, now called ITCC, in which we have a European consortium, probably
will be the ideal starting point because one of the problems that we can
see with phase III trials, there are too many centers and bigger
differences. I think already we are reaching, at least in this
consortium, a certain degree of uniformity and capability also to work
together with colleagues in the U.S.

DR. SANTANA: Dr. Boyett.

DR. BOYETT: I\'m afraid I\'m listening to people who tried to do phase
III trials and all of a sudden they decided, well, it\'s very difficult
to do, so now maybe it\'s easier to do phase I trials. Well, I\'ll tell
you, I\'m involved with a group who are doing mostly phase I trials with
10 sites within the United States, and you\'re not going to avoid the
monitoring problem that you talked about in phase III. In fact, the
monitoring problem has even increased because the success to doing rapid
phase I trials is rapid communication of accurate, timely data regarding
toxicities, et cetera during the observational period that you define.
You have to have a really slick, good infrastructure for communicating
and getting that information and verifying that information in time to
dose escalate.

Also, you\'re not going to avoid the problem of having data safety and
monitoring boards because we had to instigate a data safety and
monitoring board for our phase I trials. So you have to figure out how
to integrate those in there.

So while it\'s laudable to do it, I think that you need to realize that
the monitoring, I think, is going to be more intense than it is in a
phase III where you have more time.

DR. SANTANA: Dr. Poplack and then Dr. Reaman.

DR. POPLACK: That may be the case and I don\'t think anyone was
suggesting that we do phase I trials because it involves less
monitoring.

(Laughter.)

DR. POPLACK: Not the case at all. We understand that.

But the virtue of doing phase I\'s is something alluded to by Riccardo,
that they require a smaller number of institutions. You can be much more
selective about the institutions. You already have, as was mentioned,
existing consortia that have the expertise. So a lot of the concerns
about quality control that you might address in larger group studies are
sort of off the board and taken care of. So I think that is an advantage
in many ways.

In following up on what almost everyone has, I think, suggested, I think
it would be wonderful if we could suggest as a committee that the FDA
consider bringing together their colleagues, European colleagues, and
the appropriate representatives of the different, important constituents
in this to sort of begin to pursue this in a really intensive way.
Whether it\'s around a single phase I study as an example or case in
point which might, in many ways, flesh out the specific issues or
whether it\'s to take a look at the existing regulations and find
commonality, I\'m not sure exactly what the appropriate way to do it is.
But I think it would be great if we could suggest that to you and if you
would take up the challenge.

DR. SANTANA: Dr. Reaman.

DR. REAMAN: I just wanted to respond to Dr. Boyett that he was preaching
to the choir.

(Laughter.)

DR. REAMAN: We come from a present and a past of consortia that do phase
I studies. So we are very well aware of the need for monitoring. I
don\'t think any of us is the least bit opposed to monitoring. It\'s
overcoming the obstacles and the barriers to that monitoring because of
the multiplicity of mechanisms and means of doing it. So I think it\'s
not to say that it\'s going to be easier. It\'s really that this is more
focused, more efficient. We already have some good models in place. We
also have phase I/II data safety and monitoring boards, and I think we
can do this and I think we should do this, more importantly.

DR. SANTANA: Dr. Vassal.

DR. VASSAL: Just two comments.

First of all, I think one of the main objectives could be to really
address early drug development in terms of phase II because clearly to
have in a relatively short time enough patients to really address the
activity of the new compounds with a recommended dose in such and such
disease and avoid these type of studies we saw on the previous ODAC
committee where the drug was given to 80 to 70 patients and we don\'t
have enough patients with a neuroblastoma, brain tumor, and so on to
really conclude. So it might be one of the aims of this international
consortium to really address in a timely fashion the activity of this
new compound, once it is established in terms of recommended dose, in
several diseases.

And the second point is you mentioned the regulatory body in Europe. I
just wanted to say for the record, there is no representative of EMEA,
but EMEA is clearly dedicated to pediatrics and pediatric oncology, and
they have been working on the guidance for registration of compounds in
childhood cancer. There is now a pediatric expert group and there is now
a therapeutic advisory group in oncology with pediatric oncology
experts. So clearly EMEA is wanted to be a real partner of this dynamics
in terms of pediatric oncology and improvement of the way to develop
drugs.

DR. SANTANA: Dr. Weiner.

DR. WEINER: The Best Pharmaceuticals for Children Act has in it a
provision that asks the FDA to describe its approaches to getting access
to new oncology drugs for kids. Those of us who worked on that
legislation did it for a very specific reason; that is, we were really
interested in addressing some of the barriers that have been brought up
today. And I would hope that the report, since it hasn\'t been filed,
would take the kind of broad approach that this discussion has taken and
would include the recommendation that this committee has made. This
committee doesn\'t review drugs. This committee was really brought
together and codified to be strategic with everybody around the table.
It\'s exactly this sort of conversation today and set of recommendations
that support that act.

DR. LUMPKIN: The only thing I would add ‑‑ I think you\'ve given us some
wonderful ideas and some things for us to begin to work with you on.
It\'s been a very interesting discussion for me as a pediatrician but
not from the oncology world, but from other parts of pediatrics. At
least my experience has been that international phase I/phase II studies
in other areas of drug development are clearly basically the norm and
where things exist. It\'s interesting to hear why, within the world of
oncology, that is not where we are at this point in time.

So I think, having been part of the discussion today, has been extremely
helpful to me and I think the ideas of getting our colleagues at EMEA,
our colleagues at Health Canada, the various consortia within the
investigator group together to see if we can come up with dealing with
some of these issues on the oncology products is obviously, as Dr.
Weiner says, one of the major emphases behind the BPCA. And we thank you
very, very much for the input today.

DR. SANTANA: Yes. I also want to thank all of our international visitors
for being here today and certainly expressing your points of view and
helping us through this conversation and also all of our American
colleagues who stayed until the designated time to have this discussion.
I personally want to appreciate Steve for his commitment to pediatric
oncology and to helping us resolve these issues. Thank you.

DR. HIRSCHFELD: Thank you, Dr. Santana.

DR. SANTANA: We\'re adjourned.

(Whereupon, at 4:04 p.m., the subcommittee was adjourned.)