FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY SUBCOMMITTEE

OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

8:05 a.m.

Thursday, October 30, 2003

The Ballrooms

The Hilton Hotel

620 Perry Parkway

Gaithersburg, Maryland

ATTENDEES

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)

STEVEN E. EBERT, PHARM.D.

Department of Pharmacy

Meriter Hospital

202 South Park Street

Madison, Wisconsin 53715

MARY GLODE, M.D.

Professor of Pediatrics

The Children\'s Hospital of Denver

University of Colorado Health Sciences Center

1056 East 19th Avenue (B158)

Denver, Colorado 80218

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)

ROSELYN EPPS, M.D.

Chief, Division of Dermatology

Children\'s National Medical Center

THOMAS TEN HAVE, PH.D.

Department of Biostatistics and

Clinical Epidemiology

University of Pennsylvania School of Medicine

ROBERT STERN, M.D.

Beth Israel Deaconess Medical Center

SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)

ELIZABETH ANDREWS, M.D.

Vice President

RTI Health Solutions

PATRICIA CHESNEY, M.D., Meeting Chair

Professor of Pediatrics

University of Tennessee College of Medicine

DAVID DANFORD, M.D.

Associate Professor of Pediatrics

University of Nebraska Medical Center

ATTENDEES (Continued)

SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)

(Continued)

ROBERT FINK, M.D.

Chairman, Department of Allergy and Pulmonary Medicine

Children\'s National Medical Center

NORMAN FOST, M.D., M.P.H.

University of Wisconsin Hospital

RICHARD GORMAN, M.D., FAAP

Pediatrician

Pediatric Partners

Ellicott City, Maryland

VICTOR SANTANA, M.D.

Associate Professor

Dependent of Hematology/Oncology

St. Jude\'s Children\'s Research Hospital

FEDERAL EMPLOYEES: (Voting)

DON MATTISON, M.D.

National Institute of Child Health and

Human Development, NIH

CHARLES RABKIN, M.D.

National Cancer Institute, NIH

LOIS TRAVIS, M.D.

National Cancer Institute, NIH

BENJAMIN WILFOND, M.D.

Bioethics Research Section

National Institutes of Health

PHYLLIS WINGO, M.D.

Centers for Disease Control and Prevention

INTERNATIONAL GUEST: (Non-voting)

PATRICK SALMON, M.D.

European Medicinal Evaluation Agency

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

SUSAN CUMMINS, M.D.

BARBARA HILL, PH.D.

LOIS LA GRENADE, M.D.

DIANNE MURPHY, M.D.

SHIRLEY MURPHY, M.D.

BINDI NIKHAR, M.D.

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

MARILYN PITTS, PHARM.D.

JONATHAN WILKIN, M.D.

ALSO PRESENT:

DAVID J. MARGOLIS, M.D., PH.D.

C O N T E N T S

TRACKING CANCER RISK AMONG CHILDREN

WITH ATOPIC DERMATITIS

WHO ARE TREATED WITH TOPICAL CALCINEURIN INHIBITORS

\* \* \*

AGENDA ITEM PAGE

CALL TO ORDER AND INTRODUCTIONS

By Dr. Joan Chesney 7

MEETING STATEMENT

By Mr. Thomas Perez 11

OPENING COMMENTS

By Dr. Dianne Murphy 13

By Dr. Jonathan Wilkin 14

REVIEW OF TOPICAL CALINEURIN INHIBITORS

By Dr. Bindi Nikhar 14

TOPICAL IMMUNOSUPPRESSANTS

(CALCINEURIN INHIBITORS) - ANIMAL TOXICITY

By Dr. Barbara Hill 23

POST-MARKETING ADVERSE EVENT REPORTS

By Dr. Marilyn Pitts 34

QUESTIONS TO THE PRESENTERS 41

STUDYING THE RISK OF CANCER WITH TOPICAL

CALCINEURIN INHIBITOR USE IN CHILDREN:

DESIGN ISSUES

By Dr. Lois La Grenade 75

PRACTICAL AND METHODOLOGICAL ISSUES

IN LONG-TERM FOLLOW-UP STUDIES

By Dr. Elizabeth Andrews 96

THE ROLE OF CANCER REGISTRIES IN

LONG-TERM FOLLOW-UP STUDIES

By Dr. Phyllis Wingo 114

QUESTIONS TO THE PRESENTERS 126

C O N T E N T S (Continued)

AGENDA ITEM PAGE

OPEN PUBLIC HEARING PRESENTATION

By Dr. David Margolis 144

By Dr. Patrick Salmon 149

DISCUSSION OF QUESTIONS 150

P R O C E E D I N G S

(8:05 a.m.)

DR. CHESNEY: I think it\'s time to get started. I wanted to welcome
everybody back from yesterday and particularly welcome all of you who
weren\'t with us yesterday. I think it was a very, very interesting
session, and we look forward to adding to it today.

Just a couple of preliminary comments. I think we learned a lot about
atopic eczema, but we also learned two other unique aspects which is
that Dr. Wilkin taught us that lanthanos means hidden from view. In my
mind, my brain went looking for laudanum. So that\'s why I made that
bizarre comment, and it took Dr. Fost\'s brain about 10 minutes to find
the right file. As you get older, you discover that brains work
strangely. But anyway, thank you for that comment, Dr. Wilkin.

(Laughter.)

DR. CHESNEY: Also he reminded us of the word \"elegant,\" that we should
always think to design studies elegantly as mathematical solutions are
derived which is most efficiently and neatly.

I also wanted to take time this morning to thank the many people at the
FDA who prepared the materials for us so elegantly. It\'s everything
that you wanted and not much more, and we really appreciate that. So I
hope I have everybody\'s name here appropriately. In the Division of
Dermatologic and Dental Drug Products, it\'s Luke Markham and Lisa
Mathis who were the medical team leaders, and Mary Jean Causemafamaro,
who is the chief of project managers and Margo Owens, who\'s a project
manager. And then in the Division of Drug Risk Evaluation, Mark Avigan,
who\'s the acting Director of the Division of Drug Risk Evaluation.
Then, of course, in the Office of Counter-Terrorism and Pediatric Drug
Development, which is pronounced OCTAP.

DR. DIANNE MURPHY: OCTAP.

DR. CHESNEY: Thank you.

(Laughter.)

DR. CHESNEY: Of course, Dr. Susan Cummins, who\'s a medical team leader,
and Rosemary Addy who is the project manager. So on behalf of the
committee, we really thank you very much for preparing everything so
efficiently for us.

Our first speaker for today is Dr. Nikhar. We heard from her yesterday.
She\'s a pediatrician and a medical officer with the Division of
Dermatologic and Dental Drug Products. Today she\'s going to briefly
review the topical calcineurin immunosuppressant inhibitors.

Thank you. My colleagues remind me that our Executive Secretary, who\'s
trying to get the computer to work this morning, needs to read the
conflict of interest, but before that, I guess we need to go around the
table and have everybody introduce themselves. So forgive me for
forgetting that. Dr. Murphy, do you want to start?

DR. DIANNE MURPHY: Dianne Murphy, Office Director for the Office of
Pediatric Therapeutics and OCTAP.

DR. WILKIN: Jonathan Wilkin, Director of the Division of Dermatologic
and Dental Drug Products.

DR. LA GRENADE: Lois La Grenade, epidemiologist, Office of Drug Safety.

DR. CUMMINS: Susan Cummins, Division of Pediatric Drug Development.

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

DR. FOST: Norm Fost, Professor of Pediatrics and director of the
bioethics program at the University of Wisconsin.

DR. GLODE: I\'m Mimi Glode, Professor of Pediatrics, Infectious Disease,
Children\'s Hospital and University of Colorado School of Medicine in
Denver.

DR. DANFORD: David Danford, Professor of Pediatrics, Section of
Cardiology joint division, Creighton University and the University of
Nebraska Medical Center in Omaha.

DR. FINK: Bob Fink, Director of Pediatric Pulmonology at Children\'s
Medical Center in Dayton, Ohio.

DR. ANDREWS: Elizabeth Andrews, pharmacoepidemiologist at Research
Triangle Institute in North Carolina.

DR. TEN HAVE: Tom Ten Have, biostatistics and epidemiology, University
of Pennsylvania.

DR. CHESNEY: Joan Chesney, pediatric infectious diseases at the
University of Tennessee Health Science Center in Memphis and St. Jude
Children\'s Research Hospital.

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

DR. EBERT: Steve Ebert, Professor of Pharmacy and infectious disease
pharmacist, Meriter Hospital, Madison, Wisconsin.

DR. GORMAN: Rich Gorman, engaged in private practice of general
pediatrics in Ellicott City, Maryland.

DR. EPPS: Roselyn Epps, Chief of the Division of Dermatology,
Children\'s National Medical Center, Washington, D.C.

DR. STERN: Rob Stern, Professor of Dermatology, Harvard Medical School,
and Chief at the Beth Israel Deaconess in Boston.

DR. MATTISON: Don Mattison, NICHD.

DR. WILFOND: Ben Wilfond, peds pulmonary, National Human Genome Research
Institute in the Department of Clinical Bioethics at the NIH.

DR. RABKIN: Charles Rabkin, medical epidemiologist from the Division of
Cancer Epidemiology and Genetics, National Cancer Institute.

DR. TRAVIS: Lois Travis, epidemiologist from the Division of Cancer
Epidemiology and Genetics, National Cancer Institute.

DR. CHESNEY: Thank you.

Now Tom Perez will read the conflict of interest statement.

MR. PEREZ: Good morning.

The following announcement addresses the issue of conflict of interest
with respect to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

The subcommittee will discuss how to approach long-term monitoring for
cancer occurrence among patients treated for atopic dermatitis with
topical immunosuppressants.

The topic of today\'s meeting is an issue of broad applicability. Unlike
issues before a committee in which a particular product is discussed,
issues of broader applicability involve many industrial sponsors and
academic institutions.

All special government employees have been screened for their financial
interests as they may apply to the general topics at hand. Because there
have been reported interests in pharmaceutical companies, the Food and
Drug Administration has granted a general matters waiver to Dr.
Elizabeth Andrews, which permits her to participate in today\'s
discussions.

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

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

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.

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

Thank you.

DR. CHESNEY: Thank you. Dr. Wingo has just joined us. I wondered if
you\'d mind introducing yourself for the record, please.

DR. WINGO: Yes. I\'m Phyllis Wingo and I\'m from the Centers for Disease
Control in the Division of Cancer Prevention and Control there.

DR. CHESNEY: Thank you. I would like to introduce a visitor. Dr. Patrick
Salmon is here from the European Medicinal Evaluation Agency. I wondered
if he would just stand for a moment so everybody could see who you are.
Thank you.

Now, my apologies again, but we need to have comments from Dr. Murphy
and Dr. Wilkin as to our mission today.

DR. DIANNE MURPHY: Dr. Wilkin tells me he has no new vocabulary word for
us today.

(Laughter.)

DR. DIANNE MURPHY: So I simply wanted to welcome everybody again. It\'s
one of our glorious autumn days today that we were missing out on
yesterday.

I\'ll just note, in contrast to yesterday where we had a molecular
entity of which we had decades of experience, we have today many of the
same issues in a molecular moiety of which we have really much more
limited experience, though we do have a clearly defined signal that is
already noted in the label. I\'m not going to say much more. I think the
presenters will be able to outline for us what the question is that
we\'re bringing to the committee today in reference to our ability to
again define the best risk management approach to the use of these
products.

Thank you.

DR. CHESNEY: Dr. Wilkin, do you have any introductory comments?

DR. WILKIN: Again, I would welcome the committee. Yesterday was a very
fruitful day for those of us at FDA, a lot of constructive, very helpful
insights, things that we hadn\'t thought of before, things we\'ll now be
looking for, and we\'re looking for that again today.

DR. CHESNEY: Thank you.

Dr. Nikhar, my apologies for your preliminary introduction, but we\'re
all very, very interested in hearing about these topical
immunosuppressants.

DR. NIKHAR: Good morning. My talk today covers an overview of topical
immunosuppressants. These were discussed in brief yesterday.

Starting with a brief introduction, this is the newest pharmacological
class for atopic dermatitis. These drugs were introduced in this decade.
They have a direct immunosuppressive action in diseases with an
immunological basis, and there are two currently FDA-approved products:
tacrolimus, FK506, the trade name being Protopic; and pimecrolimus, SDZ
ASM 981, the trade name being Elidel.

Going on to background, tacrolimus ointment was approved in December of
2000 and there are two strengths available. The .03 percent ointment was
approved for children 2 to 15 years of age, while the .1 percent
ointment was approved for adults. The indication in both age groups is
short and intermittent long-term therapy of patients with moderate to
severe atopic dermatitis.

Systemic tacrolimus, or Prograf, was first introduced for prevention of
allograft rejection and is now used in kidney, liver, and heart
transplantation.

Elidel cream 1 percent was approved in December of 2001. It is indicated
for patients 2 years of age and older for short and intermittent
long-term therapy in the treatment of mild to moderate atopic
dermatitis.

Both drugs were not approved for use in children less than 2 years of
age, and systemic absorption can take place in both adult and pediatric
age groups from the topical application of both drugs.

And currently the effects of topical immunosuppressants on the
developing immune system are unknown.

Now moving on to review some of the pharmacokinetic studies done for
both drugs. Starting with tacrolimus, here studies were done in both
children and adults. Pooled results from two PK studies in 49 adult
moderate to severe atopic dermatitis patients indicate that tacrolimus
is absorbed after the topical application of .1 percent Protopic
ointment. Peak tacrolimus levels ranged from undetectable to 20
nanograms per ml after single or multiple doses of .1 percent Protopic
ointment, and 45 out of the 49 patients had peak concentrations less
than 5 nanograms per ml.

A PK study of .1 percent Protopic ointment in 20 pediatric patients,
aged 6 to 13 years, showed tacrolimus concentrations below 1.6 nanograms
per ml in all patients. The absolute bioavailability of topical
tacrolimus is unknown. Using IV historical data for comparison, that is,
comparing it to Prograf, the bioavailability of tacrolimus from Protopic
in atopic dermatitis patients is less than .5 percent. And the lowest
tacrolimus blood level at which systemic effects can be observed is not
known.

Moving on to pimecrolimus, here too studies were done in both children
and adults. In adults treated for atopic dermatitis with 13 to 62
percent body surface area involvement for periods up to a year, although
most patients had blood concentrations at or below the limit of
computation, detectable pimecrolimus blood concentrations were less than
2 nanograms per ml. In 26 pediatric patients between 2 to 14 years of
age with atopic dermatitis and 20 to 69 percent body surface area
involvement who had twice-a-day application for 3 weeks, blood
concentrations of pimecrolimus were less than 3 nanograms per ml.

What is significant is that 20 out of the 23 children investigated had
at least one detectable blood level as compared to adults with 13 out of
the 25 investigated had a detectable blood level over a 3-week period.
In 22 pediatric patients, aged 3 to 23 months, with 10 to 92 percent
body surface area involvement, a higher proportion of blood levels
ranging from .1 to 2.6 nanograms per ml was seen. The inference drawn
was that this increase may be due to larger surface area to body mass
ratio seen in younger subjects.

A higher incidence of upper respiratory symptoms/infections was also
seen in the 3 to 23 months age group relative to the older age group in
these PK studies. So a causal relationship between these findings and
Elidel use cannot be ruled out.

Although all the factors that lead to higher systemic levels are not
known, these are some of the factors that may contribute: a higher body
surface area, younger age groups, especially the 3- to 23-month age
group as seen with pimecrolimus, and reduced skin barrier function, for
example, with Netherton\'s syndrome. Netherton\'s syndrome is an
autosomal recessive condition characterized by generalized erythroderma,
extremely high IgE levels and atopic diatheses, hair shaft
abnormalities, and reduced skin barrier.

Now moving on to some of the pediatric clinical studies that were also
done prior to drug approval. The use of Protopic .03 percent ointment
was studied in children 2 to 15 years of age by conducting two phase III
studies. In these studies, varicella zoster and vesiculobullous rash
were seen more frequently in patients treated with Protopic ointment .03
percent compared to the vehicle.

Elidel cream .1 percent was studied in two age groups, the 3- to
23-month age group and the 2 to 17 years age group.

In the 2 to 17 years age group, nasopharyngitis, influenza, viral
infections, pyrexia, cough, headache, and eczema herpeticum were
increased over vehicle in the 1-year safety study.

The 3- to 23-month age group had a short-term 6-week study followed by a
20-week open-label study as well as a 1-year safety study. In the
short-term study, pyrexia, upper respiratory infection, nasopharyngitis,
gastroenteritis, otitis media, and diarrhea were seen more frequently
compared to compared to vehicle. The adverse event incidence for those
in the open-label phase of the study who switched over to Elidel cream
from vehicle approached the incidence of those patients who remained on
the cream.

In the 6-month infant safety study, adverse events occurring more
frequently in the Elidel cream group compared to vehicle included
pyrexia, upper respiratory tract infection, cough, vomiting,
hypersensitivity, rhinitis, viral rash, rhinorrhea, and wheezing.

So the indication for use for both drugs is second-line therapy in the
treatment of atopic dermatitis. Both Protopic and Elidel are indicated
for patients in whom the use of alternative, conventional therapies are
deemed inadvisable because of potential risks or in the treatment of
patients who are not adequately responsive to or are intolerant of
alternative conventional therapies.

These are the proposed mechanisms of action for both drugs. Both
tacrolimus and pimecrolimus inhibit T cell activation by binding to the
same cellular receptor, the FK-binding protein, or macrophilin-12. The
tacrolimus or pimecrolimus FK-binding protein complex further binds to
calcineurin which is an enzyme vital for early activation of both T
helper cell types 1 and 2.

The following are the adverse effects of topical immunosuppressants.
Local effects commonly seen are: burning, pruritus, erythema,
irritation, edema, and urticaria.

These are some of the systemic effects: pyrexia; upper and lower
respiratory tract infection; nasopharyngitis; viral skin rashes, for
example, molluscum contagiosum, herpes simplex and zoster, eczema
herpeticum; influenza; and further, otitis media; gastroenteritis;
vomiting; diarrhea; streptococcal pharyngitis and staph infection; and
skin infection not otherwise specified. Now, lymphadenopathy has been
seen with both drugs, and although the etiology is reactive in most
cases, in the absence of a clear etiology or in the presence of acute
infectious mononucleosis, discontinuation is recommended and close
monitoring of such patients is then required.

The advisory committee has copies of both labels and these give a
further breakdown of adverse events comparing active treatment to
vehicle in different age groups.

I would like to mention the adverse effects of Prograf that are in
relevance to the adverse effects of this class of drugs. Patients
receiving Prograf are at an increased risk of developing lymphomas and
other malignancies particularly of the skin. The risk appears to be
related to the intensity and duration of immunosuppression. A
lymphoproliferative disorder related to Epstein-Barr virus infection has
been reported in immunosuppressed patients, and the risk of this
lymphoproliferative disorder appears greatest in young children who are
at risk for primary Epstein-Barr virus infection while immunosuppressed.

Now moving on to the potential long-term adverse effects of topical
immunosuppressants. Animal studies have shown an increased incidence of
malignancies with both topical tacrolimus and pimecrolimus. Lymphomas
were seen with both pimecrolimus and tacrolimus. Follicular cell
adenomas were seen with pimecrolimus, and skin tumors with concurrent UV
radiation exposure were seen with both drugs. These will be mentioned in
further detail by Dr. Hill in the next presentation.

So since the systemic use of calcineurin inhibitors is associated with
the formation of lymphoma and skin malignancies, low systemic exposure
from topical calcineurin inhibitors over a course of time leading to a
cumulative dose effect may lead to melanomas, non-melanoma skin cancers,
Hodgkin\'s and non-Hodgkin\'s lymphomas.

In conclusion then, the concerns that we have about the long-term side
effects of these drugs are as follows. Children from the age of 2 years
and upwards with off-label use expected in even younger children will be
using these medications on a short or intermittent long-term basis.

About one-third of children with moderate to severe atopic dermatitis
may continue to use these drugs into teenage and adult years, thereby
having a long duration of exposure.

Currently, we do not have long-term safety data on either tacrolimus or
pimecrolimus, and so post-marketing evaluation of topical
immunosuppressants is needed to evaluate this potential risk. And means
of setting up these prospective studies need to be discussed.

And that brings me to the end. Thank you.

DR. CHESNEY: Thank you very much. We\'ll have time for questions and
answers for the presenters after we\'ve heard these three presentations.

As an editorial comment, I realize now the only children I\'ve seen with
atopic dermatitis who have been on these immunosuppressants have been
under the age of 2 years, which just emphasizes the point you made, that
they will be used whether they\'re approved or not in that age group.

Our next speaker is Dr. Barbara Hill. She\'s a pharmacology/toxicology
reviewer with the Division of Dermatologic and Dental Drug Products and
was the primary reviewer for the topical immunosuppressants being
discussed today. In addition to her doctorate in pharmacology and
toxicology, she completed a post-doctoral fellowship at the National
Cancer Institute of the NIH. Dr. Hill will review the animal toxicology
data for the topical immunosuppressants.

DR. HILL: Good morning. My name is Barbara Hill, and as was mentioned,
I\'m a pharmacology/toxicology reviewer in the Division of Dermatologic
and Dental Drug Products.

In today\'s talk, I\'m going to compare the animal toxicology data
available for two topical immunosuppressants known as calcineurin
inhibitors that have recently been approved for the topical treatment of
atopic dermatitis. As previously mentioned, these two compounds are
Protopic ointment ‑‑ the active ingredient in this is tacrolimus which
was approved in December of 2000 ‑‑ and Elidel cream. The active moiety
is pimecrolimus, which was approved in December of 2001.

I will compare the two structures of these chemical moieties, discuss
the general toxicology associated with these compounds, and briefly
summarize the genetic toxicology, photoco-carcinogenicity and
carcinogenicity studies conducted for both drug products, and then
conclude with an overall summary of the available animal toxicology
data.

On this next slide are the structures for tacrolimus and pimecrolimus.
Even though their chemical formulas are different, as you can see on
this slide, their overall chemical structure is very similar, which is
not surprising since they both bind to the same protein and inhibit
calcineurin.

The potential immune target organs of toxicity that have been identified
in chronic animal toxicology studies include thymus, lymph nodes, and
spleen, and so based on this information, the nonclinical toxicology
results indicate that both compounds can be categorized as classic
immunosuppressive agents.

The results of the genetic tox studies conducted for both compounds is
summarized on this next slide. For both compounds, an appropriate
battery of in vitro and in vivo genotoxicity tests were conducted, and
the results of those studies showed that they were both non-genotoxic
agents.

However, it\'s important to note that not all carcinogens are direct
acting genotoxic, meaning DNA-reactive agents. There\'s a second class
of compounds referred to as indirect acting carcinogens, which do not
interact directly with DNA and the carcinogenesis is based on another
mechanisms. A couple of examples that fall into this category are
hormones and immunosuppressive agents.

In the next few slides, I will summarize the results of
photoco-carcinogenicity studies conducted for both drug products. The
objective of this study is to determine in a hairless mouse model if
dermal test article application combined with simulated sunlight
exposure can reduce the time to formation of skin papillomas compared to
simulated sunlight exposure alone. A positive effect in this assay is
referred to as an enhancement of the UV skin photo-carcinogenic effect,
which is defined as shortening of the time to skin tumor formation.

The results for both compounds are summarized on this slide. For
tacrolimus, it was demonstrated that for the vehicle ointment alone, it
enhanced the UV photo-carcinogenesis in this assay and that tacrolimus
ointment had an additional small effect beyond what was noted for the
vehicle ointment. For pimecrolimus, it was demonstrated that for the
vehicle cream alone, it showed an enhanced UV photo-carcinogenesis in
this assay and that pimecrolimus cream had no additional effect beyond
what was seen for the vehicle cream alone.

The results of the findings from this study were that a precaution was
included in the label of each drug product advising patients to minimize
or avoid exposure to natural or artificial sunlight while using the drug
product.

This next slide summarizes the carcinogenicity studies that were
conducted for both drug products. For tacrolimus, an oral rat
carcinogenicity study, an oral rat carcinogenicity study, and a dermal
mouse carcinogenicity study conducted with the final marketed
formulation were conducted.

It\'s important to note that for our division, we recommend that the
dermal studies be conducted with the final marketed formulation because
it\'s important to understand the potential carcinogenic effect not only
with the active ingredient, but with the combination of excipients used
in the product as well.

For pimecrolimus, an oral rat carcinogenicity study, an oral mouse,
carcinogenicity study, and a dermal rat carcinogenicity study, once
again with the marketed formulation, were conducted. In addition, a
series of high-dose studies were conducted in the mouse where the active
ingredient pimecrolimus was dissolved in ethanol and applied dermally to
the mouse for a duration of 13 weeks.

A couple of definitions before I go on to show you the results of these
studies. The first is that a treatment-related tumor is identified as a
statistically significant increase in the incidence of the tumor in
treated animals compared to vehicle control animals. The
treatment-related tumors that are expressed in both labels are expressed
as a multiple of human exposure based on AUC comparisons to the maximum
recommended human dose. In other words, the multiples of human exposure
are based on the systemic exposure obtained in animals compared to that
obtained in the clinical studies under conditions of maximal use.

This next slide summarizes results of oral carcinogenicity studies
conducted for both drug products, particularly focusing on any lymphoma
signal that was noted. The first two rows summarize the results of the
oral rat and oral mouse carcinogenicity studies conducted with the
active ingredient in Protopic ointment.

In the first row in the oral rat study at a dose of 3 milligrams per
kilogram per day, which is equivalent to 9 times the maximum recommended
human dose, the results of this study were negative, meaning no lymphoma
signal was noted.

In the second row in the oral mouse study at a dose of 5 milligrams per
kilogram per day, which is equivalent to 3 times the maximum recommended
human dose, the results of this study were also negative.

But it\'s important to note that it was determined that for both these
studies an adequate systemic exposure was obtained after oral
administration. Both these studies were conducted by administering the
active moiety in feed, and there was a limitation as to how high the
dose exposure you could get. You\'ll see a comparison of that in the
next slide when I show the results of the dermal studies conducted for
Protopic.

The third and fourth row of this table summarize the results of the oral
mouse carcinogenicity studies conducted with the active ingredient in
Elidel cream. At a dose of 45 milligrams per kilogram per day, which is
equivalent to 258 to 340 times the maximum recommended human dose, a
lymphoma signal was noted. And a dose of 15 milligrams per kilogram per
day was identified as a NOEL dose. This is the dose at which no effect
level was determined for the formation of lymphoma. This was equivalent
to 60 to 133 times the maximum recommended dose.

The next slide summarizes the results of the dermal carcinogenicity
studies, once again focusing on any lymphoma signals seen. The first two
rows summarizes the results of the dermal mouse carcinogenicity studies
conducted with Protopic ointment. This was conducted, once again, with
the final marketed formulation, and at a dose of 3.5 milligrams per
kilogram per day, equivalent to 26 times the maximum recommended human
dose, a lymphoma signal was noted. And the NOEL dose, at which no
lymphoma was noted, was identified as 1.1 milligram per kilogram per
day, which is equivalent to 10 times the maximum recommended human dose.

If we go back to the previous slide, you can see that in oral studies
conducted to support Protopic, in the mouse study the highest systemic
exposure they could obtain was 3 times the maximum recommended human
dose. So it\'s not surprising that no lymphoma signal was noted in this,
whereas we did see a lymphoma signal in the dermal mouse carcinogenicity
studies conducted to support Protopic ointment.

The third row of this table summarizes the results from the dermal rat
carcinogenicity study. At the highest dose possible, 10 milligrams per
kilogram per day, equivalent to 3.3 times the maximum recommended human
dose, the results of this study were negative, meaning no lymphoma
signal was seen. But this dose was once again the highest that could be
obtained, and it was limited based on the highest amount that could be
dissolved in the formulation. So we weren\'t able to get to a high
enough dose to potentially see a lymphoma signal.

The last three rows of this table summarize the results of the special
high-dose dermal mouse studies. These studies were, once again,
conducted with pimecrolimus dissolved in ethanol and applied dermally to
the mouse for a duration of 13 weeks. At a dose of 25 milligrams per
kilogram per day, which is equivalent to 47 times the maximum
recommended human dose, a lymphoma signal was noted. The NOEL, where no
lymphoma was noted, was identified as 10 milligrams per kilogram per
day, which is 17 times the maximum recommended human dose. At a higher
dose of 100 milligrams per kilogram per day, which is equivalent to 179
to 217 times the maximum recommended human dose, lymphoma was noted, but
at a shorter duration of treatment of 8 weeks.

So, in summary, the results of this slide show that the lymphoma signal
is dependent on dose and duration. At a higher dose, you see it at a
shorter duration of time, and at a lower dose, you see the signal at a
higher duration of time. The typical duration of treatment for
carcinogenicity studies is 2 years.

This next slide summarizes other tumor signals seen in carcinogenicity
studies conducted to support Elidel cream. The first four rows of this
table summarize results from the rat oral carcinogenicity studies. At a
dose of 10 milligrams per kilogram per day, which is equivalent to 40
times the maximum recommended human dose, benign thymoma was noted in
male and female rats. At a dose of 5 milligrams per kilogram per day,
which is equivalent to 32 times the maximum recommended human dose,
benign thymoma was also noted in male rats.

The NOEL dose in female rats was identified as 5 milligrams per kilogram
per day in this study, which was equivalent to 21 times the maximum
recommended human dose, and the NOEL dose in male rats identified as 1
milligram per kilogram per day, which is 1.1 times the maximum
recommended human dose.

The last row of this table summarizes the results from a dermal rat
carcinogenicity study conducted with Elidel cream, the final marketed
formulation, and at the lowest dose tested of 2 milligrams per kilogram
per day, which is equivalent to 1.5 times the maximum recommended human
dose, follicular cell adenoma of the thyroid was noted.

On the last few slides of this presentation I will provide an overall
summary of the animal toxicology data available for both drug products.

First, Protopic ointment and Elidel cream are topical immunosuppressants
based on the study results noted in general toxicology studies.

Neither tacrolimus nor pimecrolimus exhibited a genotoxic signal.

Both Protopic ointment and Elidel cream contain cautionary wording in
the labels to avoid sunlight exposure based on the results of the
photoco-carcinogenicity study.

A lymphoma signal was evident in a dermal mouse carcinogenicity study
conducted with tacrolimus ointment. A lymphoma signal was evident in an
oral mouse carcinogenicity study conducted with pimecrolimus. A lymphoma
signal was evident in the 13-week dermal mouse studies conducted with
pimecrolimus dissolved in ethanol.

The estimates of human systemic exposure data are highly variable and
are dependent on the maximum body surface area that is treated in an
atopic dermatitis patient. In other words, if you have an atopic
dermatitis patient with a larger body surface area involvement, you
would expect to treat that patient with a larger amount of the topical
immunosuppressant and potentially have a greater systemic exposure.

Also, it\'s important to note that systemic exposure is also dependent
on the severity of the disease and the disruption of the epidermal
barrier. If you have a disruption of the epidermal barrier, you would
anticipate a greater systemic exposure.

It\'s also important to note that the biologic plausibility of lymphoma
formation in local lymph nodes cannot be ruled out at this time. It is
acknowledged that demonstrating this effect could be technically
challenging, but it is possible that you could have a lower systemic
exposure but a higher local exposure to lymph nodes, and that may also
increase the risk for lymphoma formation.

Other tumor signals noted in the carcinogenicity studies include a
benign thymoma noted in the oral rat carcinogenicity study conducted
with pimecrolimus and follicular cell adenoma of the thyroid noted in
the dermal rat carcinogenicity study conducted with pimecrolimus cream.

So, in conclusion, based on the carcinogenic signals noted in the
nonclinical studies, registry studies were recommended as a phase IV
commitment for both Protopic ointment and Elidel cream to try to
determine the potential cancer risk associated with clinical use of
these products.

Thank you for your attention.

DR. CHESNEY: Thank you very much, Dr. Hill. You covered an incredible
amount of material very elegantly, and we look forward to asking you
questions.

Our last speaker for this session is Dr. Marilyn Pitts. She is a
pharmacist and safety evaluator with the Office of Drug Safety of the
FDA. Dr. Pitts will present the post-marketing adverse event reports for
these products.

DR. PITTS: Good morning. Today I will describe the post-marketing
adverse event reports of the topical calcineurin inhibitors. I will
provide background information including drug use data, as well as
describe our methods of identifying the adverse event reports. I will
separately describe the AERS adverse event profile associated with
pimecrolimus and topical tacrolimus. I will provide a description of
adverse event reports found in the pediatric population and the cases
with the most serious outcomes, death and hospitalization, and the
malignancy and nonmalignancy cases, as well as the pediatric infection
cases.

There are two topical calcineurin inhibitors available to the U.S.
market: pimecrolimus marketed as Elidel and topical tacrolimus marketed
as Protopic. Pimecrolimus was approved December 2001 for patients 2
years and older, and topical tacrolimus was approved December 2000 for
patients 2 years and older. However, only the 0.03 percent preparation
of topical tacrolimus is approved for children between the ages of 2 and
15 years.

Both pimecrolimus and topical tacrolimus are approved as second-line
agents only. Pimecrolimus is for mild to moderate atopic dermatitis, and
topical tacrolimus is for moderate to severe atopic dermatitis. Again,
both agents are not approved for children of less than 2 years.

We obtained prescription drug use data and drug appearance data from IMS
Health. Prescription drug use data measures the number of prescriptions
dispensed for each agent and is different from drug appearance data.
Drug appearance data is determined by patient visits to office-based
practitioners in the continental U.S. Since approval, there have been
more than 3.2 million prescriptions of pimecrolimus and more than 2
million prescriptions of topical tacrolimus dispensed. Based on drug
appearance data, we see that more than 50 percent of all pimecrolimus is
used in children between the ages of newborn and 2 years. Similarly,
appearance data demonstrates that a significant amount of topical
tacrolimus is used in children with almost 10 percent being used in
children between the ages of 2 and younger.

To identify possible adverse events associated with the topical
calcineurin inhibitors, we queried the AERS database. The AERS database
is an electronic database that originated in 1969 as the Spontaneous
Reporting System, or the SRS system. In 1997, it was replaced by AERS.
Approximately 3 million adverse event reports for drugs are located in
the AERS database.

We separately searched the AERS database for all reports of pimecrolimus
used by using pimecrolimus as a suspect agent. In addition, we
separately searched for topical tacrolimus by searching for topical
tacrolimus only as a suspect agent. We will review each of these
searches separately.

The following information concerning topical pimecrolimus represents our
post-marketing experience since approval of the product in 2001.

For pimecrolimus, we found 79 reports. There were 64 reports of U.S.
origin and 15 reports of foreign origin. There were 53 females and 23
males. Pediatric cases amounted to almost one-half of the pimecrolimus
cases. The majority of the adverse events reported for all ages are
found in the product labeling and 90 percent of the adverse events
reported involved the skin. We were particularly interested in the cases
with the most serious outcomes, and for pimecrolimus that represented
hospitalization and the cases of tumor growth and then the pediatric
cases.

There were 32 pediatric adverse events associated with pimecrolimus. The
majority of the patients received pimecrolimus for atopic or allergic
dermatitis. As well, the majority of the cases were of U.S. origin. The
cases were evenly split between males and females. The patients ranged
in age from 2 months to 15 years, and there was a median age of 2 years.
However, there were 14 patients that were less than 2 years old.

The adverse events seen in this population were primarily of skin
reactions. However, there were 2 cases of nonmalignant tumors and 7
cases of infections.

As well, there were 4 hospitalization cases. Patients that were
hospitalized were all less than 2 years of age. They were 4 months old,
6 months old, 9 months, and 18 months old.

An example of a hospitalization case involved an 18-month-old child who
developed a Staph. aureus positive adenitis and was admitted to the
hospital and treated with drainage, irrigation, and intravenous
antibiotics. Unfortunately, the report did not tell us the time of onset
of the adenitis relative to the pimecrolimus use.

A second case was of a child who was 9 months old who was admitted to
the hospital and treated for osteomyelitis, osteitis, and a soft tissue
infection. However, the soft tissue infection occurred 20 days after
starting the pimecrolimus.

There were 7 cases of infections associated with pimecrolimus use. 4 of
the cases were U.S. and 3 were foreign. The children in this
subpopulation ranged from 9 months to 15 years with a median age of 18
months. The two hospitalizations were previously reviewed. The
infections seen or reported included abscess formation, bronchitis,
eczema herpeticum, and keratitis, scarlatina, soft tissue infection,
Staph. aureus positive adenitis, and strep throat.

There were 2 cases of nonmalignant tumor growth in the pediatric
population. One case was of a 5-year-old who developed a granulomatous
lymphadenitis 49 days after starting pimecrolimus. The second case was
of a child of an unknown age who developed a facial tumor after starting
pimecrolimus.

The following information concerning topical tacrolimus represents our
post-marketing adverse event experience since approval of the product in
December 2000.

There were 183 cases found with topical tacrolimus. 164 were of U.S.
origin and 19 were foreign cases. There were 103 females and 74 males.
36 of the cases occurred in children 16 years old and younger. 95
percent of the adverse events seen in the overall population are found
in the product label, and 50 percent of the reports involved a skin
reaction.

The cases that we particularly interested in were three cases coded as
death, the pediatric population, the 5 malignancies and infection cases.
Interestingly, there were also 4 cases of renal failure or insufficiency
associated with topical tacrolimus use. As a reminder, this is a labeled
adverse event for the oral and the intravenous preparation but not for
the topical.

There were 3 topical tacrolimus cases coded with death as an outcome. 2
of the cases occurred in adults and 1 case occurred in a 3-year-old
child.

The 3-year-old use topical tacrolimus for 9 months prior to expiring
from an overwhelming staphylococcal pneumonia and sepsis. The patient
had used both 0.03 percent and 0.1 percent strengths of topical
tacrolimus.

There were 36 pediatric cases of adverse events associated with topical
tacrolimus use. The patients primarily used topical tacrolimus for
atopic dermatitis. 35 of the cases were U.S. and 1 was foreign. There
were 7 cases where the patients were less than 2 years old.

For cases reporting the concentration or strength of topical tacrolimus,
one-third of the cases reported using the adult formulation in the
pediatric population. The adverse events reported primarily included
skin and application site reactions. Additionally, there were 2 cases
reporting detectable serum levels and 10 cases of infections associated
with topical tacrolimus use.

In the 10 pediatric infection cases, 9 were of U.S. origin and 1 was of
foreign origin. The patients ranged in age from 13 months to 16 years.
The median age was 4 years. There was 1 death which we previously
presented, and 3 cases of hospitalization. The infections that were
reported included pneumonia/sepsis, eczema herpeticum, Staph. aureus
sepsis, chickenpox, warts, strep sepsis, herpes zoster, herpes simplex
keratitis, erythema, and erythema infectiosum.

There were 5 malignancies associated with topical tacrolimus use. All of
these malignancies occurred in the adult population. None occurred in
the pediatric population. 4 of the malignancies were in the U.S. and 1
was foreign. The median age of the patients was 52 years, with a range
of 28 to 56 years. 2 of the 3 cases reported an outcome of death. The
onset of the malignancies was 1 month to 6 months, with a median of 3.5
months. The malignancies that were reported included anaplastic large
cell lymphoma with metastases, B cell lymphoma, Kaposi\'s sarcoma, and 2
cases of non-Hodgkin\'s lymphoma. Again, systemic preparations are
labeled for possible lymphoma development.

We have reviewed the AERS post-marketing adverse event reports for both
pimecrolimus and topical tacrolimus. We found cases of serious outcomes
with both agents. The most serious outcome associated with pimecrolimus
reported was hospitalization and the most serious outcome reported with
topical tacrolimus was death. Additionally we found pediatric cases of
nonmalignant tumor growth with pimecrolimus and adult malignancies with
topical tacrolimus, as well as local and systemic infections with both
agents.

The pediatric AERS adverse event reports demonstrated off-label use in
children younger than 2 of years of age for both pimecrolimus and
topical tacrolimus. In addition, the pediatric adverse event reports
also showed that the adult formulation of topical tacrolimus has been
used in children.

DR. CHESNEY: Thank you very much, Dr. Pitts.

These three presentations are open for questions and answers. Dr.
Mattison.

DR. MATTISON: Just a comment, Dr. Chesney, to back up your editorial
observation. We\'ve looked at data from other prescription benefit
management companies and also have information suggesting substantial
use in kids under 2 years of age for both of these agents.

The questions, though, relate to the way that the preclinical animal
studies were done. I couldn\'t tell from the data that was presented if
the animals that were used were adult or immature in these studies.

DR. HILL: They were adult.

DR. MATTISON: They were both?

DR. HILL: Adult.

DR. MATTISON: They were adult. Because I guess I would be concerned
about creating a preclinical animal study that paralleled use in
developing humans and given that they\'re approved from age 2 on up, I
would be really interested in seeing some juvenile or immature animal
and then lifetime experiments with these agents.

The second question relates to endpoints. Given the data suggesting
substantial likelihood for modification of response to infectious
agents, what about also including in the developing and adult animal
studies infectious challenges?

DR. HILL: Both points are very good. Typically for the carcinogenicity
studies, they\'re conducted over the duration of the age life of the
animal, but you\'re not specifically focusing on starting with the
pediatric and then maybe stopping after a little period of time and
seeing if lymphoma happens. Those would be special studies and actually
a very good suggestion.

The challenges with infectious agents, like a host resistance model and
things of that nature, typically aren\'t done for drug products unless
you see something that you don\'t understand. And we did understand that
these were immunosuppressive agents, so we didn\'t feel that those kinds
of studies were necessary.

DR. CHESNEY: Dr. Santana and then Dr. Stern.

DR. SANTANA: I have two questions. One is for you and the other one is
for Dr. Pitts.

Tell me a little bit more about this animal model. It kind of goes in
the direction that was being asked before. What is the time of
development of lymphomas in these mice? You told us they developed
lymphomas, but you didn\'t tell us the time ranges in which they\'re
occurring from exposure to event. That\'s one question.

And the second is, have you looked at the immune function of these mice,
and do you see changes in lymph nodes, spleen, et cetera, that would
predict or preamble the development of lymphomas?

DR. HILL: Let me address the second part of the question first. That
goes back to the results of the general toxicology studies. What we did
see is we did see effects in the thymus, in the spleen, in the lymph
nodes, that are indicative of immunotoxic effects which are classic for
immunosuppressive agents. So that was a very clear signal.

And then for the design of the carc studies and the formation of the
tumors for lymphoma, the way a typical carc study is conducted is you
have exposure over the duration of a lifetime of the rodent, which is
typically a 2-year exposure, and then we analyze the tumors usually at
the end unless there are animals that have to be sacrificed in the
interim for lymphoma formation.

The lymphoma formation, which is very clear in the special high-dose
studies that were conducted in the dermal mouse, is really a matter of
dose and duration. If you give a higher dose, you\'re going to see it at
a shorter duration, and if you give a lower dose, you\'re going to see
it at a longer duration. So with the lower doses, quote/unquote, that
were given in the carc studies, you see the lymphomas later, but with
the higher doses, we saw it even as early as after 8 weeks of treatment.
So it really very much is dependent on dose and duration.

DR. SANTANA: Are there incidence rates for those developmental
lymphomas? You mentioned I think summary cases, but I didn\'t get a
sense whether it\'s a high incidence, it\'s a low incidence. I didn\'t
get a feeling for numbers-wise what are we talking about.

DR. HILL: In my opinion it\'s a high incidence. It\'s 50 percent or
higher and that\'s a high incidence for tumor formation, but that was
just specifically for the lymphomas.

DR. SANTANA: Then my second question, if the chair would allow, relates
to these adult patients that were in one of the last slides that were
shown that develop lymphomas. Do you know more about the comorbid
histories of these adults in terms of their risk of developing lymphoma
in comparison to developing lymphoma and getting this agent? Do we know
whether they were immunosuppressed from HIV, they were immunosuppressed
from other conditions?

DR. PITTS: We do know more. One of the patients, the Kaposi\'s sarcoma,
was an HIV-positive patient. Another patient ‑‑ I have the data. I can
get the details for you, but yes, most of the patients had other
concurrent illnesses.

DR. SANTANA: So these were not purely atopic dermatitis patients that
were getting this agent. They had other conditions.

DR. PITTS: They had other confounders that were present.

DR. SANTANA: But the drug was always used as a primary indication to
treat their atopic dermatitis. Am I correct?

DR. PITTS: Yes.

DR. SANTANA: Thank you.

DR. CHESNEY: Dr. Stern, then Dr. Rabkin, then Dr. Danford.

DR. STERN: I had one comment and a couple of questions. When we talk
about potential immune targets, I think we should very much talk about
the skin. If you look at the role of photo-carcinogenesis and risk for
skin cancer, the skin is clearly a very active immunologic end organ.

With that in mind, I had two kinds of questions. We know from our
experience with transplant patients, using these drugs or similar drugs
‑‑ in one case the same; in another case, similar drugs ‑‑ that there
are a couple of problems that are of greatly increased incidence. This
goes a little bit to the question next to mine.

One is papilloma virus infection, and I\'m wondering if we\'ve done
experiments there. I think that\'s of particular interest and importance
because, in fact, in dermatologic practice, these agents seem to have
their greatest advantage on the face and in the genital area, and
they\'re clearly carcinogenic, HPV types in the latter area, and in
immunosuppressed individuals, we know that not only are warts more of a
problem, but in carcinoma in situ and eventually genital carcinomas. So
I\'d be interested about how we\'re addressing that.

The other thing is in extrapolating from experience with systemic
immunosuppression, your studies, as I understand it, were really
essentially simultaneous studies. Yet, if you look at the transplant
experience, it\'s immunosuppression following substantial mutagenic
exposure. If you look at Australians versus Swedes, one of whom prior to
transplantation had on average much higher exposure to ultraviolet, the
Australians compared to the Swedes, and yet both countries, probably
more in Australia, have very strong programs for their transplant
patients of keeping them out of the sun. Once they\'re immunosuppressed,
the absolute incidence, age-adjusted, is somewhere around 20-fold higher
in Australian transplant patients controlling for age. So I\'m as
concerned about the subsequent exposure although, because of my first
comment, I do think that simultaneous or day-after exposure because of
inhibiting apoptosis with immunosuppression is likely to be important in
terms of the body not getting rid of cells that have mutated.

DR. HILL: You raise a couple of good points. I\'d like to address the
virus for the skin tumors. Animal studies are conducted so that they\'re
animals that are virus-free. Typically we don\'t ask for studies where
we would have them exposed to the virus and then expose them to the
active moiety. My personal opinion is I would anticipate you\'d see an
increased risk of the skin cancer in that case.

Then specifically for the increased carcinogenic risk, once again we
don\'t have an animal model that would specifically address that because
we don\'t have pre-initiated mice or rats and then expose them to it
with UV exposure and then see if there\'s an increased risk. So those
are not really animal studies that we\'ve done because I think it\'s
pretty well established ‑‑ I don\'t know how much additional information
we might get from that.

I just wondered if you had any more specifics. Maybe you were thinking
of a specific study.

DR. STERN: I know very little about papilloma virus beyond the clinical
and couldn\'t even speculate about how to design those. But for
photo-carcinogenicity studies, I would think the mouse model would work
where you take a set of mice and you irradiate them to an exposure where
you expect some tumor yield farther out, so you don\'t continually
irradiate them, and there are pretty well-established markers.

I\'d probably do three groups. One group irradiation and vehicle only,
stopping the irradiation well before you expect a large yield. The
second group irradiation and the immunosuppressant and continued
irradiation. Actually, I\'m sorry. Four groups, as I think about this.
The third group, just the same irradiation and a switch from vehicle to
active, and the fifth group, just irradiation and active and then a
switch to vehicle after the irradiation stops. I think it would be very
interesting to see the various yields in those four groups. And you
wouldn\'t need huge numbers of mice to power this, and you\'d have your
answer in a year basically.

DR. HILL: Thank you.

DR. CHESNEY: Dr. Rabkin, then Dr. Danford, and Dr. Ebert.

DR. RABKIN: I\'d also, Dr. Hill, like to echo the point about the fact
that these mice are viral free. Were they housed in SPF conditions with
very little bacterial challenge? Because that\'s one of the problems ‑‑

DR. HILL: That\'s correct.

DR. RABKIN: One of the problems with these animal studies is that it\'s
a very artificial environment, and it\'s very sensitive to the amount of
bacterial or other agnogenic stimulation from the environment.

DR. HILL: Well, to support that, though, they\'re conducted under GLP
conditions so that there is a standard across the board for everything.
There have been instances where we have recommended specific types of
studies that are different under different conditions, but we didn\'t do
that for any of these drug products.

DR. RABKIN: Then my second question is about the difference that you
noted between the sexes of the rats with the sensitivity to thymoma or
thymoma development. Is that due to differences in their background
rates or differences in the rates in the treated animals?

DR. HILL: It\'s hard to tell, but part of it might be due to the
differences in systemic exposure between male and female rats.

DR. RABKIN: Just in absolute terms of the incidence of thymoma, does
that have an equivalent incidence in untreated animals?

DR. HILL: Could you rephrase the question?

DR. RABKIN: You mentioned that the detectable level refers to increase
over background rates.

DR. HILL: Correct.

DR. RABKIN: And the increase was present at a lower dose rate in male
rats compared to female rats. Is that because the untreated male rats
have a low rate relative to untreated female rats or is it because the
male rats had a high rate at a different threshold than the female rats?

DR. HILL: I\'m not entirely sure but it\'s possible that the male rat
could have a greater sensitivity.

DR. CHESNEY: Dr. Hill, while you\'re up there, I wondered if I could ask
my question.

DR. HILL: Certainly.

DR. CHESNEY: Then we\'ll go on.

You mentioned that in your opinion, the incidence of lymphoma in these
animals was 50 percent or higher. That sounds very impressive ‑‑

DR. HILL: Depending on the dose too, dose and duration. If you have a
lower dose and longer duration, the incident rate may not have been that
high, but for the higher dose studies, that\'s true.

DR. CHESNEY: For those of us who are the uninitiated, could you compare
that to any other drug that has a similar high incidence of lymphoma
development or tumor development?

DR. HILL: For tumor development in general, my opinion is that the
lymphoma formations seen in these studies was higher than general tumor
formation seen in other studies. It\'s hard to make a direct comparison
because you have to make sure that you have exactly the same sets of
standards when you\'re doing them. It\'s better to run the studies side
by side. So when you\'re comparing across studies, it\'s difficult to
say. But in general, I would say that the lymphoma signal was strong
enough that I would consider it a valid signal. Sometimes you can get a
little bit above background and statistically and biologically it\'s a
signal, but this was high enough above background and statistically
significant that it\'s a strong signal in my opinion.

DR. CHESNEY: Thank you.

Dr. Danford.

DR. DANFORD: Imagining for a moment how this drug might be used
clinically, I\'m picturing a child with atopic dermatitis who\'s treated
with a high potency topical steroid, and then when we discover that the
clinical response is not what we want, then fairly promptly switch to
one of these agents. I\'m wondering is there any animal data or any of
the adverse effects data that speaks to the issue of possible synergism
between the exposure to steroids followed in rapid succession by one of
these agents.

DR. CHESNEY: I think you just need to stay up there, Dr. Hill.

(Laughter.)

DR. HILL: You raise a very good point. There are no animal studies that
look at co-administration of corticosteroids ‑‑ well, maybe first
corticosteroids and then switching to the topical immunosuppressant or
maybe concomitant use of those two, although I think the division would
agree that that\'s an important consideration and perhaps studies to do
that would be very useful to see the results.

DR. CHESNEY: Dr. Ebert, did you have a question for Dr. Hill also?

DR. EBERT: Yes. Mine is related to the doses that you used and looking
at the relative human doses and that those are generally expressed in
terms of milligram per kilogram per day. We\'ve talked a lot in here
about the fact that children, due to their larger body surface per
weight, tend to be at greater risk. I\'m wondering whether, especially
with the derm exposures, you\'ve thought about normalizing the doses to
humans based on a dose per meter squared as opposed to a dose per kilo.

DR. HILL: Actually the information I presented was ‑‑ I presented the
milligram per kilogram dose, but the maximum recommended human dose, the
multiples of human exposure are actually based on AUC comparisons, so
systemic exposure. So the comparison is the systemic exposure achieved
in the animals versus systemic exposure in humans under maximal use
conditions. Typically what we selected was in pediatrics in particular
because it did have a greater systemic exposure. So we looked at the PK
data and our biopharmaceutics reviewer determined what was the greatest
systemic exposure under maximal use conditions, and we used that to
calculate the multiples of human exposure. So that incorporates really
the body surface area because it\'s systemic exposure.

Does that address your question?

DR. EBERT: I think so. I guess I\'m just saying that if you were to use
dose per meter squared as opposed to dose per kilogram, my guess is that
your multiples would be smaller than you\'re seeing.

DR. HILL: They may be, but when there is systemic exposure data
available in humans and in animal studies, it is preferred to base it on
that. When you don\'t have any systemic exposure data, then we do it
based on body surface area, and it would be based on milligram per meter
squared per day doses.

DR. CHESNEY: Dr. Ten Have, then Dr. Gorman, and Dr. Mattison.

DR. TEN HAVE: Thank you. I have two questions, the first one for Dr.
Hill regarding the photo-carcinogenesis result showing that the vehicle
seemed to be photo-carcinogenic versus a much smaller carcinogenic
effect for the actual moiety element. Did you try to control for
differences between the vehicle and the moiety in the lymphoma animal
studies? It looks like that may have happened with the Elidel being
dissolved in ethanol.

DR. HILL: Well, in the carcinogenicity studies, in order for a tumor to
be determined significant, it has to be statistically significantly
elevated above the incidence seen in the vehicle control. So that
controls for the vehicle there.

The studies that were conducted with pimecrolimus just dissolved in
ethanol were additional studies that the sponsor conducted on their own.
We didn\'t necessarily recommend those studies, but that data was useful
to help us to get a feel for the dose and duration before you saw
lymphoma formation.

I just want to make a comment about the photoco-carc studies, because
you mentioned the vehicle. In the literature, it\'s been demonstrated
that vehicle can sometimes have a very great effect on enhancement of
photo-carcinogenic effect because frequently what happens with these
vehicles is you basically have an increase in the amount of UV exposure
that gets to the skin. The vehicle is part of the drug product and
that\'s what\'s going to be used. So if you see something increase in
vehicle, it\'s important for the drug product. Possibly the reason why
you don\'t see such a great increase with the active in the vehicle is
that you may have, in this system, maxed out what you would see. In
another system, you may see a greater effect.

DR. TEN HAVE: Yesterday we saw a vehicle that was not ointment, but
instead I believe peanut oil. So there are alternatives I think there.

The second question is for Dr. Pitts regarding the AERS registry search.
Two questions here. One is what was the time period for the data that
you retrieved from the AERS data set?

DR. PITTS: For the pimecrolimus, it was from marketing till August of
this year, I think August 21st.

DR. TEN HAVE: That would be how long?

DR. PITTS: From December 2001 to December 2002.

DR. TEN HAVE: About a year.

DR. PITTS: About 18 months or so.

And then for topical tacrolimus, from December of 2002 to I think August
of this year, about the same period.

DR. TEN HAVE: A second question is the time of onset for the
malignancies associated with topical tacrolimus ‑‑ the onsets range
between 1 and 6 months.

DR. PITTS: Yes.

DR. TEN HAVE: And there was a discussion about the comorbidity of these
patients, and I\'m not sure what the latency period is for these
malignancies. Can you comment on those onsets in terms of the known
latency period for these malignancies?

DR. PITTS: I think Lois can give me a little better information in terms
of the latency of the actual, but for these particular cases, the
28-year-old had a history of HIV, onset of 1 month. A 50-year-old had an
onset of 4 months. Another patient had an onset of 6 months, and another
patient, an onset of 3 months. So I think somewhere in the Prograf
label, there may be some language about an acceleration or a decrease in
time to occurrence, but I can\'t tell you what the natural history is. I
can\'t but I think someone else may be able to help us with that.

DR. RABKIN: I can address that a little bit.

DR. PITTS: Thank you.

DR. RABKIN: Both of those malignancies are seen very rapidly after the
onset of severe immunosuppression in the transplant setting and other
situations in which people have sudden loss of immune function. So post
transplant, within several months, lymphoproliferative disease that\'s
EBV associated is seen and these can rapidly progress to lymphoma, and
similarly Kaposi\'s sarcoma can be seen very rapidly after transplant
associated immune suppression and can be occurring within months.
That\'s in contrast to the usual latency for carcinogenesis which tends
to have a much longer period, including in the setting of immune
suppression, the carcinomas that occur tend to be much later.

DR. CHESNEY: Thank you. Dr. Gorman, Dr. Mattison, and Dr. Fink.

DR. GORMAN: I have a specific question for Dr. Pitts concerning one of
the cases in the tacrolimus database on slide 16, the 3-year-old who at
9 months had streptococcal pneumonia. Was that a domestic case, a United
States case? Was the child immunized with a commonly available vaccine
against streptococcal disease?

DR. PITTS: That was a foreign case. There\'s not a whole lot of detail
to the case. The patient I know had used both products, the 0.03 percent
and 0.1 percent, and we had the onset information. So I have no idea in
terms of the immunization history.

DR. GORMAN: Thank you.

The second question is for Dr. Hill, and it is looking for a slightly
different viewpoint on information. Is there a dose response to this
agent? If I understand these agents correctly, they bind to proteins
that then interfere with a phosphatase activity. Is there a dose at
which that activity falls to zero? So when we\'re dosing mice and rats
and children repetitively with higher and higher doses, do we
effectively run out of benefit and then only increase the risk?

DR. HILL: It\'s a good question. We don\'t have data that could really
address that at this point. There haven\'t been studies conducted in
animal models in vivo looking at when you give different doses and you
see lymphoma formation, when is the cutoff period where you still see
calcineurin inhibition, an efficacy effect possibly, and then when it
progresses on to lymphoma. Most of the calcineurin inhibition has been
in vitro and it\'s very difficult to extrapolate in vitro to in vivo
situations.

DR. GORMAN: Is there a whole cell model that might begin to answer that
question?

DR. HILL: Could you rephrase the question?

DR. GORMAN: Is there a model either animal or in a test tube that will
give you a dose-response curve that will tell you when you\'ve maxed out
on the response for this particular group of agents?

DR. HILL: Well, I think it would be difficult because I don\'t know of
an animal model that could mimic atopic dermatitis. So it would be
difficult to get that efficacy signal as well as the lymphoma risk.

DR. GORMAN: Thank you.

DR. CHESNEY: Dr. Mattison, then Dr. Fink.

DR. MATTISON: Three questions. One relates to the bioavailability. In
Dr. Nikhar\'s presentation, on the sixth slide, she indicates that
bioavailability of topical tacrolimus is unknown. Given that that\'s the
case, how are systemic exposures estimated or evaluated for this drug?

The second question relates to practice. Yesterday we heard that it was
thought that common practice among dermatologists is to encourage fairly
aggressive use of these topical agents initially and then tapering as
the skin response occurs. Is that also thought to be the case with
these?

Then given that these agents are used in immature individuals, what do
we know about the interaction of these agents with the development of
the immune system? Do they alter immune system development?

DR. NIKHAR: I will try and answer your PK questions. As far as the IV
bioavailability, it\'s about .5 percent, and as far as the oral
administration of Prograf and so on, the information I have is that in
adults with an average about 53 body surface area involvement treated
with Protopic, the exposure of tacrolimus is about 30-fold less, and
that\'s seen with oral immunosuppressive doses in kidney and liver
transplantations.

Then as far as your second question goes, yes. The use is limited to
about 6 weeks or less depending upon clinical response at present.

And the third question, the answer to that is that it\'s still being
evaluated. I can\'t really talk more, but some studies are being
conducted looking at the immune system, the interaction with vaccines,
and so on.

DR. CHESNEY: Dr. Stern, you had something immediately pertinent?

DR. STERN: To take up your point, I think the issues about these are ‑‑
and I\'d like to make a comment and then ask a question. It\'s my
perception as a practitioner that in fact there\'s a perception in the
community at large, in spite of that labeling, that among parents
particularly, that these agents are safer than even mild topical
corticosteroids. That goes to my question of do we have IMS data that
tells how many of these prescriptions are by primary care physicians
versus by specialists, because if an agent is supposed to be for people
who are intolerant or nonresponsive to first-line agents, we\'d expect a
high proportion of specialists prescribing.

In my own practice, which does not have very many children, but lots of
adults, I see this being given as a first-line drug to people where the
diagnosis is not necessarily even within the indications and certainly
not people who have had mild to moderate potency steroids because of, I
think, as we\'ve seen by sales, a very active place in the marketplace,
if you read the journals.

So I\'d like to know is this really being used and promoted in a way
that is consistent with the indications or is there evidence to suggest
that the perception of prescribers and in fact patients is that this is
safer than topical steroids and used more widely?

DR. CHESNEY: Dr. Pitts.

DR. PITTS: I can answer the question about IMS data. We don\'t currently
have IMS data on these specialties that are prescribing. I think we can
probably request that information, but right now we don\'t have that,
and I don\'t have any further information.

DR. CHESNEY: Dr. Fink. Dr. Wilkin, did you want to add to that?

DR. WILKIN: I share Dr. Stern\'s perceptions on I think what may be out
there. I\'m not implying that the manufacturers are presenting it this
way, but I saw really bold headlines in one of the throwaway journals:
\"Move over Steroids.\" Then the article talks about topical calcineurin
inhibitors.

I think there is a great enthusiasm for things that are new. This is not
just for drug products. This is for everything. In fact, I like
occasionally to read things about ancient Rome, and Tacitus who wrote
Agricola ‑‑ I think it\'s in chapter 29 or 30 ‑‑ is talking about the
young centurions and the Romans that want to make a name for themselves,
and there\'s this great opportunity beyond the unknown borders of the
frontier and it\'s very exciting. And the line is, omne ignotum pro
magnifico. Anything not understood is seen as glorious.

(Laughter.)

DR. WILKIN: I think quite literally everything new, whether it\'s a new
drug product or anything else, there\'s a lot of hope that goes into it.
So I think that plays into it.

Then I think there has been some, if you will, pharmaco fear mongering
about the topical corticosteroids. They have definite things that we
have to think about that would be considered potential adverse events,
but they really have been a stable workhorse. I think a lot of
physicians really understand the good and the bad and understand the
balance and how to use them very effectively. But I think what we\'re
talking about, the steroids versus topical calcineurin inhibitors,
really plays out in a lot of other areas of new drugs versus drugs that
have been on the market, new technologies versus ‑‑ I don\'t think it\'s
limited to pharmaceuticals.

DR. CHESNEY: Thank you. I had actually just given that same line to Tom,
but it was in chapter 28. So I just wanted to correct that.

(Laughter.)

DR. CHESNEY: Dr. Fink.

DR. FINK: This is a question I guess for Dr. Hill or Dr. Wilkin. Given
the fact that you have a fairly strong animal signal for lymphoma and
that you have at least human case reports of occurrence of skin
malignancies and that you\'re treating a non-life-threatening condition,
how much stronger does the signal have to be before the drug is
considered inappropriate for a non-life-threatening condition? I\'m sort
of wondering if you see it in 50 percent of rats, but the drug was still
approved for use, if it were at 75 percent, does it become unapprovable?
At what level would this drug be considered nonapprovable for a
non-life-threatening disease even though it\'s one that clearly is quite
bothersome to the individuals affected?

DR. WILKIN: I think the compelling piece for approval is that there is
this safety margin, in other words, the difference in the AUCs. Our
concern with the topical calcineurin inhibitors is we know from the
systemic exposures that it seems to be cumulative dose that has
something to do with the eventual development. We don\'t have in the
short-term studies really good evidence that these events are occurring.
We made them second-line therapies. We have in the labeling the
information about the animal studies. I think it\'s labeled so that
physicians can make good choices, and not every patient can take topical
corticosteroids. So I think there\'s a place for these products.

Our goal is to learn more, and when we learn more, we may have a better
understanding of the risk- benefit calculus that we may say they\'re
first-line therapies or we may go in the other direction and be more
restrictive. I think it\'s the issue of uncertainty right now.

DR. CHESNEY: Dr. Ten Have.

DR. TEN HAVE: This is a question for Dr. Wilkin and maybe Dr. Rabkin.
What is a margin of safety with these doses? Because we had a wide range
of margins ranging from 258 to 340 times the maximal dose in humans
compared to the rats down to 26 versus 17 times. Do you have a range
that you work with in terms of safety?

DR. WILKIN: I just gave away my only copies of the labeling. I think we
have incorporated these safety margins in the labeling. They\'re being
copied because we actually are going to share parts of this with the
committee. Maybe we could defer and come back to that.

DR. DIANNE MURPHY: I think what we\'re going to be doing is handing you
the patient package insert because we\'re going to incorporate into the
first question this risk management issue so that we can get some
feedback on that.

DR. CHESNEY: Dr. Ebert and then Dr. Epps.

DR. EBERT: It\'s kind of a corollary to Dr. Stern\'s question earlier,
but it seems as though part of the issue here is whether the adverse
effects are associated with suppressing the immune system versus
inherent carcinogenicity of the compound. Given the limitations of the
AERS data, do we have any ideas as far as the nature and types of
adverse effects for topical corticosteroids versus these calcineurin
inhibitors? Are the same types of adverse effects coming up for those
agents as well? Mostly yesterday I think we talked more about adrenal
insufficiency, but are there some of these same neoplasms that come up
in that database?

DR. CHESNEY: We did receive in our blue handbooks for the committee
copies of the package inserts already.

DR. STERN: And the patient information as well.

DR. CHESNEY: And the patient information. It\'s under tab 4 for those of
you who wanted to check it out.

DR. PITTS: Dr. Ebert, you\'re referring to the malignancies? I don\'t
believe we saw those particular reports for the topical corticosteroids.

DR. STERN: And I do believe there\'s a fairly substantial animal and
human data of photo-carcinogenicity with topical steroids, which is
largely a negative one essentially. Beyond vehicle effects, there\'s
little to suggest that for photo-carcinogenicity, topical steroids are a
problem.

DR. CHESNEY: Dr. Epps, but I think Dr. Wilkin wanted to make a comment.

DR. WILKIN: In response to the earlier question, what are the safety
margins, if you turn to that tab 5 and go to page 11, you\'ll see the
carcinogenesis, mutagenesis, and impairment of fertility section for the
labeling for one of the products. Towards the bottom of the large
paragraph in the middle of the page, it says, no lymphoproliferative
changes were noted in this study at a dose of 10 milligrams per kilogram
per day. Then in parentheses it says, 17 times MRHD, and you have to
read further where it says that\'s the maximum recommended human dose
based on AUC, which is area under the curve, comparison. So those would
be the safety margins that we\'ve placed into labeling.

DR. TEN HAVE: So most of those margins were above the safety margin of
17 in the studies that were presented.

DR. WILKIN: Yes.

MR. PEREZ: That\'s tab 4, by the way, page 11.

DR. WILKIN: Oh, yes. It\'s tab 4. If I said another tab, excuse me on
that.

Yes. In fact, you can read through and read what some of the other
findings were, and the longer I look at this, I can see 17 times for the
mouse dermal carc. No increase in incidence of neoplasms was observed on
the skin or other organs up to the highest dose of 4 milligrams per
kilogram per day. And that\'s 27 times.

We don\'t have some sort of standard at FDA on the safety margin. It has
a lot to do with the risk-benefit calculus. I would think that we could
find approval for a product that might be used over a short-term basis
that is rescuing a patient who is in severe distress from something that
is potentially life-threatening and they might actually have a safety
margin that literally is less than 1. But we do take the numbers and
think about the potential benefits from a product and try to weigh that.

DR. CHESNEY: Dr. Epps.

DR. EPPS: I guess I have kind of a comment for Dr. Hill and I guess a
point of information. To piggyback on what Dr. Danford said, patients
who are referred to me as a subspecialist usually are tried initially on
a class VI or VII steroid and then switched over to some of the immune
modulators rather than a potent topical steroid.

Also, I do think it\'s aggressively promoted to primary care providers
as something that doesn\'t cause atrophy and something that is perhaps
safer or an alternative because there are quite a few patients who have
never even tried steroids. They don\'t use emollients. They don\'t use
any of the other things that we use to treat atopic dermatitis. So for a
study, if you\'re going to do something in addition to the strong
topical steroids, which we use in older kids, followed by some of the
newer ones. You could do weak ones perhaps in animals.

Also there are people out there who are compounding these new drugs with
steroids. So you may want to find out if there\'s something synergistic
going on, whether that affects what\'s happening. Is it as effective or
is it increasing with suppression? So I would look at that too.

DR. CHESNEY: How can you do that? How can you just compound it with
anything you want?

DR. EPPS: Write the prescription and a compounding pharmacist does it.

DR. CHESNEY: Dr. Ebert, could you comment on that? I didn\'t realize
that they could mix it with anything they want to.

DR. EBERT: Yes. Extemporaneous compounding is a relatively common
procedure.

DR. CHESNEY: Hello.

(Laughter.)

DR. CHESNEY: So much for all our perseveration about some of these
issues.

Dr. Fink.

DR. FINK: Just a comment I guess. In some classes of drugs, a safety
factor of 17 ‑‑ if it was an antibiotic, it\'s hard to imagine a
physician prescribing 17 times the maximum recommended human dose or a
patient swallowing it. But as we heard yesterday, with some of these
topical agents, they seem to be fairly commonly used at doses that may
approach or exceed 10 to 20 times what most of us would consider a
prudent dose if not a maximum recommended human dose.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: One of these agents is also approved in an oral form. It\'s
for a more life-threatening indication. Are there ongoing studies in
that particular formulation that might give us some information in a
forward-looking mode?

DR. HILL: If you\'re referring to animal studies in particular, no,
there are not any studies currently ongoing.

DR. GORMAN: I was thinking of phase IV post-marketing studies for those
agents. If we\'re looking for signals of tumors, perhaps we could look
at the oral forms to at least know where to look.

DR. STERN: Well, there\'s a large literature on the calcineurin
inhibitors or rather in solid organ transplant patients. And there are
not just signals, there\'s clear evidence for both squamous cell
carcinoma and for lymphoma, both the so-called post-transplant part, but
also in terms of other forms of lymphoma with long-term therapy.

Let me briefly summarize the data on the calcineurin inhibitors used in
relatively low risk patients. If you take a group of Swedes and you
transplant them and you maintain them generally at fairly low doses of a
calcineurin inhibitor, sometimes in conjunction with another
immunosuppressant, often in conjunction with some corticosteroids
systemically, you see a small increase in the risk of squamous cell
carcinoma or a modest increase in the first 2 years. Beginning about 2
years after use and at least as far as the studies I\'ve seen, not very
dependent as much on dose, but as on duration of immunosuppression, you
start to see an increased risk such that the relative risk compared to
what\'s expected by year 5 exceeds a 100-fold increase in squamous cell
carcinoma.

It\'s also interesting, although I\'m interested about the papilloma
virus, if you look at genital neoplasms that are often papilloma virus
associated, there are modest increases in risk also in a time-dependent
fashion, but on the order of sort of 5 to 10, not 100-fold. So there\'s
no doubt that long-term immunosuppression with this class of agents is
in fact the sine qua non for making squamous cell carcinoma in the skin
in susceptible individuals.

If you take Australian transplant recipients who stopped going out in
exposure, their incidence rate approaches 38 tumors per 100 persons per
year of squamous cell carcinoma, in other words, an average of one tumor
every 3 years for every person who is transplanted, again beginning 2 to
5 years after transplantation.

If you take patients of particular interest to me and in fact some in a
therapy that is mainly used for psoriasis and cutaneous T cell lymphoma,
oral psoralin photo-chemotherapy which is a very excellent
photo-carcinogen and in fact is used in some animal
photo-carcinogenicity studies as the positive control for systemically
administered agents, if you take those individuals who\'ve had more than
200 PUVA treatments, which is a level that is shown to be associated
with a substantial, about 10- to 20-fold, increase in risk by itself,
and you treat them with cyclosporine, a drug that\'s approved for the
treatment of psoriasis, generally used at fairly low doses, typically
about 2 to 3 milligrams per kilogram, rather than the higher 5
milligrams or so per kilogram used in transplant patients, you see a
6-fold increase in their risk compared to what they had on the basis of
PUVA alone, and you see an incidence approaching, after 2 years of
exposure, 1 per person per year of squamous cell carcinoma of the skin.

So it\'s not a question of whether immunosuppression in the skin will
lead to an increased risk of squamous cell carcinoma. It\'s a question
of how much, how soon, at what doses, and what the level of risk will
be, and how we moderate that.

I think there are some very interesting questions in the pediatric age
group. One of the interesting things is that, to the best of my
knowledge, there are no robust data. There are two things. There are no
robust data on basal cell carcinoma risk in transplant patients.
There\'s some suggestion of modest increases in risk, but certainly not
the same as squamous cell carcinoma.

But we believe that the key interactions between sunlight, probably UVB,
and skin cells that predict basal cell carcinoma risk are either after a
very long latency or after childhood exposure. If you look in nature at
when sun exposure matters in terms of squamous cell carcinoma, it\'s
cumulative and in fact recent exposure has a real impact on subsequent
risk. If you look at basal cell carcinoma, the level of childhood risk,
after controlling for other risk factors, is the principal determinant.

So one question is with these patients in childhood, are we changing
something in terms of apoptosis of cells that are going to go on to
basal cell carcinoma 20 or 30 years later independent of their
continuous use?

Similarly, with melanoma, at least as I read the transplant literature,
there\'s relatively little evidence to suggest a very substantial
increase in melanoma risk with long-term immunosuppression. There are
some studies that suggest modest increases in risk with very long
exposure, but it\'s nothing like squamous cell carcinoma. But again, if
you look at when are probably the salient mutagenic events occurring for
melanoma, it\'s also probably early in life, the same kind of thing with
most types of melanoma, childhood exposure rather than cumulative
life-time exposure seems to be the main, at least UV determinant of
melanoma risk. So if you\'re changing how you\'re handling UV insult at
that presumably susceptible period, you may impact lifetime risk of
melanoma in a way different than we\'ve been able to observe or not
observe when we follow adults who are immunosuppressed for long periods.

DR. CHESNEY: On that sobering note, I think we\'re right on time, and
we\'re scheduled for a break. If everybody could return at 10 o\'clock,
we\'ll resume at that point.

(Recess.)

DR. CHESNEY: Could we get started please?

The first speaker for the second half of the morning is Dr. Lois La
Grenade. Dr. La Grenade is an epidemiologist in the Office of Drug
Safety, the Division of Drug Risk Evaluation. She is a British-trained
dermatologist and epidemiologist, and she will present on the design
considerations to be considered when studying the risk of cancer from
use of topical calcineurin inhibitors.

DR. LA GRENADE: Good morning. I am Lois La Grenade, and up until a
minute ago, my slides were perfect. I don\'t know what has happened.

(Laughter.)

DR. LA GRENADE: But in the interest of time, we\'ll proceed with the
presentation and I hope that you can follow as I can.

As you\'ve heard, I\'m an epidemiologist in the Office of Drug Safety,
and my presentation this morning will discuss some of the design issues
that are important in studying the risk of malignancies with topical
calcineurin inhibitor use in children.

For the first part of my presentation, I will discuss the methods that
are available generally in observational epidemiology. Then in the
second part, I will focus more closely on the methods that would be
appropriate to study the risk of cancer with long-term use of
calcineurin inhibitors.

In observational epidemiology, we have a limited number of design
methodologies. First of all, there\'s the case-control method, and
there\'s the cohort method, and then there are registries which are
really surveillance tools.

Case-control studies are basically retrospective in nature. That is to
say, we start the study after the disease of interest has already
occurred from the suspected exposure. We then compare cases who are
people with the disease of interest to controls who are people without
the disease of interest. What we compare is the frequency of the
exposure of interest between the cases and the controls.

Because the advantages of a case-control study are that it\'s fairly
inexpensive compared to the others, it can be done relatively quickly
within a few months or at most a year or two usually. And it\'s
generally useful for studying rare events, particularly those with a
common exposure.

However, because of its essential retrospective nature, there are a
number of disadvantages. It\'s subject to a number of important biases,
recall bias being a very common problem, and this is because the disease
occurs so long after the exposure occurred, you then have to go back and
try and get information on the exposure. Very often cases may
systematically recall the exposure differently from the controls, and
this leads to what we call recall bias.

It\'s also subject to selection bias. The cases may not be
representative of all cases. The controls may not be representative of
all controls.

And it may be unsuitable for studying diseases with a very long latency
period such as cancers.

It\'s also difficult to study diseases with a very rare exposure.

Cohort studies, on the other hand, are prospective studies. In a cohort
study, we compare essentially exposed to non-exposed persons. We start
with a defined group of people and they may be defined by a common
exposure, by a common disease, or by a place of residence. The
Framingham study in Massachusetts, is an example of a cohort study
defined by a place of residence, the Town of Framingham in
Massachusetts. And you follow your cohort through time for the
ascertainment of the disease or diseases of interest.

The advantages of a cohort study are that the exposure and the case
status are determined prospectively. So recall bias is minimized. All
cases can potentially be captured, so selection bias certainly in regard
to cases can also be minimized. Another advantage of a cohort study is
that you can study several diseases or outcomes at the same time.

Cohort studies are most closely related to the experimental design where
a toxin is administered and then you follow the subjects for outcomes.
As a result, there is a high acceptance of results generated by a cohort
study by the scientific community. And cohort studies often are used to
confirm findings that are found in quick and dirty case-control studies.

Now, the disadvantages of a cohort study is that they tend to be very
expensive. They require large sample sizes, particularly so for rare
disorders, and they take a long time, many years, sometimes many
decades. Because of the length of the cohort study, we often have
subjects dropping out for one reason or another with resulting problems
from losses to follow-up.

One of the ways of overcoming this disadvantage of length of a cohort
study is to use a retrospective cohort study, and the way this is done
is that you use a preexisting cohort, for example, an occupational
cohort or a drug-exposure cohort. Then you look in that cohort for cases
of the disease of interest, and then you compare the frequency of the
disease of interest or the incidence in your cohort to population
incidence rates in a method called the standardized incidence ratio.
This is a method what was first popularized in occupational
epidemiology.

Registries, which as I said, are surveillance tools are rarely little
more than rosters of subjects, subjects who are identified by a common
exposure, and those are exposure-based cohorts, and occupational cohorts
would fall into this category as well.

Or registries can also be disease-based. Our State and national cancer
registries are examples of disease-based registries.

Registries may either be complete or incomplete. Complete registries are
usually mandatory, and all subjects with the exposure under
investigation or the disease under investigation are captured and
entered into the roster. Incomplete registries are usually voluntary,
with subjects choosing whether or not to participate.

Registries can be used in a variety of ways in epidemiology. Exposure
registries can be used as cohorts, in which cases can be ascertained and
incidences calculated within the exposure cohort. Case-based registries
can be used as a source of cases for case-control studies. In general,
complete registries are far more useful in epidemiology and they can be
used to determine incidence rates for diseases as is done with our
cancer registries. Incidence of rare events can also be calculated in a
rare exposure registry.

Now we turn from general methods to the methods that would be
appropriate for the specific topic of investigating the risk of
malignancies with calcineurin inhibitor use in atopic dermatitis.

There are very special problems with cancer studies because cancer is a
rare event, and particularly in young people, in adolescents and young
adults. Cancers have a very long latency period usually in that many
years, sometimes many decades elapse between the exposure and the
clinical appearance of the malignancy. For this reason, the prospective
method, either the cohort or the registry, is ideal.

Case-control studies, as I said, are generally used for quick and dirty
studies, studies where a signal has been generated by case reports of an
association between a previously unsuspected exposure and a particular
disease.

In designing a cohort study for this purpose, it should be prospective,
as I said. The exposure assessment could then be done accurately and in
a standardized fashion. We could collect information on dose and
duration of topical calcineurin inhibitor use. And dose and duration
information on these two factors is very important in cancer studies and
in trying to do causality assessments. The cases can also be ascertained
as completely as humanly possible and as accurately as possible. In
addition, in a cohort study we could collect data on confounding and
other risk factors as well.

Cohort studies are expensive and require a lot of effort, and they\'re
generally indicated where there is good evidence of an association
between a disease and exposure. This good evidence could come from
clinical studies, from case-control studies, or from other studies, for
example, animal studies, and I will put forward the view that we have
good evidence in this case. We have good evidence from clinical studies
in humans with oral calcineurin inhibitor use for organ transplants, and
we have good animal toxicology data.

Cohort studies are also indicated when a new agent that requires
monitoring for its possible association with several diseases is
introduced into a society. Again, I think that the case of calcineurin
inhibitor use in topical treatment of atopic dermatitis fulfills this
criterion.

Fletcher and Griffin in 1991 wrote an article entitled International
Monitoring of Adverse Drug Reactions of Long Latency, and in it they
wrote, that for adverse reactions of long latency to be detected methods
have to be used that permit observation of the patients to be followed
for many months or years. An essential requirement is the establishment
of a cohort of patients who can be accessed later on at specified
intervals.

These are some of the important issues that we have to consider in
designing a cohort study for the development of malignancies with
calcineurin inhibitor use. In the next few slides, I will spend a little
time discussing each one of these features.

The background you have largely heard from Drs. Nikhar and Hill, who
have spoken before me this morning, but I thought it useful to summarize
it basically in these slides.

First of all, with the vehicles of both topical calcineurin inhibitors,
we have found enhanced photo-carcinogenicity. In animal carcinogenicity
studies, there has been a signal for both lymphomas and other systemic
malignancies. Use of oral calcineurin inhibitors in solid organ
transplants has shown that there is a high incidence of lymphoma and
cutaneous malignancies particularly. The risk is greatly increased, as
Dr. Stern has told us earlier this morning.

The objective of the study would be as outlined in the approval letter
for both products which required a phase IV commitment study to
investigate the risk of developing cutaneous and systemic malignancies
in children with atopic dermatitis who have long-term intermittent
treatment with topical calcineurin inhibitors.

Now, the outcomes of interest would be malignancies. Cutaneous
malignancies, including melanomas and non-melanoma skin cancers, and
systemic malignancies, including lymphomas, both Hodgkin\'s and
non-Hodgkin\'s, and other systemic malignancies.

I want at this stage to introduce a question of whether, bearing in the
light of the information that we have, we ought to consider the use of
an additional endpoint, for example, actinic keratoses. I will come back
to this point later on in my presentation.

We have to choose a study population. If this were to be a traditional
cohort study, we would choose a cohort of children ‑‑ and we define
children as being aged 2 to 16 years ‑‑ who had atopic dermatitis, and
we\'d follow this cohort for the next 10 to 15 years and document during
that time the type of treatment each child had received, the response to
treatment, the presence of confounding or other risk factors such as
sunlight exposure, skin type, disease severity and extent, and so on.
And we\'d document the occurrence of malignancies as they appeared. At
the end of the follow-up period, we would compare the incidence of
malignancies in subjects treated with calcineurin inhibitors to that in
subjects not treated with calcineurin inhibitors.

But there are difficulties with this traditional cohort approach. For
one thing, we\'d require very large sample sizes. It would take a very
long time, and we may find at the end of the follow-up period either
that most patients had used both calcineurin inhibitors and
non-calcineurin inhibitors or vice versa, that only a very small
population had used calcineurin inhibitors as treatment. What we might
find in that situation is that it would be difficult to compare. We
would have reduced power and we may, at the end of all that time, end up
with no answers.

An alternative method would be to use the occupational cohort or the
exposure cohort type of methodology. We could enroll a cohort of
calcineurin inhibitor users, aged 2 to 16, children who had used it for
atopic dermatitis, follow the subjects I think for a minimum of 10
years, possibly longer, and we could use as our comparator age-specific
population incidence rates for cancer. These we would get from our
cancer registries or data from national sources. We could then calculate
the standardized incidence ratio in a method similar to the occupational
cohort method. I believe that Dr. Stern himself has used this method in
a long-term cohort of PUVA-treated patients for psoriasis, studying this
exact question, the development of malignancies in the PUVA-treated
patients.

Now, there are difficulties, nevertheless, with this approach. We have
no U.S. national incidence data for most cutaneous malignancies. Dr.
Wingo is present today and she will speak to us later on exactly what we
can and cannot do with our national and State cancer registries. But
it\'s my understanding that we have limited information on cutaneous
malignancies, other than for invasive melanoma.

We may, therefore, have to extrapolate from data from other countries
which do collect such data such as Finland or from regional data in the
United States. We have, for example, the southeastern Arizona skin
cancer registry which does collect information on incident non-melanoma
skin cancers.

Now, this slide is courtesy of the SEER cancer statistics web site. What
it shows is the age-specific incidence for all cancers by gender. I use
this slide to illustrate the very low incidence of malignancies in the
age groups younger than 20. The incidence begins to rise in the mid to
late 20s.

This slide is similar, but I\'ve used data from the southeastern Arizona
skin cancer registry and I\'ve shown here the age-specific incidence by
gender for squamous cell carcinoma. Again, we see that it is low in the
very young age groups and it doesn\'t begin to rise until about age 30
or so.

Similar for basal cell carcinoma. It doesn\'t begin to rise until about
age 30.

This low background incidence rate of malignancies in young children and
young adults is going to have problems or implications for a sample size
and power later on. This is the reason for my showing them.

What I\'ve done, because of the issues that we are going to have with
power and sample size, I\'ve done a number of specimen calculations on
the various scenarios using different background rates for malignancies.

This particular slide uses data for all malignancies and some of my
information is not showing at the bottom of the slide, but it\'s for all
cancers in the 25 to 29 age group. The incidence is 6 per 10,000, and
the data is taken from SEER. What we have done is calculated possible
sample sizes for the traditional cohort method where we would have two
comparison groups with atopic dermatitis. We can see that to detect the
relative risk of 3, we would need a sample size of just over 20,000. To
detect a relative risk of 4, we would need a sample size in total of
12,000, and a relative risk of 5, a sample size of 8,000.

If we want to study all malignancies in the 0 to 19 age group ‑‑ again
this is SEER data ‑‑ but using a single group using the occupational
cohort analogy here, we would find that to detect a relative risk of 4,
we would need 14,000; of 6, 8,000; and of 8, 6,000 in a single group. So
this is probably doable.

However, if we looked at lymphoma, which has a much lower incidence rate
‑‑ and this is lymphoma, all types, in the 0 to 19 age group. The
background rate is 24.1 per million population annually. We can see that
to detect a relative risk even as high as 4, we would need 115,000
patients, and to detect a relative risk of 10, we would need 32,000
subjects.

Given these problems with the sample size and power, I thought it might
be useful to look at the problem from another angle. Perhaps we could
have a fixed sample size and then see what would be our probability of
not detecting a case when in fact we had a given relative risk.

So here I\'ve done sample calculations for a sample size of 10,000. If
we try to detect a relative risk of 4, we would have a 38 percent
probability of not seeing a single case. If we tried to detect a
relative risk of 8, we would have a 15 percent probability of not seeing
a case, and conversely an 85 percent probability of seeing a case. If we
had a larger sample size, say, 20,000, we would have a lower probability
of not seeing a case for a given relative risk. So one approach might be
that we could decide on a sample size and then decide what level of
certainty or uncertainty we\'d be comfortable with.

This slide just demonstrates graphically the same thing that was
illustrated in the table slide previously, that the higher our relative
risk goals, the lower the probability of us not finding a case for a
given sample size.

Another way in which we could boost our power and sample size would be
to have a multi-center or even a multinational cohort study, and I\'m
hoping that Dr. Salmon who represents the EMEA today will speak to this
issue of the multinational participation in a cohort study.

I come back to the possible use of additional endpoints in the form of
actinic keratoses. Actinic keratoses have traditionally been regarded as
precursors of malignancies. In fact, they are abnormal proliferations of
keratinocytes confined to the epidermis. More recently we\'ve studied
them in greater detail and have found, to a large extent, the cell types
in actinic keratosis is identical to that of squamous cell carcinoma and
abnormal cells in actinic keratosis possess the same P53 mutation as is
found in squamous cell carcinomas. Recently there\'s a movement to have
them regarded as squamous cell carcinomas in situ.

In some studies, up to 60 percent of all squamous cell carcinomas have
been found to arise in preexisting actinic keratoses, and actinic
keratoses are very rare in young people. They usually are a marker of
sun exposure and for that reason it might be useful for us to include it
as an endpoint. If we didn\'t have a duration of the study long enough
to pick up squamous cell carcinomas later on, we could use it as a
predictor perhaps of who would go on to develop squamous cell carcinoma.
Certainly we don\'t normally see actinic keratoses in very young people
and it would be a signal that all was not well.

We need to define our exposure both from a minimum definition at
enrollment to use as an enrollment criterion. We need to define what we
mean by long-term intermittent exposure to calcineurin inhibitors. Some
of the suggestions that we have toyed with in our division and the Derm
Division is whether 6 weeks exposure, continuous or intermittent, would
constitute a minimum definition of long-term intermittent, whether we
should extend it to 3 months, whether we should use a dose amount, the
use of 30 grams intermittently or continuously over a 6-week period. All
these are things for discussion.

Now, we also need to define exposure assessment during the study itself.
How are we going to assess the exposure? One method is to use the
issuing of a prescription plus self-report of use by the caregiver or by
the subject him or herself once they were old enough. We could also use
a combination of methods used in clinical trials to return unused
portions of the tubes, to weigh the unused portions of the tubes, but in
deciding how to define exposure assessment during the conduct of the
trial, we\'d have to consider the additional burden to participants and
consequent losses to follow-up that might result versus the obtaining of
more accurate information.

Another question is how would we ascertain malignancies. We could use
histopathological definitions. We could use international classification
of disease codes as our definitions. If we had an exposure cohort on
whom unique identifier information had been collected at baseline, we
could link with our national and State cancer registries certainly to
ascertain systemic malignancies. But we could not do this certainly in
the United States in most instances for cutaneous malignancies because
we have only limited data on cutaneous malignancies in our cancer
registries. Self-reporting of cutaneous malignancies has not been shown
in most studies to be reliable.

So we\'re left with the problem of how to ascertain cutaneous
malignancies. We couldn\'t use, as I\'ve said, linkage to State and
national cancer registries because these do not routinely collect the
information. Non-melanoma skin cancers, specifically basal and many
early squamous cell carcinomas, are often treated in office or patient
settings, so we could not use hospital records or hospital discharges to
ascertain cutaneous malignancies either. In addition, basal cell
carcinomas and actinic keratoses may be treated with a variety of
locally destructive methods with no samples even being taken for
histology. So if we use pathology logs to ascertain cutaneous
malignancies, we would be missing a substantial number of them.

Bearing all these things in mind, I would suggest that ascertainment of
cutaneous malignancies should best be done by periodic, possibly annual,
physical examination of the skin by a physician, preferably by a
dermatologist. I say preferably by a dermatologist because in at least
one study recently in Ireland, they compared general practitioner
diagnosis of lesions that were subsequently found to be malignant on
histology with the pre-histology diagnosis by a dermatologist, and
general practitioners got it right 22 percent of the time compared to
dermatologists who made the correct diagnosis of a malignancy 87 percent
of the time on clinical grounds.

Physical examination is particularly important if we want to capture all
the malignancies or as many as possible in a short enough period of time
so that we can have an early and accurate assessment of the risk.

The duration of follow-up is another important point. I would recommend
a minimum of 10 years for each subject. Ideally this should be longer,
but I think to reflect a minimum latency period of cancers, a minimum of
10 years would be suitable. It could be that the latency period is
shortened and we would get results sooner than 10 years, but I think the
minimum is 10 years.

Now, a very important aspect of such a study would be minimizing losses
to follow-up because this is an important source of bias in cohort
studies. Entire papers have been written on how to minimize losses to
follow-up in cohort studies. I\'m not going to spend a lot of time on
this except to say that vigorous methods will need to be pursued to
reduce losses to follow-up. I believe that Dr. Andrews, who speaks later
on in the morning, may address some of these issues.

We\'ll also need to incorporate statistical methods for handling losses
to follow-up. In our statistical analysis plan, we would be able to
calculate crude and adjusted incidence rates within our cohort and to
calculate the standardized incidence ratio. Depending on the numbers, we
might also be able to explore dose-response relationships and the
effects of other confounding factors such as disease severity and that
sort of thing, but that depends on how many cases we would find.

Now we turn to whether the registry design were used to investigate this
problem. A registry would have to be mandatory with all users
registered. If this were done, we would at least know the number of all
the patients or close to the real number of all patients who had used
calcineurin inhibitors topically. If we could ascertain all the
malignancies, the registry would probably be the fastest method for
getting incidence rates.

Unfortunately, however, there are problems with the registry method.
There is generally poor acceptance of mandatory registries by both
physicians and patients alike, and sometimes they go to the extent of
avoiding use altogether to overcome the problem of having to be
registered.

Registries are also expensive, perhaps not quite as expensive as cohort
studies, but they\'re expensive nevertheless, and we have probably
nowadays patient privacy issues to deal with.

Although we would get accurately the number of people who had used
topical calcineurin inhibitors, we would not be able, in a typical
registry, to get information on the dose and duration of exposure, nor
would we be able to get information on disease severity, on skin types,
and that sort of thing, other confounding factors. Again, we come back
to the problem that it\'s not possible to ascertain most skin cancers.

So in this slide, I thought I would summarize important factors that we
require in a study to investigate the risk of malignancies with
calcineurin inhibitors and how each of the possible design methods
measured up.

Exposure assessment in a cohort study would be good. It would be fair in
the registry situation because we wouldn\'t have detailed information on
dose and duration of therapy, for example. And in a case-control study,
this would be not very good largely because of the retrospective nature
of the study.

Outcome assessment would be good in a cohort study, but incomplete in a
registry because we would not be able to ascertain completely cutaneous
malignancies. Likewise, it would be incomplete in a case-control study.

The duration of both the cohort and the registry studies would be long.
A case-control study would be short, but we\'d have to wait 20 or so
years down the line before we could conduct it.

The cohort is probably the most expensive, with the registry coming in a
close second, and a case-control study being relatively inexpensive.

Both the cohort and the registry would require large sample sizes. A
case-control study would require probably a much smaller sample size,
but again, we\'d have to wait for a considerable time before we could
undertake such a study, and I do not believe that the public health
would be served by waiting 20 years to undertake a case-control study.

Risk factors and incidence could be calculated fairly well or could be
assessed fairly well in a cohort study. We\'d have incomplete incidence
in a registry and we couldn\'t calculate incidence in a case-control
study.

The relative risk we could calculate in a cohort study, not in a
registry, and the metric that we calculate in a case-control study is an
odds ratio which is an approximation of the relative risk but is not
itself the relative risk.

We could calculate the standardized incidence ratio in a cohort study
and for systemic malignancies in a registry, but not in a case-control
study.

On balance then, it would seem from the scientific point of view the
cohort study would be the method to choose because it has advantages
over the other two methods.

Nevertheless, if we chose a cohort study, practical issues remain: the
duration of follow-up, power, and sample size considerations, how to
ascertain the endpoints, how often, who should do this. We\'d have to
explore measures to reduce losses to follow-up, and we\'d have to decide
what level of uncertainty was acceptable.

Finally, I\'d like to acknowledge the help of Dr. Yi Tsong,
statistician, acting Director of Quantitative Methods Research in the
Office of Biostatistics, and he is present today to answer any
statistical questions that you might have.

I\'d like to also acknowledge the help of Dr. David Graham, Associate
Director for Science in the Office of Drug Safety.

Thank you.

DR. CHESNEY: Thank you very much, Dr. La Grenade, another very elegant
presentation.

Our next speaker is Dr. Elizabeth Andrews, and she will discuss the
practical and methodological issues for these studies. Dr. Andrews is an
epidemiologist and Vice President of RTI Health Solutions. Prior to
joining RTI, she developed the worldwide pharmacoepidemiology programs
for Glaxo SmithKline. She brings many years of practical experience with
drug safety monitoring for a variety of short-term and long-term events.

DR. ANDREWS: Thanks very much for asking me to present today on
methodologic and practical issues in doing a registry. Dr. La Grenade
has given us a lot to think about in terms of designing a study to
answer this question.

I\'m going to take a slightly different approach and step back and ask a
number of questions relating to methodologic design and analysis as well
as the practical issues where the rubber meets the road.

So, first of all, we need to think about when we would do a long-term
follow-up study, and there are three general circumstances.

One is when adverse events may not be manifesting until months or years
after treatment, which is the case in this particular case relating to
cancer.

Another example would be when adverse events might have been ambiguous
in clinical trial programs and in short-term therapy but might manifest
themselves clearly with long-term use. Yesterday\'s discussion gave us a
great example of adrenal suppression in long-term topical steroid use.

And a third example would be when adverse events may be too frequent to
have been observed in clinical trials. Again, the issue at hand meets
this criterion.

It seems there are several key questions we have to be able to address
before we can design a study. Are these drugs, the calcineurin
inhibitors, associated with cancer at a level that would warrant
modifications of current prescribing and treatment recommendations? We
need to answer that question.

We need to know what the baseline level of the risk of skin cancer and
lymphoma is in the pediatric population, and as we\'ve heard, we don\'t
know a lot about that, specifically around skin cancer.

And then we need to answer the question of what is the estimated
increase in risk that must be detected for safety assurance; namely,
what is our threshold for action?

With that in mind, how are we going to measure that increase? Do we
measure it through a relative risk or do we use a public health measure
of risk difference? For example, if the baseline 10-year risk of either
lymphoma or skin cancer in kids is 2 per 10,000, that\'s the best
estimate I could derive from the figures I looked at. And if we observe
through this long-term follow-up study a risk of 10 per 10,000, that
translates into a relative risk of 5. It sounds pretty scary. If we look
at the risk difference, that\'s a risk difference of 8 out of 10,000
over 10 years, translating into 1 new case of skin cancer per 1,000
patients exposed over a period of 10 years.

We need to understand what potential increase in risk meets this
threshold for action at a policy level. What\'s the regulatory need at
this point?

And what level of increased risk would be acceptable from a patient and
family perspective to receive the benefits of the treatment?

As we continue to discuss the goals of the study, we need to think of
whether the study will be an etiologic study or a surveillance study,
and that\'s already been discussed to some extent. In a typical
etiologic study, we\'re attempting to either detect or rule out some
specific increase in risk that we can define a priori. We use a standard
study design and we power the study to achieve our objectives.

In a surveillance study, however, we tend to take a different approach,
and that has implications for design as well as analysis. We use a
general standard study design, but in our analytic methods, we need to
think about how we review the evolving data over time in a qualitative,
as well as quantitative way.

An example of a surveillance study that I thought I would use today is
the international acyclovir pregnancy registry. This is a study that was
established back in 1984 to look at the exposure to oral acyclovir, a
drug used to treat herpes infections, following inadvertent exposure in
pregnancy. Those patients were identified and followed up to term and
beyond. The outcomes were identified through patients\' physicians to
identify infants with birth defects.

The frequency of birth defects in that study was compared to a
population expected rate, and that comparison was based on data
collected in a generally similar manner to the way the data were
collected in the registry. That study, after about 15 years, concluded
that the overall frequency of birth defects was similar in the acyclovir
exposed patients as in the general population, about 3.2 percent with a
very tight confidence interval compared with an expected rate of about
3.2 percent.

Now, you might not expect an increase in the risk of a specific birth
defect to actually be manifest in an increased risk of overall birth
defects, analogous to our situation here with cancer and all cancer
versus individual cancers. In this particular study, we determined after
following over 1,000 thousand pregnancies that the study had the ability
to detect a 7-fold increase in the risk of specific birth defects that
occurred in 1 out of 1,000. The study was at that point closed to new
enrollment because it was difficult to continue enrollment, and also
because of the marginal utility of additional data collection in
reducing the uncertainty around specific birth defects was very low.

Another key point in thinking about a study of calcineurin inhibitors
and cancer is whether to have a comparison group. Dr. La Grenade pointed
out a number of useful points here. This also goes back to the goal of
the study. Is it to detect a possible signal or is it to reduce the
uncertainty relating to a possible increase in risk?

A single-arm registry can be very useful to identify incidence of events
over a defined follow-up period. And it can identify if and when the
event rate exceeds a threshold of an expected rate, if you can measure
that threshold. It can identify characteristics of the patient
population that you might want to look at if you were doing a more
formal comparative study that might be confounders. In order to take
this approach, however, we need a very well defined estimate of the
expected risk which we have for lymphoma, but which we do not have for
the non-melanoma skin cancers.

A study with a concurrent comparison group can do some other things. It
can certainly establish whether the incidence of events is similar
between the exposed in the comparison group. It can explore the role of
potential confounders which would have been measured in both groups, and
it also can help assess a signal that arises in the exposed group.

I\'ve identified a potential scenario, and that is if we are looking at
a baseline rate of 2 per 1,000 cases of cancer over 10 years, what if in
the first 3 years we observe 2 cases out of 5,000? Well, that\'s more
than would be expected. Have we crossed the threshold? What do we do
with that information? It would be very useful to have comparative data
at that point so that we could begin to look at the distribution of
confounders rather than wonder if we have exceeded a threshold.

An example of a study that did use a comparison group is the Rheumatoid
Arthritis Azathioprine Registry that was started in 1984. The issue here
was that azathioprine, an immunosuppressant, was used in transplantation
and was associated with potential increased risk of lymphoma and other
lymphoproliferative malignancies. Transplantation is associated with a
significantly increased risk of cancers. Azathioprine was being used for
rheumatoid arthritis at a much lower dose. The lower dose use of
azathioprine also was associated increased risk of lymphoma.

This is a study that enrolled patients over a period of 10 years in
Canada, enrolled patients who initiated therapy with azathioprine, and
for each azathioprine patient, another 2 patients who were initiating
therapy with another disease modifying antirheumatoid drug. Patients
were followed up for a minimum of 5 years each for additional exposures
and serious events like lymphoma, all cancers, and some acute events.
Specifically excluded from these outcomes were non-melanoma skin cancers
because of the potential detection bias, as well as the potential to
under-ascertain these events.

The study was designed to enable the study to detect an increased risk
of around 3-fold with full follow-up. The most recent information that I
reviewed was after the end of the 10 years, and there should be another
5 years of information.

So this study is analogous to the situation that we\'re dealing with
here in a number of ways and is an example of a study that absolutely
had to have a comparison group because there would be an expected
significant increase in lymphoma in the azathioprine group compared with
the general population because there\'s an increased risk of malignancy
in patients with severe rheumatoid arthritis.

So we need to consider potential study designs that can include
longitudinal follow-up studies, case-control studies. These can be done
with de novo data collection. They can be done in existing databases,
and there can be variations on the design.

You\'ve already heard a little discussion about design of cohort
studies. There are a number of examples of looking at long-term events.
The azathioprine registry is one example. Patient registries; large,
simple trials follow this scheme.

And case-control studies. While I think that a case-control study would
be extraordinarily difficult in this particular case, I thought I would
point out that there are a couple of cases where case-control studies
have been useful in looking at antecedent drug exposure and outcomes
where there has been a significant latency period. One case is looking
at neural tube defects in infants and antecedent exposure to folic acid,
and don\'t forget the DES and vaginal cancer story. I\'ll also point out
the point that Lois made earlier, which is you can\'t define an
incidence rate from a case-control study.

So if we decide to set up a study, perhaps a longitudinal follow-up
study, we need to think about how to recruit patients. We need to think
about what are those methods for identifying patients. Will we go to
referral centers? Will we do something to recruit patients directly? As
we think about this, will these methods select patients who are typical
of users or will they be a highly skewed cohort, and does it matter?
Will the patients be newly treated, or can we include people who\'ve
already been on drug in the past?

When we look at inclusion criteria, in terms of indication and severity
of disease, will we try to increase the efficiency of the study by
selecting high-risk patients, patients perhaps with substantial sun
exposure? Will we perhaps look for older patients who might have a
higher rate of background cancer? Maybe adults. Or should the study be
representative of the typical user population? That depends on what
you\'d like to extract findings to.

And if there is to be a comparison group, will this comparison group
have the same baseline risk as the exposed group? Well, in a
nonrandomized study, we know the answer is no. They will have a
different risk. Maybe that\'s okay, but you need to know what the
differences are by collecting enough information to measure this and
understand what analytic methods will be used in the analysis to control
for this, for example, propensity scores.

In looking at exposure, there\'s the question of what\'s the minimum
exposure that\'s required in order to qualify someone for the study, and
then how much information on exposure to these and other drugs will be
needed over the course of the study, what level of detail. And then what
periodicity of follow-up will be needed over that 10-year period or
5-year period in order to make sure that we\'ve adequately captured the
information?

In measuring outcomes, well, how will we do that? Will we allow outcomes
to be reported by the patient? Will we abstract medical records from the
patient\'s treating physician? Will there be required physical exams
periodically to identify skin cancers that might otherwise not be
identified? Will we link the patient records with cancer registry,
National Death Index, or other data files that are already in existence
with outcome data?

What level of detail will we collect?

And what biases might be expected in our data collection? For example,
in the calcineurin inhibitor group, we might expect to see a higher rate
of reporting of skin cancer even if there isn\'t an increase, if there
is that perception, just as in a study of topical steroids we might see
a higher reporting of short stature irrespective of the truth.

So we need to consider confounding, other treatments, other conditions.
I would give some thought to the occurrence of asthma frequently in
atopic dermatitis patients that might be distributed equally across the
comparison groups. It\'s certainly worth considering.

And there will be other variables that will be published in the
literature after the time the study has started, and there will be the
semi-annual discussion of whether the study needs to be modified to take
into account the new data on potential confounders.

I think it has already been mentioned in the writing of the analysis
plan, one needs to consider analytic methods that will handle
time-dependent variables. If patients are enrolled over a series of
years, then those patient characteristics at enrollment will be
different from year 1 to year 2 to year 3. Medication exposures will
change over time. We need good methods for grouping, lumping,
considering different exposure categories. Potential confounders may
change over time. And there will be the unanticipated events and
practice patterns that will change, and the study will need to be able
to handle that in the analysis.

So having said that, the ideal study design would be a long-term
follow-up study in which there was an exposed and unexposed group that
was recruited with the same baseline risk. Exposure measurement would be
handled perfectly. Dose and duration of all relevant treatments and all
potential confounders would be ascertained. Outcome measurement would be
complete in both groups. Follow-up would be sufficient to observe all of
the outcomes of interest. Maybe that\'s 10 years. Maybe it\'s 20. And
the power. Well, the study would need to be able to detect or rule out
an increased risk of whatever your notion of the threshold for action is
over the expected or observed in the unexposed group.

However, the ideal is rarely practical, and that\'s what I intend to
address next. In thinking about where the rubber meets the road in study
designs, we can turn to some examples and think about bigger issues of
how do we implement a study like this. We can look at a number of
examples, but there are two characteristics of studies that are
inversely related that I think are important here.

One is study complexity and the other is study size. Here I\'ve taken
study size from small, being 1,000 or so, up to large, tens of thousands
of patients. And then there are studies that are very simple that may
collect data annually by mail up to a highly complex study where we may
be doing routine skin examinations on an annual basis.

We do these highly complex studies all the time. These are our
randomized clinical trials, and there is a reason they\'re small. We do
large safety studies that tend to be very, very simple, but the studies
up in the upper right quadrant where we do highly complex follow-up with
physical exams with large numbers of patients are typically studies that
have been designed to address major public health issues like the
Women\'s Health Initiative, the Physicians\' Health Study, the ALLHAT
study.

So some of the things that need to be considered in going into this
enterprise are the cost of the study, not insignificant.

Equally important would be the opportunity costs to all involved. That
means the time and effort, as well as money, that will be spent by
regulators, sponsors, physicians, and patients in addressing this
question at the expense of other things they might be doing.

We need to also consider the potential indirect impact of doing the
study. If a major study is launched to look at calcineurin inhibitors
and the risk of cancer, what will the impact be on physician treatment
choices knowing the study is out there? Will it impact adversely
prescribing behavior, complaints behavior by patients and their family,
and will there be some additional impact on reimbursements?

Then my fourth question here is when is it reasonable to do this kind of
a study? What are the benchmarks and what is standard practice? There\'s
not a whole lot of experience to share in this respect.

Well, the key issue in making a study like this successful is a high
retention rate over multiple years of the study. There are a number of
tools to help maximize follow-up, and I\'ll get into some of them.

Retention really has at least two components. One is the ability to
track and locate patients. Can you find them? And the other is
participation. If you can find them, are they still willing to
participate in your study? Tracking can be done in a number of ways and
can be done very, very successfully. It involves keeping up with a
patient and maybe a neighbor, next of kin, knowing when they move, and
getting new contact information. It also involves linking patient
identifying information against publicly available data that can help
track them down, all conducted with IRB approval.

There are a number of studies that show that you can locate people at a
high rate over many years. One example is the Piedmont Health Survey of
the Elderly which was able to track 99 percent of an elderly population
over a period of 10 years, and there are other examples showing very
high rates of tracking over many years even without intervening contact.

I think there are special issues relating to follow-up of kids over time
into adulthood. Many of them ‑‑ and I hope mine will be one of them ‑‑
will leave home when they go to college.

(Laughter.)

DR. ANDREWS: That just proves that\'s another issue of tracking. So we
need to consider those various factors that make the study more complex.

Study participation. Are people interested and willing to follow up?
Really, there is a lot of literature and there are a lot of examples. I
didn\'t bring many specific examples, because everywhere I turn, the
answer I get is the epidemiologist\'s answer to everything, which is
\"it depends.\" And it really does. It depends on the mode of data
collection. If data collection is done by mail surveys, the response
rate is going to be very, very low. Not always. I\'m involved in a study
where we\'re getting over 95 percent follow-up in quarterly mail
surveys.

It depends on the periodicity of contact. Participation increases when
there\'s a frequent level of contact.

Salience of the study to the patient is key here, and so it needs to
capture the interest of the patient and the parent.

Incentives are critically important. They don\'t have to be large
incentives, but appropriate to keep people involved.

And the burden on the participant has to be minimized.

Now, there are special considerations in pediatrics. You have both the
patient and parent participating, so that\'s two people or maybe three
people who have the opportunity to say I\'ve had it, I want out of the
study. You also have changes in consent over time, giving you more
opportunities for people to think about whether they want to continue on
in the study.

So my advice would be to plan for annual attrition, but that should be
based on the methods that are selected and you can select a study design
that can optimize patient follow-up. Probably you would use a mixed mode
of data collection. Certainly in-person interviews is very helpful, but
maybe considering mixed modes of data collection, mail, telephone,
visits.

One other issue of practical consideration that is incredibly important
and that is the issues of IRB approvals and HIPAA privacy concerns.
We\'re all struggling with this new environment now in which IRBs would
normally have approved studies that looked quite reasonable and are
having second thoughts. When you take a study design that looks a little
novel, you may have to go through two or three iterations before
convincing them that it really is a worthwhile study.

A key issue that was raised in Dr. La Grenade\'s presentation was the
issue of a mandatory registry. I would just point out that if the study
is to be a study, then an IRB will not approve a study in which
treatment is conditioned on participation in research. So that would be
an issue, and I would suggest that a mandatory registry probably is not
a viable option.

We need to consider in the design who gives assent and consent, when
that occurs, how often that occurs, how does it change over time.

What IRB approvals will be needed? Will there be a central IRB and lots
of local IRBs?

And if the study involves chart abstraction to validate outcomes, then
you might need to consider HIPAA waivers in the institutions where the
charts would be obtained.

So in conclusion, considering a study design like this requires some
epidemiologic expertise in addition to folks who have been in clinical
trial design because the design and the analytic methods and the
practical methods really approach more an epidemiology study design or
survey.

The key focus in the design must be a long-term retention strategy.

The study must minimize burden to the patient or the dropout rate may be
so high as to render the study meaningless.

And the successful design will be a compromise between the ideal and
what\'s actually practical.

But fundamentally, back to basics, the design must be tailored to the
ultimate goal of the study, and I\'m not sure that we\'re clear what the
ultimate goal of the study would be.

Thank you.

DR. CHESNEY: Thank you very much, Dr. Andrews, for a very clear
discussion of the issues involved in long-term follow-up studies.

Our last speaker for this morning is Dr. Phyllis Wingo. She is an
epidemiologist and Chief of the Cancer Surveillance Branch of the Cancer
Division of the Centers for Disease Control and Prevention. Her primary
responsibilities include the National Program of Cancer Registries and
the design, conduct, and analysis of descriptive epidemiologic research
on trends in cancer incidence, mortality, survival, and patterns of
cancer patient care.

DR. WINGO: Good morning, everyone. I\'d like to thank Susan Cummins for
inviting me to talk about cancer registries in the United States. Before
I start my presentation, I think it\'s important to make clear we\'ve
been talking a lot about exposure registries, and now I\'m going to
switch gears slightly and talk about disease registries.

Briefly I\'m going to talk about the cancer registry infrastructure that
currently exists in the United States. I think it\'s a very strong
infrastructure, and as I will show you, it is nationwide, and we do have
data for every State. I\'ll talk about what kinds of data are available
in the population-based cancer registries.

I\'m also going to talk a little bit about data quality, and the reason
I\'m going to talk about data quality is that part of the registry
infrastructure is fairly new, and because it\'s fairly new, not all of
the States are in a place where they should be participating in special
research studies, but many of them are. And I\'ll describe that to you.

I\'ll do that description through the combined publication of cancer
data that currently exists. This publication combines information from
the very long-term SEER program, as well as the National Program of
Cancer Registries from the Centers for Disease Control.

I\'ll also give a little bit of information about follow-up. Again, this
is follow-up of cancer patients as opposed to follow-up of persons
exposed to a particular drug. And I\'ll then try to summarize.

I\'m not going to go through a 70-year history of cancer registries in
the United States. What I would like to say is that cancer registries
have been around for a very long time. They started with a bone sarcoma
registry in the 1920s that was set up by the American College of
Surgeons, which is still around today. The standards that were set in
these early days and the focus that this group had on data quality are
factors that influenced the development of population-based registries
and, as I said in my opening remarks, still affect what we\'re doing
today.

I also will talk a little bit bout the SEER program, which has already
been referred to in some of the presentations this morning, and talk a
little bit more about the newer program from the Centers for Disease
Control so that people know what it is and what it offers and where it
is in its state of development, and then what kinds of data are
available from the two systems combined.

The SEER program, or the Surveillance Epidemiology and End Results
program, is funded by the National Cancer Institute. They just
celebrated 2 weeks ago ‑‑ I was up here for their 30-year celebration.
They are the gold standard for cancer registries in the United States,
and they are the kind of registry that all the other population-based
registries aspire to be like.

They have data from the diagnosis year beginning in 1973. For most of
their history, they have covered five States and six metropolitan areas,
and in the year 2000, 4 of the CDC program States that are in the
turquoise color here joined the SEER program also. They\'re actually
funded by both programs, and now the SEER program covers 26 percent of
the U.S. population.

The National Program of Cancer Registries, or NPCR, is the program
that\'s funded by the CDC. It is a relatively new program. It\'s only
been around for 10 years. The first year of diagnosis for some, but not
all of the States, because not all of the States started in the program
with that first diagnosis year, is 1995. It covers 45 States, 3
territories, and the District of Columbia. It covers 96 percent of the
U.S. population.

The bottom line is the SEER program plus the NPCR program cover all 50
States in the United States and the District of Columbia.

As I said, I\'d like to talk a little bit more about NPCR. It was
created by the Congress through the Cancer Registries Amendment Act in
1992, which authorized the CDC to minister to this program, and the
legislation set into place requirements for establishing cancer
registries in States where one currently did not exist. At that time, 10
States did not have a statewide population-based registry, and to
enhance registries in the other States where there already were
registries, but they did not have adequate resources to do a very solid
job of getting complete reporting that was high quality and timely.

As part of the congressional law, as part of the Cancer Registries
Amendment Act, each State had to put into place a State law that
established a statewide population-based registry. In addition, each
State also had to develop legislation and regulations for reporting and
for protection of confidentiality.

Here\'s the issue of data quality. Our acronym is CTQ. Completeness. We
need complete reporting of all cases that occur within the States. We
need timely data. We need high quality data.

At the time this program was created, the registries that existed in the
United States did not have standardized definitions for reporting
cancer. They did not have standardized data elements. They did not have
standardized data collection procedures. So part of the congressional
legislation was to mandate that data be collected in a uniform way, and
States are required to report out annually.

Just again to repeat, each State has to have authorizing legislation.
The State legs and regs require comprehensive reporting. They allow
access to records. They require the reporting of uniform data,
confidentiality protection, promoting ultimately, when the data are of
sufficient quality, access to the data by researchers, and authorization
to conduct research, and protection from liability.

The laws obviously from State to State vary a great deal. In some
States, there are a lot more teeth in the laws than in other States. We
had a State, for example, that was not able, with the existing laws, to
get all of the hospitals to report cases, and when the Medicare folks
stepped in and said, well, that\'s very nice. We will hold up your
Medicare payments unless you report your cancer cases. And all of a
sudden, we had ‑‑ this came from the State. This didn\'t come from us ‑‑
complete reporting for that State. Whatever works I guess, and different
States have different methods for getting things to happen.

What kinds of data are available in the population-based registries?
There has been some allusion to this already. Basically, as our previous
two speakers pointed out, the reportable cancer case is defined in the
Cancer Registries Amendment Act as each form of invasive cancer with the
exception of basal cell and squamous cell carcinomas of the skin, and
each form of in situ cancer, except for carcinoma in situ of the cervix.
The cervix piece was added after the law was written, but as I
mentioned, population-based registries in the United States do not
capture basal and squamous cell skin cancers. They do capture melanomas
and other nonepithelial skin cancers as well as the melanomas that
we\'ve talked about this morning.

What kinds of data elements are available? The demographic information
is as listed on this slide. Most of these data are retained at the State
level. Data that are sent to CDC, sent to NCI have personally
identifying information stripped off, such as age, address, census
tract, and so on, Social Security number. So at a national level we have
only the basic statistics for describing the burden of disease in this
country and in each State. Special studies have to occur at the State
level where there would be access to personal identifying information.

The registry also contains basic clinical information, including date of
diagnosis, date of admission or first contact, the source of that
information, date and type of the first course of definitive treatment,
usually surgery. There\'s also limited information on hormone therapy,
chemotherapy, and immunotherapy, basically a yes/no kind of did you
receive it, that may or may not be available in the medical record of
the hospital, information on date of death and underlying cause of
death.

Pathology information is required for all of the tumors identified
through these programs, including primary site, morphology with behavior
and grade, the sequence number of the tumor, laterality, and diagnostic
confirmation.

Data quality, as I said, is really important again because not all of
the States that participate in the NPCR program have achieved the
quality standards that have been set by law. I\'m not going to spend a
lot of time on those. You can look at the details of these requirements
and how they are evaluated. I\'ll just go through them fairly quickly.
But these are important attributes for determining whether or not we
will include a particular State\'s data in the national estimates of the
burden of disease. These are also measures that should be considered
when you\'re looking at doing research using the cancer registry in a
particular State.

We look at measures of completeness and we evaluate those in a variety
of ways related to case sharing with bordering States, case reporting
from all facilities, audits.

Death clearance. One way of finding cases is through death certificates
only, and if you identify a case through a death certificate, you don\'t
have the information about the tumor unless you do follow-back and get
that information from the pathology reports.

Dealing with duplicate reports of cases is also part of measuring
completeness.

Issues of timeliness. We want cases reported within 6 months of
diagnosis, and we look at a variety of dates that are collected to
evaluate the timeliness of cancer data.

We put time frames around these. In other words, we don\'t want just
quality data. We don\'t want just complete data. We don\'t just want it
in a timely way. We want them to do all of these things, including
follow-back within a certain period of time. We want States to find at
least 90 percent of unduplicated cases within 12 months and 95 percent
of unduplicated cases within 24 months.

We also do a variety of data cleaning operations on the data to check
for consistency and validity between various variables in the data set.

There is an external group. It\'s called the North American Association
of Central Cancer Registries, also called NAACCR, that does a variety of
things with population-based registries in the United States. One of the
things they do is evaluate the quality of population- based cancer
registries. They have been doing certification of data beginning with
the 1997 year of data submission, and as we have come through time, you
can see that the number of States that they now certified as of this
year\'s data submission has gone from 9 to 36. So we value this external
evaluation of the quality of cancer registry data.

So what\'s available? Right now, we are in the process of, for the
second time, jointly publishing with the NCI data from the SEER program
and high quality data from the NPCR. These data are for the year 2000
diagnosis year. This report contains crude and age-adjusted incidence
rates per 100,000 population for adults and per million population for
children 0 to 19. This report covers 84 percent of the U.S. population,
and it will be out next week.

The quality issues that we looked at for including States in this report
are listed on the slide. I\'m not going to go through each one again. It
has to do with completeness of reporting, cleaning the data, clearing
death certificate only cases, quality of race, sex, and age data.

There are data from 41 statewide and 6 metropolitan area registries that
met these criteria, and these are the States that are included. As you
can see, we have generally poor representation in the Southeast.

The report has basically three kinds of data. It has national cancer
incidence data by site, sex, and race. As I said, it covers 84 percent
of the U.S. population for the year 2000. It includes more than 1
million new diagnoses of cancer and more than 10,000 new cases of cancer
among children ages 0 to 19 years.

Here are the ranked age-adjusted incidence rates per 100,000 population
for men in the United States, and you can see that non-Hodgkin\'s
lymphoma among men in the United States lists as the number 5 cancer,
followed by melanoma as number 6.

I don\'t have the endocrine cancers listed here, cancers of the thyroid
and thymus. This was mentioned in one of the presentations this morning,
but there are also data for about 5,000 males and about 13,700 women in
this data set with new diagnoses of endocrine cancers in the year 2000.

Here are the top 15 cancers for females in the United States.
Non-Hodgkin\'s lymphoma is sixth on this list behind some female
cancers, and the usual top three, again followed by melanoma.

I pulled out the lymphoma incidence rates and the counts for both
Hodgkin\'s and non-Hodgkin\'s disease. The rate in males in the United
States for the year 2000 is 22 per 100,000 and in females it\'s 14 per
100,000.

Looking at invasive skin cancer incidence, this is melanoma and other
nonepithelial skin cancers, there\'s a rate of 25 per 100,000 in males
and 18 per 100,000 in females.

Here I have some information on the occurrence of cancer in children by
gender. As I said, there are slightly more than about 10,000 cases in
this data system for children of these ages with a rate of 166 ‑‑ this
is per million. We\'ve changed the denominator in reporting the
childhood cancers ‑‑ per million population in males and 147 per million
population in females. There are the data also for lymphomas listed
there.

In addition to these national kinds of data for both adults and for
children, there\'s another part of the report that contains the
State-specific data for the top 20 cancers as well as regional data.
Here you can see the population coverage for these regional data. It\'s
really quite good, as you\'ve already seen, except for in the South.
There are the regions as listed there.

The third part of this report contains gender- and race-specific data
that are ranked within those groups for each State. I\'m not going to
present those data, just make you aware that in fact it exists.

Follow-up in the registries is not about follow-up for exposures but in
fact for vital status. All registries that participate in the two
federal programs do linkage with State death certificate files, Social
Security files, the National Death Index to confirm deaths from cancer
and other causes for patients that are already ascertained in the cancer
registries.

The SEER registries and a very few of the NPCR registries also do
follow-up to determine alive status. The SEER registries do this to
maintain having a current address on the cases in their registries, and
so they link with the other kinds of files that are listed here on this
slide. I guess what I would say is that this is an important activity
for keeping up with a current address, although there are other means of
doing that for doing special studies.

I\'d just like to summarize, make a couple of points. We do have
population-based cancer registries in all 50 States and the District of
Columbia. As I tried to illustrate to you, the quality of the data
varies across the States. That quality is also a reflection of
individual State\'s experience and ability to do special studies. But I
think it\'s a community that has made remarkable progress over the past
10 years such that there are now good quality data available in 41
States.

Follow-up is good for death status. It\'s limited for alive status.

So I think we do, in fact, have a very strong nationwide cancer registry
structure in place and that we do have data available at many levels,
including at the national, regional, State, and local levels, for
monitoring the burden of disease, planning comprehensive cancer control
programs and conducting special research studies.

Thank you for you attention.

DR. CHESNEY: Thank you very much, Dr. Wingo.

Questions for our three speakers of the second half of the morning. Dr.
Stern.

DR. STERN: I wanted to bring out a couple of issues which I think were
well covered but I think deserve a special concern with these agents.
We\'ve talked about the difficulty of ‑‑ we expect these risks to be in
some way dose and duration related.

Now let me speak about the risks of skin cancer. One added confounder is
the fact that we also expect that the risks of skin cancer are likely to
be a result of local rather systemic effect primarily in these agents.
Therefore, in order to understand the relationship of dose to risk,
which in these studies is perhaps the most persuasive evidence for an
increased risk is looking at the entire cohort and seeing how risk
varies with exposure over time, one also has to think about site of
application. And I would have to say that after trying to reasonably
quantify exposure to topical agents over the last 28 years and a little
bit longer in clinical practice, reasonable quantification even on an
annual basis in patients who have been educated of what they\'re using
in the last year, how often they use it, and where they use it has at
least certainly eluded all of my capabilities. So I just think it\'s not
an easy task, and I\'m sure there are other folks who can do it better
but I\'ve never succeeded in a way that I thought that I could well
quantify really relative exposure over time and particularly exposure by
site.

That was one and I have a bunch of other points that I think will be
better raised in that. I think the issue of actinic keratoses as an
endpoint is an interesting one and one I\'ve also thought about. I have
some concerns about it in both ways. One is the clinical diagnosis of
actinic keratoses varies substantially person to person.

The second is that there may be some confounding due to disease in these
individuals. At least in people with seborrheic dermatitis, which is in
fact one of the conditions that Elidel is used off label for, in my
experience in sun-exposed areas, telling seborrheic dermatitis from
actinic keratoses could be very difficult, except in Dr. Wilkin\'s hands
I think, but for some of us it can be very difficult, although I
understand the Greeks found it an easier differential diagnosis.

(Laughter.)

DR. STERN: Clearly people, if they\'re educated to this, may lead to
over-diagnosis, beyond the point of it being a squishy endpoint subject
to ascertainment bias.

My other concern is at least as one looks at the transplant literature,
if you think about lesions, if you think about the actinic keratosis,
there\'s a probability over time it will go forward. In fact, what may
be happening in transplantation is that whether they go through a
transitional stage of actinic keratoses or first manifest themselves
with tumors, the duration of being clinically a pre-malignant ‑‑ a
carcinoma in situ either clinically or histologically may be shortened.
One of the things you see is a shortening. Therefore, if you look at an
intermediate lesion, if you look at the in situ lesion ‑‑ and you\'re,
after all, measuring prevalence as caught on doctor\'s exams, say, once
a year ‑‑ you may be under-representing the real number because the real
interest is those that go on.

So I\'m just not sure that it\'s either a feasible endpoint or really
that a negative finding or a small increase in risk of actinic keratoses
would really be ‑‑ you\'d know how to extrapolate that finding, be it
positive or negative to what the real interest is, what\'s the increase
in risk of squamous cell carcinoma.

DR. CHESNEY: Dr. Fink.

DR. FINK: I would just like to bring up what I think may be a major
confounder to study design and would, I guess, argue for the inclusion
of a non-treatment control group. In the spring of this year, the
Pulmonary Allergy Drug Advisory Committee of the agency reviewed the
preclinical data on omalizumab, or anti-IgE. And cancers, including
non-melanoma skin cancers, were of concern there. One of the issues of
that data, although not definitive, pointed out that it appears that
elevated IgE levels ‑‑ these would be in atopic asthmatics with IgE\'s
above 200 ‑‑ actually had a protective effect for epithelial cancers. So
in those studies, there was a question as to whether you are losing a
protective effect and the comparison to SEER\'s database or the SIR\'s
methodology would be inaccurate.

What was seen there is that the control population had a significantly
decreased risk of epithelial cancer compared to SEER. And the anti-IgE
treated group came up to the population norm. So there was a loss of
protective effect. If that is also true for atopic dermatitis where IgE
is elevated, you really have to have a control group that is untreated
to detect that loss of the anti-IgE protective effect.

DR. CHESNEY: Dr. Glode.

DR. GLODE: This is a question for Dr. Andrews. When you discussed the
rheumatoid arthritis study as possibly analogous ‑‑ and I could see the
analogy that perhaps dermatologists would enter patients, et cetera ‑‑ I
just wanted to ask you if this type of study design has, over time in
general, been validated, been helpful because I see the problems as time
goes on with other drugs being introduced into therapies, for example,
obviously with rheumatoid arthritis, other immune modulating drugs. So
it comes back to the issue again of your comparison group sort of
changing over time perhaps in terms of their risk for malignancies. But
has this study design, which looks like it doesn\'t have to involve too
many patients, for example, given us good information historically?

DR. ANDREWS: That particular study proved very useful in looking at some
of the short-term toxicities. It was also useful, as other drugs were
being developed and there was the need to look at short-term infection.
It was able to provide a comparison group for an uncontrolled clinical
trial population. So there were a number of uses for the study data over
time.

Yes, treatment patterns changed a lot, and the analytic strategy had to
accommodate that fact. So you didn\'t have a single ever
azathioprine-exposed population. You had azathioprine plus methotrexate,
whatever. It was very complex.

We were able to achieve a very high rate of retention. I think one of
the factors that made that a very successful study had to do with
practice of medicine in Canada. Patients with rheumatoid arthritis tend
to be seen by rheumatologists repeatedly. So the rheumatologists were
actively engaged and contributed data for many, many years. I think in
the States most patients might have seen rheumatologists once or twice,
but would be treated by their primary care physician. So everything
conspired to a good, feasible study in that case. And because the
anticipated rates of lymphoma and other outcomes are fairly high in that
population, we didn\'t need a huge sample size.

DR. CHESNEY: Dr. Gorman and then Dr. Santana and then Dr. Danford.

DR. GORMAN: Is not the goal of this study, when we were talking about
goal-setting, which I found re-informative perhaps rather than
refreshing, but re-informative ‑‑ we\'re looking immune-modulating
effects on a systemic basis. While we\'re waiting for the 20-year cancer
incidence to change or the 5-year cancer incidence to change, could we
not be looking as well on the perhaps not as serious but equally telling
dermatological changes such as recurrence of zoster or invasive viral
diseases or invasive bacterial diseases? Could they be not incorporated
in the same design whether it be cohort or surveillance?

DR. CHESNEY: Do you have any one special to address that to?

DR. STERN: I\'m sorry to be talking so much, but this is an area of
interest of mine.

At least with UV and PUVA in carcinogenesis, acute UV is associated with
flares of HSV but not herpes zoster, but in terms of chronic exposure,
they\'re not good predictors for cancer risk. They\'re good predictors
for acute immunomodulation in the skin, but they\'re not good predictors
for cancer risk probably because some of those phenomena are more when a
person has exceptional exposure as opposed to steady exposure. Steady
exposure is important for cancer. Bringing out HSV is when you get a
sunburn is when you get herpes simplex reactivation, and they may be
correlated, but they\'re certainly not good predictors.

DR. GORMAN: Well, perhaps not herpes simplex, but zoster is something
that would be a sentinel event in a pediatric practice as being an
unusual ‑‑ not rare, but unusual ‑‑ occurrence. Incidence rates that
were different I think would have a signal-to-noise ratio that would
rapidly be high even if it\'s not a predictor of eventual cancer.

DR. STERN: I guess when I think of zoster earlier than usual, it\'s
usually again in the background of fairly profound immunosuppression or
fairly acute insult like radiation therapy to a ganglion, to an area
where there\'s latent virus, and it doesn\'t seem to be so much of a
problem when we just modestly but chronically immunosuppress
individuals, whereas those kinds of insults do seem to be a problem with
long-term exposure in terms of carcinogenesis.

So again I think there is obviously some correlation between cumulative
dose and peak doses, but to me, most of those signals have to do with
exceptional acute doses or very profound immunosuppression, which if it
occurs, is certainly like to be associated with a high risk of cancer if
it occurs on a long-term basis, but I don\'t think is directly analogous
to what we expect to these less profound but chronic exposures.

The question really is when we get down lower in the magnitude of
immunosuppression, how much is that going to alter things long-term. I
think that is a bit different than the acute conditions in the skin, at
least as I\'m aware of them.

DR. DIANNE MURPHY: I\'d like to follow up on that question, though,
because in the limited controlled studies that were done, we already saw
this come out statistically. So I think the question is really one of
background noise and ability to pick this up from your experience
because we had to label it because we already saw it in the rather
limited numbers of studies that we had. So I think that\'s what you were
trying to get at, not as a particular cancer, but just a shorter-term
signal that some sort of additional immunosuppression is going on here
that\'s more systemic.

DR. GORMAN: That is the question I want to answer. If I can be convinced
or unconvinced whether ‑‑ if we\'re going to down-regulate children\'s
immune systems for atopic dermatitis, I want to know that, and I think
that\'s the question that we look at with the signal of cancer long
term, dermatological cancers or perhaps lymphoma long term, but there
are other markers perhaps not as sensitive and perhaps not as
life-threatening, but perhaps equally important to parents who are
taking care of these kids.

DR. DIANNE MURPHY: Just to clarify. The division wanted to make sure
everyone realized that that signal is picked up in the less than
2-year-old population.

DR. CHESNEY: Dr. Rabkin, did you want to say something? And then Dr.
Santana and Danford.

DR. RABKIN: Similar points to those that have already been raised. I was
going to mention that you would need to distinguish between markers of
systemic loss of immunity and perhaps even more difficult to discern
losses for cutaneous immunity that could have very local effects for
which there\'s very little tools, not that the tools for systemic
alterations are that sensitive, but the tools for cutaneous changes in
immunity would be even more difficult to discern and the clinical signs
are also more nebulous.

Also, I\'d like to make the point that the effects of these conditions,
regardless of treatment, on immunity and risk of diseases such as
lymphoma are uncertain. So the importance of a comparison group is very
real and even with the comparison group, in the absence of the usual
specter of a randomized clinical trial, it\'s going to be very difficult
to ascribe any particular differences to the treatments, as opposed to
differences in the disease.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: I just want to make two general comments.

First of all, as a practicing oncologist, if there\'s anything I can do
to prevent a patient from getting a malignancy, which is very rare in
pediatric malignancies that we have that opportunity, we should do.
Obviously that comment is biased in the sense that we rarely have these
opportunities and it has to be taken in the context of what other
conditions the patient may have in which the use of the particular agent
was necessary in order to ameliorate or cure their primary disease.

Having said that, I do want to publicly applaud Elizabeth Andrews\'
presentation about bringing the issue of stewardship forward. Many of us
who live in academic ivory towers who have a lot of access to support to
do our studies sometimes don\'t recognize this issue of stewardship. And
as we think whether it is appropriate for this particular class of drugs
to conduct these studies that will consume time, that will consume
talent, and that will consume money, the three cornerstones of
stewardship, that we carefully do that because I don\'t think I\'ve
heard yet this morning during the presentations that the goals of the
study were defined, and if I\'m now going to be a good steward of these
three elements, I want to make sure that the goals are clearly defined
so at the end of the study, all these three variables have been
accounted for and then we can publicly say that we were good stewards of
the trust and the monies that people gave us to do this.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: I\'m also impressed by the amount of money and effort and
time that\'s going to be invested in a study such as this, and I am
interested, in that context, whether there are any anticipated practice
pattern changes that might occur during that extremely long time frame.
I am wondering, therefore, if the FDA is in any position to comment as
to whether there are, in the drug development pipeline, agents that show
exceptional promise for the treatment of this condition. And if there
are, would the development of such agents render the studies we\'re
contemplating moot?

DR. WILKIN: Well, apologies. I was having a side bar. I missed the
question.

DR. DANFORD: The question is this is a long, difficult, and costly
process that we\'re talking about. Is FDA aware of any alternative
agents in the drug development pipeline that might be safer, more
effective and drastically change practice patterns in the next 20 years
that would render this investigation essentially moot?

(Laughter.)

DR. SANTANA: Predict the future is what he\'s asking you to do.

(Laughter.)

DR. DIANNE MURPHY: He couldn\'t tell you anyway because he\'d go to
jail.

(Laughter.)

DR. WILKIN: That\'s exactly right.

But at the beginning before we have very much information, they all look
wonderful.

(Laughter.)

DR. SANTANA: Does anybody from the FDA have an idea how much a study
like this would cost based on some of the studies that Elizabeth
addressed earlier?

DR. WILKIN: Well, I\'m not going to talk to the costs because I think
there\'s a wide range depending on how we actually approach this.

I am taken by actually Dr. Stern\'s reformulation into more of a
dosimetry type of approach, and maybe there\'s something that can be
thought of along that line.

DR. DIANNE MURPHY: The only data that we have that really is only
marginally relevant is in the report to Congress, aand Rosemary Roberts,
you can correct me if I\'ve got this wrong. In our report to Congress
for the FDAMA, the Food and Drug Administration Modernization Act, on
pediatric studies we were asked to give an estimate of the cost of
studies. I can tell you that we went to PhRMA, we went to a variety of
people, and no one could come up with a good number. I will give you the
range, the range that was given to us in writing versus the range that
was given to us verbally.

(Laughter.)

DR. DIANNE MURPHY: The range in writing was that for a very small study,
maybe \$500,000. We\'re talking pharmacokinetic, PK, type studies, a
limited number of people, short, quick, not long-term follow-up. To
studies involving ‑‑ I think the outer figure was ‑‑ was it \$300
million or \$30 million, Rosemary? Do you remember? It was \$30 million,
something like \$30 million for a randomized clinical trial. That was
not addressing long-term follow-up trials. That was addressing
randomized trials. So the unofficial lowest statement that we got was
\$50,000 for less than a half a dozen kids to get a PK study, something
like that. So those are the sort of huge ball parks for some randomized
trials, and that was in this country.

DR. STERN: I hate to always be adding data, but in terms of costs of
long-term follow-up of cutaneous diseases in adults, much more simple
than in children, at least what the NIH pays for long-term, as in
25-year studies, in years where we do not have dermatologic
examinations, direct costs on the average of about \$300 per patient,
all direct costs for telephone contact and for following up on all
endpoints, cancers, hospitalizations, et cetera. On years when we have
dermatologic examinations, it about triples to roughly \$1,000. That\'s
an annual cost. In fact, it was cheaper early on because it was easier
to get patients to continue and they get to be more complex as follow-up
and retain the cohort continues.

So those are sort of, at least in some ways a simpler study where we
were trying ‑‑ our principal endpoint was really trying to quantify a
real event in people\'s lives, that is, getting a therapy where we could
get a record from the doctor, going to an outpatient clinic or a
doctor\'s office for a therapy. And that was the thing we quantified
most accurately. That\'s kind of a ball park of who we\'ve been able to
do it over the years, and it\'s also a little bit cheaper because when
you do it for the NIH, you have salary caps and other things that keep
down your costs a little bit compared to some other costs.

I think if this were adults and a chronic disease as opposed to a
disease where ‑‑ what do we expect with many of these children who are
initially dosed? I mean, both the most difficult part of it and the
saving grace of this therapy is that most people will only use it
hopefully for a number of years, at least using it extensively because
atopic dermatitis tends to get better. That\'s great in terms of
lowering exposure. It\'s terrible in terms of having a sufficiently
exposed group among those you originally select, and it\'s also terrible
with respect to being able to keep the cohort together because once
people don\'t have the disease and aren\'t using it or other therapies
to the disease and it\'s gone from being one of the top three problems
in their daily lives, they very much lose interest in these studies.

In my study, where we\'ve done pretty well over the years in terms of
follow-up, we had the advantage of ascertaining people at the time
almost all with very severe psoriasis, and as a result the disease kept
on being high on their platters. They kept on being under treatment, not
the treatment necessarily we were initially studying over the years so
we could keep them in.

I\'ll raise one point. Someone talked about incentive. I think one has
to be very honest about what are the incentives for the sponsoring
institutions. One of the two sponsors here sponsored a study very
parallel to mine for another agent, and was very proud with a 49 percent
follow-up at the end of 5 years as published in a journal recently.
Those kinds of follow-ups ‑‑ you may as well not bother at all when you
have that in terms of really well quantifying it.

So I think one of the things we have to think about is we\'re very
concerned with this today, but what are going to be the incentives to
the sponsor going forward to be sure ‑‑ what\'s in it for them to get a
90 percent follow-up after 10 years? The first question is, is it
feasible for anyone? And the second question is, what\'s in it for the
people who are paying for it?

DR. CHESNEY: Thank you.

I apologize to the three people who are still on the list, but I
anticipate lots of discussion this afternoon, and given that people are
always having another eye on the airport terminal, I think maybe we
should break for lunch at this point and plan to be back at 1 o\'clock
please. Thank you.

(Whereupon, at 12:02 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:06 p.m.)

DR. CHESNEY: Let\'s get started.

I understand there is at least one person who has requested time, and
the FDA does have a new regulation that I have to read before people can
speak, and that is that both the Food and Drug Administration and the
public believe in a transparent process for information-gathering and
decision-making. To ensure such transparency at the open public hearing
session of the advisory committee meeting, FDA believes that it is
important to understand the context of an individual\'s presentation.

For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement, to advise the committee
of any financial relationship that you may have with any company or any
group that is likely to be impacted by the topic of this meeting.

For example, the financial information may include a company\'s or a
group\'s payment of your travel, lodging, or other expenses in
connection with your attendance at the meeting. Likewise FDA encourages
you at the beginning of your statement to advise the committee if you do
not have any such financial relationships.

If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.

And if you have the courage to speak after that, please do so.

(Laughter.)

DR. CHESNEY: Yes, Dr. Margolis.

DR. MARGOLIS: My name is David Margolis. I\'m not going to use the
presentation. You guys covered everything basically.

My name is David Margolis. I\'m board certified in internal medicine and
dermatology and I have a Ph.D. in epidemiology.

My conflicts I guess would be that I don\'t currently have a consulting
relationship with either of the companies who I guess would benefit from
this, but do have a consulting relationship by employment at the
University of Pennsylvania through a project submitted to Novartis which
was then submitted to the FDA to do a study similar to ones that have
been discussed today. That would go through the University of
Pennsylvania through a contract, and I\'m employed by the University of
Pennsylvania, so I have a conflict I guess with the University of
Pennsylvania.

(Laughter.)

DR. MARGOLIS: The reason that I came here to speak was that about 18
months ago we put together a proposal to do a cohort study to look at
the rate of mainly lymphoma in individuals with atopic dermatitis. That
was then submitted to the FDA in the spring of 2002, and we received
comments in the summer of 2003.

The reason why I wanted to speak at first was that many of the comments
were sort of very clinical trial like comments, which were very
important, but certainly increased the complexity of the study. After
I\'ve sat through most of the morning, I realize that most of those
concerns have been addressed in the presentations, and I think the
presentations were very nice at pointing out the importance of doing an
epidemiologic study and the importance of those study designs.

There were just a couple of things that I wanted to highlight which are
not on the slides that I had previously prepared, so it may seem a
little disordered, and I apologize for that in advance.

These studies are incredibly important. Somebody did ask about the price
and the cost of doing one of these studies. The study that we submitted
really looked at lymphoma. Lymphoma is going to be a less complex study
because you really can rely on issues of records and the likelihood of
diagnosis. It prevents the fact from having to necessarily see the
patient on a frequent basis to look for skin cancers. Even the cost of
that study was well over \$1 million a year to look at 20,000 to 40,000
person-years of follow-up. So the costs are substantial here.

I think it\'s also very important to realize what is the goal of the
study and what is the major health concern or public health concern
here. I\'m a dermatologist and I\'m sure at some point somebody will
scream at me for what I\'m about to say. I apologize right off the top,
Dr. Stern. But the public health concern here is lymphoma which is a
life-threatening disease in these kids, if they were to develop it. Skin
cancers aren\'t in most cases. As Dr. Stern pointed out, the latency for
skin cancer is going to be probably well beyond the 10-year period that
we\'re supposedly talking about following these individuals. So in my
mind, there\'s a real need to either do two separate studies or realize
that the complexity of the two studies are going to be very different,
and the costs, as a result, are also going to be very different.

The other issue, which I also think is very interesting and important
was also brought out in some of the FDA presentations, is the issue of
exposure. Individuals with atopic dermatitis are likely to be exposed,
and as was also pointed out, exposure may be for a very short period of
time as the atopic dermatitis may go away or they may choose a different
therapy.

So it certainly is possible to enroll individuals who were exposed to
one of these agents, follow them over years, and then stratify an
exposure thereby sort of giving you a group of individuals with perhaps
similar severity who may never really see the agent again. As was
pointed out in one of the presentations, there are some concerns about
what should be chronic exposure so you\'ll have this group in this large
cohort who are chronically exposed and another group who aren\'t, and
you may actually have natural exposure patterns.

You will also, by doing that, perhaps have dose-response effects or
dose-duration effects that you can also look at over time. So it may not
really be necessary to have this second cohort who completely aren\'t
exposed and will never be exposed for 10 years who have atopic
dermatitis, which also may be unlikely. So it would be somewhat
unethical to impose restrictions on their treatment for years and years
and years.

The other important point I think that is very important to bring out is
that if these studies were to begin, the amount of information that
would be gleaned from these studies would be incredibly important to
individuals interested in cutaneous disease. There really are no good
long-term studies on individuals with atopic dermatitis. It\'s a very
common disease, yet we don\'t have good studies. As was just pointed out
earlier, there really aren\'t even good studies on what the rate of
cancer is in these individuals.

We actually also recently completed a study looking at the rate of skin
cancers in atopes and actually found almost nothing in the literature to
compare it against. There are maybe one or two studies that have
actually looked at other cancers as well. That study will probably be
published ‑‑ well, it\'s been accepted for publication, but hasn\'t been
published yet.

There\'s also the information just on what goes on in atopic dermatitis
in terms of the atopic diathesis in terms of the onset of asthma, the
duration of the asthma, the severity of the asthma, seasonal allergies,
drug allergies is also very poorly understood for a disease that\'s as
common and as prevalent as what it is. In one of these studies, you
would be able to do that because you\'d finally have enough individuals
and you\'d be following them long enough that it could be done.

In conclusion, I think it\'s incredibly important that these studies be
done, and I think I agree with what\'s been presented, that there is a
signal which says that it should be done. But we need to be prudent and
careful in terms of how they\'re going to be done in terms of the costs
and whether or not they\'re even feasible. We also need to get started
on them before, as was pointed out, other agents are available and the
use of these agents becomes relatively less important.

I thank you for your time and consideration.

DR. CHESNEY: Thank you, Dr. Margolis.

I did want to share one other piece of information. Dr. Santana had to
leave, but he tells me that 8 months ago the Children\'s Oncology Group
established a registry for cancer in children which will be going
through the NCI, but it is the first comprehensive registry of cancer in
children. He says there\'s some regulation that people have to report
all cancers in children now to this registry. So that began 8 months
ago.

I\'d like now to invite Dr. Patrick Salmon, who we introduced before,
who\'s with the European Medicinal Evaluation Agency, just to say a few
words about how you all are looking at this issue in Europe. I guess the
best thing is to come up here. You don\'t have a microphone.

DR. SALMON: I do.

DR. CHESNEY: Oh, you do. Well, that\'s fine then.

DR. SALMON: Thank you very much. As you say, my name is Patrick Salmon.
I actually work for the Irish Medicines Board, and I\'m here
representing the EMEA because I was the rapporteur for one of these
agents that we\'re discussing today when it was approved by the CPMP
around the same time I think as it was considered by the FDA.

The short comment I can make is in fact we share all of your concerns
and have been examining these issues in the last year or two. There are
various studies ongoing, but none which I think will address the major
issues that are being discussed today. As you know, we\'ve had some
preliminary discussions with the FDA on this general area and are
continuing to do so.

As to how we eventually address these issues, our main concern is that
we do and as soon as possible, the main concern being that, as our last
speaker just said, these drugs are actually on the market, so patients
are being exposed. So we need to sort of try and address the issues as
quickly as possible, but as to how we do it, as long as we will get an
answer at the end of the study, I think we\'ll be happy. So I think that
would be just a brief comment on what we\'re doing.

DR. CHESNEY: Thank you very much.

Is there anybody else who would like to speak at the open public
hearing?

(No response.)

DR. CHESNEY: All right. Then we\'ll move on to the main issue for the
afternoon which is the questions the FDA would like us specifically to
address, and you received a new version at your place when you sat down.
You\'ll see that there are several pieces to each question and five
questions. In looking at them quickly, I felt that there were maybe some
redundancies.

I asked Dr. Cummins, who\'s going to read the questions for us, if she
could read through all of them, and if you could in your own minds sort
of focus on the main issues.

We\'ve also been asked, when we get to question 2, because it\'s fairly
long, rather than just having general discussion, to start at one end of
the table and go around and ask people to address all the issues in
question 2, and if the next person says, I agree, that\'s fine. But
again, so that we can get through these in a timely fashion.

So, Dr. Cummins, if you could go through all the questions with us
please.

DR. CUMMINS: What I\'m going to do is just read these to you quickly in
their entirety, every question, and then we\'ll back through them one by
one.

Question 1 is what is a clinically meaningful increase in cancer risk
from a treatment for a chronic non-life-threatening disease? And the
next part of that question is, does the present patient package insert
appropriately reflect the information concerning cancer risk? And I
would just add that in our review of the patient package insert for both
of these products that we did over the noon hour, we do not see that
either of them contains any information of a potential cancer risk.
Please discuss any recommendations.

Question 2. There\'s a series of facts that precede the asking of the
question. Fact 1, lymphoma has been associated with systemic use of this
class of immunosuppressants in both preclinical studies and in human
use. Cutaneous malignancies are the most common malignancy associated
with systemic use of this class of drugs.

Fact 2, topical use of these immunosuppressants results in some, albeit
modest, systemic exposure. This may be increased in pediatric patients
due in part to increased body surface to mass ratio.

Now, the premise for this question, malignancy may only be discernible
via long-term exposure, especially with modest systemic exposure.

So given all that, what is the best way to ascertain the clinical risk
of malignancy, e.g., lymphomas or skin cancer, in clinical studies?

Please discuss the merits and drawbacks of each of the following, as
well as study design considerations: the duration of follow-up for each
enrolled patient, keeping in mind that the latency period of most
cancers is at least 10 years. And the following study design
requirements: the sample size needed to detect rare signals and
feasibility issues; the approach to ascertainment of skin cancers, e.g.,
by physical exam by a physician, by physical examination by a
dermatologist ‑‑ they\'re also physicians ‑‑ by interview or
questionnaire; the role of a comparison group; and design strategies to
optimize retention.

The next part of question 2, endpoint issues. What are the specific
cutaneous and systemic malignancies we should consider? Are there other
biologic endpoints such as viral infections of the skin, such as, for
example, warts, EB virus infections, or pre-malignancy or early cancer
endpoints such as actinic keratoses?

Question 3, FDA has not asked for such long-term studies in topical
products before. To require such screening means that we are asking
companies to take on very large, lengthy studies with substantial
logistical challenges in patient retention, follow-up, costs, and other
factors. We\'ve heard a lot about that today. In what situations should
we require such studies? And what criteria would you identify as
important in deciding that this type of study be done?

Question 4, is there a role for cancer registries and/or the SEER
program in this long-term follow-up project? Please discuss how one
might utilize existing registries or programs.

Question 5, what other studies would you recommend, for example,
additional animal studies? And what other risk management for this class
would you recommend? And just to remind you of the risk management
approaches we discussed yesterday, these include additional studies; a
boxed warning in the product label; limiting the indication to certain
age groups; recommending against use in certain age groups;
contraindicating use of the product in specific populations; including a
patient package insert to inform the patient or parent/guardian of the
risk; requiring that a medication guide be dispensed with every
prescription; unit-of-use packaging; issuing a Dear Healthcare Provider
letter to groups of healthcare providers most likely to prescribe; or
conducting education programs for providers and patients and/or
caregivers.

So those are the questions, and I\'m going to go back to question 1 so
that you can begin your discussion. Again, question 1 is what is a
clinically meaningful increase in cancer risk from a treatment for a
chronic non-life-threatening disease? And does the present patient
package insert appropriately reflect the information concerning cancer
risk? Please discuss any recommendations you may have.

DR. CHESNEY: Dr. Cummins, could I also add the last bullet of question
5, which is what other risk management for this class would you
recommend?

DR. CUMMINS: Do you want to put those together?

DR. CHESNEY: I think that falls into question 1 as well.

DR. CUMMINS: Okay. Well, I\'ll go forward to that, which is what other
studies would you recommend, for example, animal studies? And what other
risk management for this class would you recommend? I\'m just going to
leave this list up on the screen so that you have it to refer to.

DR. CHESNEY: Maybe we could start with the easiest part of question 1,
which is the present patient package insert says nothing about cancer.
Would we recommend any changes in that in terms of risk management?

For those of you who weren\'t here yesterday, the committee did
recommend that a package insert or something comparable be put into the
packages for topical corticosteroid use describing
hypothalamic-pituitary-adrenal axis suppression and that physicians also
be informed about this specifically saying that we don\'t know what the
risk is. Dr. Murphy and Dr. Wilkin pointed out that if we do that for
the topical corticosteroids, that may actually scare people away from
using them and into using the topical immunosuppressants.

So we need to decide I think at this point do we need more information
for the patient and for physicians in terms of managing a potential risk
which is unknown.

Comments. Dr. Fost.

DR. FOST: On that point, it seems to me clear. That is, it would be odd
to have the FDA spend a whole day flying people in from all over the
country to discuss this, but don\'t think that doctors or patients need
to know about their concerns about this. So it seems to me unavoidable
that the patient information sheet and the information that goes to
doctors, not just through package inserts but educational programs and
so on, need to explain why this is a second-line drug, that there is
this great concern about lethal toxicity, no evidence for it in humans
yet, or at least not enough to say anything concrete, but based on the
animal data, there is serious concern about this, and this is why this
should be a second-line drug.

Having said that, I don\'t know if 10 or 20 years from now the mortality
from potent steroids is going to be greater than this or less. As we
discussed yesterday, we have no data on that either. We know that
there\'s far more risk because of the huge number of children that are
getting them now and because of the very high incidence of adrenal
suppression, but we have no idea whether that degree of suppression is
going to result in serious illness or fatality and in how many.

The bottom line of all that for me is that both the inappropriate use of
the potent steroids or this drug is inappropriate and should be
discouraged. And to me, the patient information sheet and the doctor
information through all these sources should be the same for both of
them. That is, both should be second-line drugs; that is, potent
steroids should be second-line drugs to less potent steroids. And the
calcineurin inhibitors ought to be the same; that is, they should be
used only in situations in which almost certainly much safer
therapeutics are effective.

I don\'t know how you can get patients\' or doctors\' attention other
than by scaring them, and if they\'re scared, so be it. That\'s what we
want them to be. I mean, we want them to be a little bit concerned about
using these drugs inappropriately. Now, obviously, if a patient has
severe atopic eczema and it\'s unresponsive to other management and
it\'s disabling in all the ways that we know about, then it may be worth
the risk, but parents should be informed of that. Doctors should know
what they\'re doing, and they shouldn\'t be dispensing it in what seems
like a casual way from the anecdotes that we\'ve heard.

DR. CHESNEY: I would totally emphasize the inappropriate issue in the
children under 2. We\'ve seen how many prescriptions are being given for
that population in particular, and I think that the vast majority of
physicians who are prescribing these don\'t even think about or know
about a potential cancer risk. So I would totally agree with Dr. Fost.

Does anybody on the panel disagree with that position? Dr. Wilkin.

DR. WILKIN: It\'s not so much a disagreement, it\'s a clarification
mostly from Dr. Fost. Before I describe the issue of symmetry of what I
heard yesterday and what I heard today, this is largely Dr. Dianne
Murphy\'s interest because she heard the comments about the patient
package insert yesterday and thought we might need some parity today and
think about that.

Dr. Fost, I thought yesterday your comment was it would be prudent to
have statements in the patient package insert to describe good
principles of patient use of the product, not using it beyond a certain
period of time, limiting it to small amounts and the areas of
involvement, consulting a physician if different sorts of things happen.
But I thought I heard not mention adrenal suppression. If there\'s
symmetry, then would that not be the case in the case of the topical
calcineurin inhibitors to simply describe limited amounts?

And I\'d point out, you do have your patient package inserts. We have
things in here that says apply a thin layer ‑‑ and then it\'s the name
of the product, and I think it\'s roughly the same for both products ‑‑
to all skin areas that your doctor has diagnosed as eczema. So it\'s
actually asking that the physician point these areas out. Try to cover
the affected areas completely. Most people find that a pea-sized amount
squeezed from the tube covers an area about the size of a 2-inch circle,
approximately the size of a silver dollar. So it even gives some fairly
descriptive advice, which I thought was pretty much in line with what
you were discussing yesterday.

DR. FOST: Well, I\'m happy to clarify it. No, I think it\'s essential
for the steroid creams to inform parents and doctors about the HPA
suppression. There\'s one obvious reason. What you want parents to know
is not just that there\'s a risk but if their child gets sick or has
surgery or has trauma, they need to tell their physician who otherwise
would never know that maybe they need supplemental steroids. That\'s why
parents need to know specifically about the HPA suppression in language
that they can understand. So that\'s one reason why it has to be on that
insert and the doctor\'s insert so that he or she knows also.

But second, I think it needs to be on there to get people\'s attention
as a shot across the bow. Just saying something, use this carefully,
don\'t use it when other things are available, is not going to win an
election. I think unless you say you can die from this, because it
doesn\'t occur to people that you can die from using a topical cream. In
whatever lay language that is on there in understandable language, it
needs to be there. And the specific adrenal part of it needs to be on
there, and for the CI inhibitors, that it may cause cancer, an
untreatable form of cancer.

DR. CHESNEY: Dr. Stern.

DR. STERN: In terms of risk management, we look at these options and
some of us wonder about the efficacy in clinical practice of any or all
of them. I wonder for a product like this where there are two
manufacturers, how did it come that these agents are so popular and so
widely used outside of the labeled indications, including when
contraindicated. Well, it\'s a matter of, I think, promotion both to
consumers and to physicians. So I wonder whether the two sponsors might
come forward and say, we\'re going to make an effort to make sure that
people understand the labeled indications, which apparently they are
supposed to agree with the counterindications. We will not directly
market to consumers these products, which I\'ve seen on my television
set, and we will be good corporate citizens so that in fact the
physicians will rely principally on the peer-reviewed literature and on
the package insert rather than the pressure from patients, doc, there\'s
something new for my eczema and I know it\'s safer than those steroids.
So I wonder if what we really have to do are some non-regulatory things
if the companies are willing to step up to the plate and make a pledge
to help protect our children.

DR. FOST: I want to second that and approve it by acclamation.

(Laughter.)

DR. FOST: As a corollary to it, without knowing anything about this
field, I\'ll just bet that the miracle of CME is at the root of a lot of
this also. That is, we\'ve seen this over and over again in these
meetings how these drugs that are approved for narrow indications get
used expansively through the miracle of pharmaceutical-sponsored CME
laundered through MECs. I realize the FDA can\'t regulate that, but in
terms of whatever leverage you can apply for good citizenship, as Dr.
Stern points out, the CME on these things should be ‑‑ I don\'t know
what\'s going on. I\'m just guessing, but it ought to be the opposite of
promotion of them. It ought to be educational programs that promote
caution in their use and limitation on their use unless there are clear
indications.

DR. CHESNEY: Unless anybody has any other comments on the risk
management issue, I feel like we\'re all unified on that.

Dr. Fink, you had a comment.

DR. FINK: I agree with everything that\'s been said. I am particularly
concerned about the widespread use of this drug under age 2. I would
almost favor registration of providers, but if that\'s felt to be too
restrictive, I think a boxed warning about nonapproval and
contraindication of this drug under age 2 is really important. Because
of the developing immune system and because of the thin skin and all of
the things that impact under age 2, I really think it deserves
highlighting, and I think a boxed warning would not be inappropriate.

DR. CHESNEY: Dr. Mattison.

DR. MATTISON: I actually missed some of the earlier discussions, so if
I\'m repeating something, I apologize.

I don\'t know that I could even support 2 as a cutoff. I know that 2 is
where it\'s currently labeled at, but given the lack of understanding
about interaction between immune system and central nervous system
development, as well as the development of those systems individually,
and recognizing that these act quite profoundly on those systems, it
seems to me that special concern needs to be given to the use of these
agents in individuals who are still developing. So I would even have
some difficulty knowing that we could use age 2 as a cutoff.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I\'d like to echo Dr. Mattison\'s comments. If we\'re
answering the question that was presently 5, what other studies would we
recommend, my concern is, whether we allow or disallow the use of this
drug in earlier age ranges, it will be used in those age ranges. I think
we\'ve been completely unsuccessful in regulating drugs once they\'re
out on the market in terms of keeping them from populations we wish not
to expose.

Saying that, the question that remains uppermost in my mind, not to
minimize the risk of cancer later on or the risk of other dermatological
diseases later on, is whether this drug is absorbed systemically in a
dose that alters immune function. That\'s the question that\'s most
important to me in the young age range. I would like to see a study
design that allows us to look to see whether we shift the curve of
infections to the left ‑‑ or to the right. Excuse me. I\'m not an M.P.H.
person. Are there more infections in kids who use this drug? Is there an
increased death rate overall? Are there increased numbers of infections,
more missed school days, and more missed work days by their parents?

I think these are relatively hard outcomes with relatively vague
associations. It will be one of those epidemiological studies that
allows you to say they\'re associated with but the causality would not
be well defined. But we\'re talking about an immune modulator and we\'re
looking at outcomes that we see a lot of in kids, and if we see more
serious ones in this population, I think we can attribute causality to
this agent.

DR. CHESNEY: They\'ve already demonstrated that. Are you talking about a
longer-term study? At least the children under 2 did have an increase in
a whole variety of different infections.

DR. GORMAN: They did, and then the question is in terms of quantifying
that to determine a risk versus benefit for this particular agent I
think would be important. If they have an increased number of colds, I
might be willing to treat my atopic child with this drug. If they have
an increased number of pneumococcal sepsis, I would not personally be
willing to treat my child.

DR. CHESNEY: So it would be a larger group, longer-term, older children.

DR. GORMAN: I\'m not going to try to dictate the study design. It would
be a larger group and it would be looking for more serious infectious
disease outcomes. The varicella data in the very small studies is a
fairly large signal. It tells you that there\'s at least one infectious
agent that is much more likely to produce disease in this group.

DR. CHESNEY: You just reminded me of something, and this is for Dr.
Wilkin and Dr. Murphy. When I briefly looked over the patient
information, I think it says that an increased incidence of colds,
nasopharyngitis, strep infection, and so on has been associated with
this drug. But I don\'t think it makes it clear that there may be an
association with the immunosuppressive aspects of the drug. When I first
read it, I thought so big deal. You get more colds. But I think if
parents understood that that was maybe because the immune system is
being suppressed, that that would have a much bigger impact on them, I
think as Norm said, in language that they can understand.

I\'d like to go on to the very first part of question 1 and then come to
the other studies of question 5, but I want to be sure that you all feel
as strongly as I do that we need to better inform patients and
physicians about all of the issues related to these drugs. I know that
you all can do it in the best way that you think. I think it\'s not
appropriate to make it a required medi guide, but in almost every other
way that\'s been mentioned, I think we all feel fairly strongly that
this information needs to be made more public than it has been.

Dr. Danford.

DR. DANFORD: I agree with all of that.

The one thing that has not been mentioned is perhaps the medical
community needs to come clean with the public about our uncertainty in
the matter. We don\'t know, and maybe we need to let the public know
that the FDA is asking for more long-term research on the issue of
cancer in these patients and that the answers are unavailable to us now
and may be unavailable for decades. One thing that I think may ring some
bells of caution in the public\'s mind is, gee, this could show up a lot
later.

DR. SHIRLEY MURPHY: Dr. Chesney, I\'m Dr. Shirley Murphy. I\'m the other
Murphy. It\'s good to have two blondes. We can switch.

(Laughter.)

DR. SHIRLEY MURPHY: I\'m the division Director for the Division of
Pediatric Drug Development.

Dr. Wilkin and I were just saying that we thought it would be helpful if
we could just go around to each person and ask them what kind of risk
management they would recommend, and if it\'s the same as another
person, just say, agree, just so that we could hear from every single
person. Would that be okay with you, Dr. Chesney?

DR. CHESNEY: That\'s fair. We\'ll start down at this end of the table.

DR. CUMMINS: Do you want me to advance to that list? Would that be
helpful?

DR. SHIRLEY MURPHY: Yes.

DR. TRAVIS: Did you want me just to address question 2 right now?

DR. SHIRLEY MURPHY: I think if you could just tell us from this list
what\'s your first choice or what do you feel just so we have a feeling
for all the individuals like changing the patient package insert, for
instance.

DR. TRAVIS: I actually had just gone through that and marked off the
ones that I would do at a minimum. I\'d at least do, to start with, a
boxed warning, recommending against use in certain age groups, including
a patient package insert to inform the patient or parent/guardian of the
risk, require that a medication guide be dispensed with every
prescription, the unit-of-use packaging, the issuing of the Dear
Healthcare Provider letter, and then education programs as well. Almost
all of them at a minimum.

DR. CHESNEY: Everything except the required medication guide. Did you
say you would include the medication guide?

DR. TRAVIS: The ones that I had not included is I\'m on the fence right
now with regard to additional studies because I see the incredible
expense involved, and also I\'m a cancer epidemiologist, so I study
cancer, and I know about the long latency periods. This age group is not
at a cancer bearing age now. Their underlying incidence rates are so low
that I don\'t think you\'re going to really find that much. You\'re
talking about an immense amount of time and money.

Limiting the indication of certain age groups. I had already thought
that had been done, so I didn\'t mention that one.

And contraindicating the use of the product in specific populations,
that\'s beyond the scope, I think, of what I can do given my background.
Someone else may want to do that.

And then I had voted yes for the others.

DR. CHESNEY: Dr. Rabkin.

DR. RABKIN: I just wanted to not answer the question that you posed, but
I\'ve been trying to get a word in just to remind people about what the
issues are here in terms of lymphoma. The parallel with the systemic
administration of high doses of tacrolimus. There, from every
indication, it appears that the mechanism by which that\'s associated
with lymphoma is strictly through the induction of immune suppression,
and if that\'s what we\'re positing as a potential risk for the topical
medications, then it would be possible to look for subtle disturbances
of systemic immunity, if it\'s systemic immune suppression and systemic
lymphoma that\'s of concern.

So I\'m still aware that although that\'s a very difficult problem to
study, I\'m less pessimistic than I would be if we were only to be able
to look for lymphoma as an outcome because I agree with the comments
that have been made around the room that that\'s going to be a very rare
outcome to be able to detect.

I don\'t believe that the pharmacology suggests that there\'s some kind
of a cumulative effect of these medications that will be independent of
their immune suppressive action. So immune suppression is something
where we can find other indicators, not perfect indicators but we can
detect that, and in the absence of alterations of immune function, then
we may be less concerned about the possibility of lymphoma as a
long-term complication of these medications.

DR. CHESNEY: So that could even be potentially under the first part of
question 5, which was other studies you might recommend.

DR. RABKIN: I\'m more getting towards Dr. Andrews\' question about what
needs to be known because I share Dr. Stern\'s concern that lymphoma may
not be the most frequent or most troubling long-term consequence. But if
it is systemic lymphoma, that is something that we can do something
about.

DR. CHESNEY: Did you want to weigh in on the risk management list? You
could agree with the person next to you or ‑‑

DR. RABKIN: I\'m more agnostic about the evidence that\'s been presented
so far and also not certain of the benefits that could be obtained from
some of these, given the state of knowledge being so low. If we say it
causes cancer, a lot of people will shrug their shoulders.

DR. CHESNEY: Dr. Wingo.

DR. WINGO: I guess if I had to pick one, just a few items in this list,
to put at the top, I would certainly put something about recommending
against use in certain age groups, similarly contraindicating use of the
product in specific populations, issuing a Dear Healthcare Provider
letter ‑‑ I would include that ‑‑ and the last one on the list, which is
the education programs for providers and patient categories.

This is a very complicated problem. It\'s like you want to do one kind
of study design to look at one outcome and a different study design to
look at some of the other outcomes. Again, it takes us back to Dr.
Andrews\' question of is one more important than the other. Is there one
question that we feel like we must answer, and if so, what is it and
what\'s the best study that we can do to answer that question?

DR. CHESNEY: Thank you.

Dr. Mattison, risk management specific recommendations.

DR. MATTISON: I\'m comfortable with the proposals that have been
suggested prior to my turn to talk.

I\'m just going to reiterate a point that I made earlier. I\'m concerned
about the substantial uncertainties that are addressable and resolvable
about the use of this class of agents in immature animals. I\'m
especially concerned because it\'s been suggested that one of the
mechanisms is to alter apoptosis, or programmed cell death, and normal
development depends critically on cells dying at appropriate times in
developmental processes. So I think there are major, major gaps in our
knowledge about what this class of agents can do during the course of
development and would just simply add that as the component of
additional studies.

DR. CHESNEY: Dr. Stern.

DR. STERN: When I think about levers, I\'ve already mentioned the one
that I think, in fact, would be most effective, which is a
non-regulatory one.

Also, in thinking about these levers, given our absence of being able to
quantify risks, when I think about the behaviors I would like to change
‑‑ we\'ve already heard about very young children but the others are
amount of application and duration of application. So perhaps things
that convey that at least in my perspective the likely long-term risks
of this agent are likely to be much higher with persistent long-term,
substantial use than they are with intermittent local use. So trying to
use the levers to have people use it as a second-line drug when they
really need it and not rely on it chronically.

DR. CHESNEY: Thank you.

Dr. Epps.

DR. EPPS: Thank you. There are several things for those of us who treat
atopic dermatitis and those who have had it, obviously there\'s always a
risk-benefit that is always taken into consideration. When we talk about
atopic dermatitis at our pediatric dermatology meetings, we always talk
about quality of life because that is a huge issue for young people.
They don\'t go to school for months. They\'re in and out of the
hospital. Their own self-esteem and appearance and missing out of school
and delays, it\'s quite a problem.

Certainly I don\'t consider axis suppression and risk of cancer
equivalent at all. There\'s always a risk and a benefit, what I tell
patients, when there\'s a risk like that, is it\'s either 0 or 100.
Either you get it or you don\'t. 30 percent. It doesn\'t matter. If your
kid has cancer, you have it. There\'s no in between.

So as far as risk management, additional studies, a boxed warning, if
you all think it\'s appropriate. I think it\'s okay to limit to certain
age groups and recommending against use in certain age groups. It should
be contraindicated in HIV. There are certain childhood diseases, whether
it\'s ataxia telangiectasia, inherited diseases, which not only feature
eczema but also have an increased risk of malignancy. Those should be
contraindicated. Package insert is probably okay. I don\'t think we need
to give one with each prescription.

Now, as far as unit-of-use, when we talk to patients, usually we say a
pea-size can cover an entire face. So, a small amount can cover a larger
area. So sometimes we\'ll just say just touch the top of the tube and
that can cover a certain amount. \"Sparingly\" is our mantra, as I said
before.

I think a Dear Healthcare Provider letter can be very helpful. It\'s not
just the dermatologists. The allergists prescribe it. The internists
prescribe it. Everybody is out there, oh, I have a little rash, by the
way, Doc. Oh, let me give you a little something to put on there. So I
think everyone should be aware.

Educational programs should be at all levels. Start in medical school.
Get it in Goodman and Gilman. Get in the CME, everything. I think the
more education and information, the better. I don\'t know you
necessarily need to be an alarmist, but I think people should be aware.

DR. CHESNEY: Thank you.

Dr. Gorman.

DR. GORMAN: I agree with Dr. Epps in the one thing that I think she\'s
disagreed with the other presenters, which is that a medication guide I
would also not support.

I would ask in the patient package insert that there be some wording
that deals with sharing this medicine with others. There are certain
products that the FDA and the manufacturers have done an excellent job
in scaring people about touching and sharing. I think this product
should be in that group.

DR. CHESNEY: Dr. Ebert.

DR. EBERT: Just to go through the list, first of all, of course, I think
I would support additional studies, as have been mentioned already and
certainly will be discussed in the upcoming minutes.

As far as the boxed warning and other issues of labeling, I guess I
would also want to look at what is currently available for the systemic
product of tacrolimus and whether we have boxed warnings or patient
package inserts for that particular product, and if so, if those might
be able to be used as at least a template for the topical formulation of
the product, and perhaps there might have to be some inferences made
that if there is some established side effects associated with the
systemic form, then by inference, if there is some absorption of the
topical form, one might at least expect to see some of those same
adverse effects associated there.

I also support recommending against use in certain age groups, as well
as the patient package insert to inform the patient.

As far as the unit-of-use packaging, again, I\'m a little bit unclear on
that whether that is something that could be incorporated into the
patient package insert or whether it has to be a separate entity. I\'m
not sure if the FDA is at all involved in, for example, limiting refills
or prohibiting refills, if that could be something that also could be
looked at, that it would require a follow-up visit to obtain another
prescription.

Then as was mentioned both yesterday and again today, I think increasing
the emphasis on dermatology in curricula or in CME programs and
reinforcing the significance of these products is certainly going to be
welcome.

DR. CHESNEY: Dr. Ten Have.

DR. TEN HAVE: Not being a clinician nor a behavioral change person,
everything sounds reasonable to me.

I do have one question. Somebody mentioned compounding earlier today,
and I don\'t know. Is that a no-no or is that something should be
mentioned in the inserts?

DR. CHESNEY: Maybe that\'s not a bad suggestion given that we hear that
people are mixing it with steroids. Maybe there should be some
additional information put about use this only as packaged.

Dr. Wilkin.

DR. WILKIN: I was just going to comment that my understanding is that
compounding is largely covered by the different State jurisdictions, the
boards of pharmacy in the different States and also the boards of
medicine, and that either pharmacists or physicians themselves may, on a
patient-by-patient basis elect under the standards of medical care to
put together two different materials, and that\'s the compounding.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: I\'m not too sanguine about the effectiveness of these
various risk management interventions. What I would like to see happen
is that there should be discouragement against using the drug in the
very young.

I\'d like to see some education of patients and families about two
things. One is the possibility that a topical drug can be absorbed
systemically and have systemic effects. Therefore, amount and duration
of use are very important. And I\'d like some messages about using these
drugs sparingly, do not share, some warnings about misuse.

Because I\'m not too sanguine about the effectiveness of these things, I
would like to see them tested. I think that the wording is really
important and I would love to see this kind of wording and the
variations go through some kind of cognitive testing process with a
variety of potential patients to see what they really understand. You
could also test language about potential cancer risk to see the reaction
and whether it might be advisable or not to include that in some kind of
patient education brochure.

I don\'t think I\'d recommend a medication guide.

I definitely think that some education of physicians is appropriate,
stressing the importance of these drugs as second-line therapy and
potential long-term risks.

DR. CHESNEY: Thank you.

Dr. Fink.

DR. FINK: I would agree with much of what\'s been said. The primary
thing I would push for is a boxed warning in that that legally has a
greater implication to the manufacturer of the drug to change their
behavior in terms of promoting the drug than any of these other steps
because I don\'t know that we can rely upon them to voluntarily change.
But if there is a boxed warning that says, not approved for use under
age 2, that really puts them on notice in terms of staying away from
that indication.

I\'m not sure it would be bad to have something about compounding
because for these two drugs, there could be a cautionary note, at least
in the package insert, that says, these drugs have specifically been
compounded in vehicles that promote their cutaneous absorption and any
extemporaneous compounding may actually destroy their activity.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: I would point out that we\'re not so much managing risk
here, although that\'s a little part of it. We\'re really managing
uncertainty about the character and magnitude of the risk. We don\'t
know what we\'re trying to manage. So we do need to make that clear to
the public in some way, and we need to focus additional studies on
reducing that uncertainty as much as we possibly can.

I agree with the remarks that say there should be more education and
less advertising, and a Dear Healthcare Provider letter sounds like a
very good idea to me.

DR. CHESNEY: Dr. Glode.

DR. GLODE: I would go back to the suggestion someone brought up earlier
of just looking at the oral compounds and seeing again for consistency
purposes if they have the boxed warning. I\'m very much in favor of the
patient package insert, and I think that part of what it should inform
people is that the basis for approval was essentially short-term safety
and efficacy, and what we\'re concerned about is again the unknown, but
the issue of long-term safety when using a drug that has some, but it
appears from what we know minimal absorption but some capacity for
systemic immunosuppression.

So I\'m in favor of the patient package insert, the boxed warning if
it\'s on other formulations, and education and additional studies.

DR. CHESNEY: Dr. Fost.

DR. FOST: I agree with almost everything that\'s been said. Just one
comment on the relevance of whatever is on the present insert of
patients who get it in other settings. I\'m not sure what the relevance
of that is. Those are patients with major diseases highly informed and
have long-term relationships with their doctors, have hours and hours of
conversations about things, highly literate about medical matters. For
sure, they should be told too, but I\'m guessing they know five times
more than their intern does about all these things. So I don\'t know
that that should be the standard for what\'s on the package insert for
the topical use where it will be a complete surprise to doctors and
patients.

DR. CHESNEY: Dr. Wilkin and Dr. Murphy, have we covered risk management?

DR. SHIRLEY MURPHY: I think that was very helpful to hear from all the
individuals. Thank you.

DR. CHESNEY: I\'d like now to go back to the very first part of question
1, what is a clinically meaningful increase in cancer risk from a
treatment for a chronic, non-life-threatening disease? Comments please.
Dr. Fink.

DR. FINK: I\'m not sure there\'s any scientific basis to us but I\'d
throw out less than a 1.5 increase and that if it had a 2-fold increase,
I would somehow consider that unacceptable. So I guess I might pick 1.5.

DR. CHESNEY: That was my reaction. I haven\'t a clue.

Dr. Stern.

DR. STERN: Well, I think, first of all, all cancers are not created
equally, and secondly, all chronic diseases are not equal in their
impact. So to me that\'s an unanswerable question. We use a variety of
agents long-term for debilitating chronic diseases that certainly
increase the risk of certain cancers by more than 2 and perhaps if you
look at least suggestive data for the TNF-alpha inhibitors that are
being used for rheumatoid and psoriatic arthritis, there is good
suggestion there that there\'s a substantial increase in lymphoma with
long-term risk and certainly a risk of other things as bad as cancer
like demyelinating diseases, and I\'m not sure which one I\'d rather
have, quite frankly, in terms of treatment.

So I think that\'s an unanswerable question. I think you have to look at
the risk-benefit. Does the patient really need it? What are the
alternatives? What is the burden of the disease, and for things that you
expect dose and duration to be a strong part of it, how can I use a
strategy that minimizes exposure and hence that? Sure, if the increase
in lymphoma risk with 1 year of use was a relative risk of 2, then I\'d
say that\'s out of the ball park for any treatment for atopic
dermatitis, but that\'s not the kind of thing. We\'re talking about a
continuum of severity and we\'re talking about a dose and duration
dependence of risk. So to me it\'s an unanswerable question.

DR. CHESNEY: Dr. Rabkin.

DR. RABKIN: Dr. Andrews already made this point, but relative risk is
perhaps not the best measure when we\'re worried about patient risk. And
there\'s a lot of attention being shifted to the excess risk, the
absolute magnitude. So doubling a very extremely rare occurrence is not
of concern. If you\'re going to assign a level ‑‑ and I\'m not sure that
you can ‑‑ if it certainly has all the complexities that were mentioned,
you probably wouldn\'t want to be looking at a relative risk when
you\'re worried about effects on patients.

DR. CHESNEY: Dr. Epps.

DR. EPPS: We also use other medications to treat severe atopic
dermatitis and some people use cyclosporine, maybe some other immune
modulators orally even to treat, PUVA. There are some other treatment
modalities, and I guess what the acceptable increase is there I guess
could be applied to this one as well, although it\'s topical and there
are some unanswered questions. But obviously, this disease can be severe
enough that we\'d accept a certain amount of risk.

I guess the other problem is that you don\'t use cyclosporine in
everybody, and it\'s not used as widely.

Also, I should comment that the method of practice or ‑‑ I won\'t say
standard of care, but the patterns of practice have evolved since these
medications have been approved. First it was second-line, and then well,
perhaps you could use it this way. And then certainly there was a recent
paper, oh, it decreases flares, and some people interpreted that to
mean, well, use it suppressively. Use it all the time whether you have
rashes or not. So those are other issues that need to be dealt with
because some people are putting it on normal appearing skin, although in
the world of atopic dermatitis, I don\'t think the skin is normal
anyway.

DR. CHESNEY: Dr. Fink and then Dr. Danford.

DR. FINK: Just a comment that I think as we deal with particularly
long-term induction of cancer risks, we potentially should look at some
of these smoking-related literature and other experiences which says the
average human being has no ability to conceptualize a risk that is
greater than 10 years down the road. So even if it is high, the average
person ignores it. I think we\'ve got to take some responsibility there
to say ‑‑ I don\'t know what the number is, but if there\'s a certain
amount of increase, it\'s unacceptable.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: Along those lines, I was intrigued by Dr. Epps\' earlier
comments about how when dermatologists get together, they talk about
quality of life in the context of atopic dermatitis. I\'m wondering if
they talk about it in sufficient depth to have maybe some decision
analytical models and quality adjustments to know what sort of tradeoff
in length of survival versus quality of life is acceptable to the
patient population in question. Although I don\'t think the first part
of question 1 is really answerable, we could make up an answer based on
that sort of an analysis I suppose.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I would agree with Dr. Fink on almost everything except what
he just said.

(Laughter.)

DR. GORMAN: I think UV exposure is an excellent example of a very
minimal increase over baseline risk that has really penetrated the
consciousness of the American population.

DR. FINK: It\'s wrinkles, not cancer.

(Laughter.)

DR. GORMAN: Touche.

(Laughter.)

DR. CHESNEY: Speak for yourself, Dr. Fink.

(Laughter.)

DR. CHESNEY: Drs. Murphy and Wilkin, do you need more of an answer to
number 1?

DR. WILKIN: If I could just comment on some of the quality of life
instruments that have been proposed to us. Not all, but many of them
actually focus on disease-specific pieces, and they\'re really designed
in a way ‑‑ they tend to go in the positive direction even in the
vehicle group. Do you feel better now that your atopic dermatitis is not
so itchy? In general, in these inflammatory diseases that sort of wax
and wane, folks get recruited early on when they\'re sort of at a
disease maximum. So even in the vehicle group, they tend to have some
improvement. They tend not to focus on the adverse events that might be
associated with the product or the difficulties of applying or ingesting
or those sorts of things. So I think there are some limitations with the
quality of life data sets that we actually get.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: I\'d like to respond to the earlier question about
eliciting patient preferences and do patients understand risks that are
low. I think this basic question is sort of unanswerable, but it is
potentially studiable, and that is through some methods that ask people
to trade off risks and benefits. It certainly would be an interesting
thing to do in a patient population, as well as among physicians who
treat these patients, and get an idea of how the risks and benefits are
traded off for different levels of disease severity.

DR. CHESNEY: Dr. Fost.

DR. FOST: Well, it\'s complicated for adults treating themselves, but
it\'s much more complicated for parents making decisions on behalf of
their children. They may discount, even if they believe it, a long-term
cancer risk in exchange for relief from the burden of caring for a child
who\'s got this chronic skin condition that\'s driving everybody crazy.
So it\'s just more complicated than finding out what parents want or
what kind of risk they\'d be willing to accept. That is, they may be
willing to accept the risk that we would think was not acceptable. Easy
for us to say.

DR. CHESNEY: Actually I think that\'s a very important point because
it\'s not the 3-month-old that chooses to have this cream put all over
their body at 10 times the dose every day for a year. So this is a very
intriguing issue.

Shall we go on to question 2, which I\'m dreading?

(Laughter.)

DR. CHESNEY: Well, let\'s see if we can sort out ‑‑ well, I\'ll let Dr.
Cummins tell us what you really want us to answer.

DR. CUMMINS: I\'m just going to read through the whole thing again,
about four slides.

Fact 1, lymphoma has been associated with systemic use of this class of
immunosuppressants in both preclinical studies and in human use.
Cutaneous malignancies are the most common malignancy associated with
systemic use of this class of drugs.

Fact 2, topical use of these immunosuppressants results in some, albeit
modest, systemic exposure. This may be increased in pediatric patients
due in part to increased body surface to mass ratio.

And then a premise. Malignancy may only be discernible via long-term
exposure, especially with modest systemic exposure.

So then we get into the questions. What is the best way to ascertain
this clinical risk of malignancy, e.g., lymphomas or skin cancer, in
clinical studies?

Please discuss the merits and drawbacks of each of the following, as
well as study design considerations: the duration of follow-up for each
enrolled patient, keeping in mind that the latency period of most
cancers is at least 10 years. Study design requirements: the sample size
needed to detect rare signals and feasibility issues; the approach to
ascertainment of skin cancers, for example, by physical exam by a
physician or a dermatologist or by interview or questionnaire; the role
of a comparison group; design strategies to optimize retention.

And then endpoint issues: reflect on the specific cutaneous and systemic
malignancies, whether other biologic endpoints should be collected, such
as viral infections of the skin, or other, for example, warts or EBV
infections, and/or pre-malignancy or early cancer endpoints such as
actinic keratoses.

DR. CHESNEY: Thank you.

DR. CUMMINS: We actually really would like your reflections on all of
this, if that\'s possible.

(Laughter.)

DR. CHESNEY: I guess the bottom line question is the first one. What is
the best way to ascertain this clinical risk of malignancy in clinical
studies? Who would like to tackle that first? Dr. Fink and then Dr.
Glode.

DR. FINK: I don\'t want to tackle the question. I would like to get a
point of clarification from what\'s been said earlier. If we said that
the latency for these cancers is 10 years ‑‑ I thought I heard earlier
that for skin cancers it was less because if it really is as long as 10
years, then all of the clinical reports of adverse events to date are
unmasking of a preexisting malignancy, not occurrence of a malignancy.
That actually may be an important issue because most of those reports,
the drugs haven\'t been on the market 5 years, and is that to say then
that none of the reports are new-formed malignancies? They\'re all
unmasking of preexisting pre-malignant conditions? Or is skin cancer
different? Because I thought Dr. Stern said skin cancers could ‑‑

DR. RABKIN: I made a comment about lymphoma being a very short latency
in the setting of immune suppression.

DR. STERN: There are three things you have to take into consideration
with skin cancer. One is are you looking at the effects of a primary
mutagen or carcinogen, and the second is are you looking at the effects
of some way in people who already have mutagenic injury, that their
mutated cells that have not undergone apoptosis may go on to cancer. So
if you look at the relationship between ‑‑ and since everyone is exposed
with UV, if you look at the relationship for carcinogens, most of which
in the skin have some mild immunosuppressive effects as well, when one
looks at the relationship between dose and risk, there seems to be a
long period between those two things, a long latency.

If you look at quite profound immunosuppression in the skin ‑‑ and one
of the things we don\'t know ‑‑ remember, 5 milligrams of cyclosporine
compared to a usual immunosuppressive dose orally, we know that these
agents systemically are much less immunosuppressive. But I haven\'t seen
studies of relative immune response on the skin. How immunosuppressed am
I where it matters for cutaneous carcinogenesis when I apply one of
these products versus when I take 5 milligrams per kilogram per day of
cyclosporine? That\'s data that we could probably have to get some idea
in this end organ of interest. What\'s the extent of immunosuppression?

If these agents were as immunosuppressive as oral calcineurin
inhibitors, we would expect in people who are in the susceptible age
groups to begin to see a substantial increase after about 2 years of
continuous use and by 5 years, get pretty close to where it thresholds.

However, the important thing is, as has been talked about in terms of
relative versus absolute risk, the risks of non-melanoma skin cancer
before age 35 in people who have not had X irradiation exposures,
children who do not have genetic abnormalities that pre-dispose them or
some unusual other exposures is very close to 0. Therefore, you\'re
dealing with people who aren\'t susceptible. How many heart attacks do
you see in 18-year-olds who have cholesterols of 400? They haven\'t
gotten there yet, but if they don\'t change and they have a bad ratio,
what are the odds that that\'s going to happen in the next 40 years? So
it\'s a very complicated problem and quite frankly, I don\'t think we
can well quantify it for these agents.

DR. FINK: Would you conclude from that then the adverse event report
data that were presented here are not necessarily reflective of drug
effect? Because none of them were on the drug for as long as 5 years or
even 2 years continuously.

DR. STERN: I don\'t remember a lot of any skin cancers except for two
nonmalignant tumors, as I recall, one basically probably secondary to
inflammation and another that we don\'t even have the diagnosis. Then I
guess, depending on how you count it, there was an HIV- infected person
with Kaposi\'s, and who knows what\'s going on there. I don\'t think we
have any data, and I would say that when it comes to skin tumors and
spontaneous reporting, I don\'t think that the Medwatch system would say
that\'s one of their strong points, but I defer to them.

DR. PITTS: Thank you. Well, actually I wouldn\'t say that there was a
masking because I think if you look at the Prograf label, you\'ll see an
acceleration of lymphomas. The other thing is that with the two
pediatric patients, one was a granuloma and the other was a facial tumor
without any information. However, with the topical tacrolimus, there
were five cases. One was a Kaposi\'s sarcoma, two non-Hodgkin\'s, and
one was a B cell lymphoma, and then an anaplastic large cell lymphoma.
But I\'m not sure if that\'s a masking of a previously existing ‑‑

DR. STERN: There were no squamous cells detected which is really, for
skin cancer, likely to be the strongest signal from everything we know,
and if it had occurred within weeks or months of use, I would have
discounted it as ascertainment bias rather than an effect. And the big
problem is this is not a susceptible population.

Someone mentioned to me ‑‑ and I had forgotten about this ‑‑ if you look
at the experience of childhood radiation ‑‑ and it\'s interesting. It\'s
mainly basal cell cancer ‑‑ if you studied a group of kids who got
childhood radiation at age 5 and examined them at age 15, there would be
few basal cells. You come back to those people when they\'re 45 years
old, if they\'re cancer survivors, and in the fields of radiation, some
but not all of them will be getting basal cell after basal cell after
basal cell. So it\'s analogous to that problem. I think your 10-year
answer is not going to be a robust answer in a childhood study.

DR. CHESNEY: Dr. Rabkin and then Dr. Glode.

DR. RABKIN: By the same token, there are characteristics of lymphoma
that would be more likely to be ascribable to effects of these
medications if we\'re thinking it\'s being generated by the pathway of
immune suppression. So EBV positivity you\'d anticipate would be
universal. The histology would be high grade and diffuse. So it
wouldn\'t be as informative to lump all lymphomas from some system like
Medwatch, but rather to collect more information, perhaps going back to
these individual records and determining if those lymphomas resemble
lymphomas that are seen in other settings that are similar.

DR. CHESNEY: Dr. Glode.

DR. GLODE: My question was just with regard to the clinical trial, I
wondered if it would be possible for Dr. Margolis to just share with us
in 1 to 2 minutes the study design of his study that the FDA has
apparently looked at to look at lymphoma and about how many patients
that would enroll or whatever, the power of the study, anything like
that just very brief.

VOICE: Dr. Margolis left.

DR. GLODE: Is he gone? Because maybe the study has already been designed
and reviewed and it\'s great.

DR. CHESNEY: Dr. Wilkin, do you have any information about Dr.
Margolis\' study?

DR. WILKIN: No. We didn\'t bring that material. Don\'t have the detail.

DR. CHESNEY: Does anybody else want to comment on the best way to
ascertain this clinical risk of malignancy in clinical studies? Dr.
Andrews or Dr. Wingo. She actually volunteered.

(Laughter.)

DR. WINGO: Well, given that you can\'t study both cutaneous skin cancers
and the lymphomas using the same registry, even if you had a registry
for the cutaneous melanomas, if you decided that maybe an important
thing to look at would be the risk of the systemic drug with lymphomas,
you could certainly design a study to look just at that issue and not
try to do too much in one study.

Another thought would be that if the data supported this ‑‑ and the data
are weak. I think that\'s been part of the discussion today ‑‑ you could
also make a recommendation for the squamous cell carcinomas that persons
who use these drugs should have the recommendation to be screened more
frequently, to have the body screens for the development of skin cancers
more frequently as opposed to doing a special study to look at that
issue.

DR. CHESNEY: Thank you.

Dr. Gorman.

DR. GORMAN: Back to what we know about these agents, if we\'re going to
apply them to the skin ‑‑ and we know that the drug is removed through
the blood stream. Is it also removed through the lymph, and would the
regional lymph nodes then be at somewhat greater risk than a systemic
absorption where the only way to get into the lymph node would be
through the blood supply? Do we know how this drug is removed from the
skin? Because it might make some difference in where the lymphoma would
then appear. Perhaps.

DR. RABKIN: I think those are very plausible scenarios, and we don\'t
have knowledge there.

DR. STERN: And it\'s also not only where the drug is getting to, but in
fact there\'s something in dermatology called SALT. Basically they\'re
interactions and interplay and T cell trafficking between skin and lymph
nodes as just part of normal immune response. So in fact, you\'ve got to
remember, as I said earlier, when we talk about the effects of
immunosuppression, the skin is in fact a very active immunologic organ
with a lot of T cell trafficking going back and forth.

DR. CHESNEY: Dr. Danford, you had your hand up.

DR. DANFORD: I think we need to be a little bit cautious about making
special recommendations for people who have been exposed to these
topical agents to have examinations frequently by dermatologists, not
because I don\'t think it\'s a good idea. I think that\'s probably an
excellent idea in clinical medicine, but it may confuse us for the
scientific question of are they at special risk for developing these
malignancies early because we\'re not subjecting whatever we\'re going
to use as a comparison group to the same sort of diligent search for the
malignancies, and we may falsely uncover a risk that\'s not there
because of differences in ascertainment of the outcome.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: If I were pressed to do a study, I would look at the
outcome of lymphoma and make use of the State cancer registries for case
ascertainment. And I wouldn\'t limit the study only to children. I would
try to get a population where the incidence is higher where it would be
more likely to be able to detect a difference.

DR. CHESNEY: Dr. Stern.

DR. STERN: If one were to embark on one study, I think we\'ve heard over
and over that there\'s a big power problem, and one of the things is
there are two sponsors, and I just wonder whether rather than
encouraging two separate, under-powered studies, one of which will turn
out to be positive and negative, whether we might not say if you\'re
going to do a study, take it all in one shot, and that also might help
guarantee a little bit of investigator independence from the sponsoring
company. Also, there\'s a lot of cross-use between these two drugs. In
my practice who gets Protopic versus Elidel is what their insurance
company is, and that\'s something that changes over time because most
insurers, at least in Massachusetts, have one or the other and not both
as a covered drug. So if you\'re going to do it, which I\'m not really
terribly enthusiastic about, you may as well do it once jointly for all
the reasons I\'ve said.

DR. CHESNEY: Dr. Epps.

DR. EPPS: I would make full use of the Children\'s Cancer Registry.
Perhaps a few questions about calcineurin inhibitors would be helpful
even though that\'s sort of retrospective, but I think that would be at
least moving in the right direction. Obviously, longitudinally, it would
be very difficult, very expensive. I don\'t think that looking for
actinic keratoses is helpful. As far as viral infections, warts, EBV,
probably also molluscum contagiosum seems to be increased as well. I
would look at that a little bit, although we already know that they\'re
all increased.

So I agree, I don\'t think other than our routine dermatologic exams ‑‑
a lot of the primary care physicians do see things that if they aren\'t
sure what they are, they do refer on, so that if we started seeing
teenagers and young people with suspicious or skin cancers, then we
should certainly be aware and think about it, especially if they\'re
atopic or chronically. A lot of the chronically or more severe atopics
we see regularly. You have to certainly not only for insurance purposes
because they won\'t renew their prescriptions forever, but we don\'t
renew the prescriptions forever because as the disease evolves and it
changes and certainly therapy should change.

DR. CHESNEY: Dr. Rabkin and then Dr. Wingo.

DR. RABKIN: Deliberately repeating myself, the underlying condition is
controversially associated with an increased risk of lymphoma. So if a
study like that were to identify those patients to have an elevated
risk, it wouldn\'t be straightforward to ascribe that to the medication.

DR. CHESNEY: Dr. Wingo.

DR. WINGO: I just wanted to make a comment about the Children\'s
Oncology Group cancer registry just to point out that it is not
population-based. It\'s facility-based. There are advantages and
disadvantages to going with such a registry as compared to the
population-based registries.

DR. CHESNEY: Other comments about question 2?

(No response.)

DR. CHESNEY: That is enough?

DR. SHIRLEY MURPHY: Yes.

DR. WILKIN: Yes.

DR. CHESNEY: Question 3.

DR. CUMMINS: FDA has not asked for such long-term studies in topical
products before. To require such screening means that we are asking
companies to take on very large, lengthy studies with substantial
logistical challenges in patient retention, follow-up, costs, and other
factors. In what situations should we require such studies? And what
criteria would you identify as important in deciding that this type of
study be done?

DR. CHESNEY: Dr. Danford.

DR. DANFORD: I have a question. Leaving the FDA aside and the issue of
topical products aside, can anybody think of examples of investigations
that have been as long-term as we\'ve proposed and as complicated as
we\'ve proposed that have actually come to fruition and provided
valuable information for us?

DR. MATTISON: I think the DES study is a good example, a double-blind
trial looking at the impact of this drug. There are a host of
reproductive and developmental endpoints that would have never been
identified actually had the study not been conducted. That\'s not the
only one, but that\'s certainly one that comes to mind.

DR. CHESNEY: Dr. Mattison, I have you down here. Was that what you
wanted to say?

DR. MATTISON: Oh, sorry.

(Laughter.)

DR. MATTISON: It seems to me that coming back to the mantra that I\'ve
been singing here today, long-term studies generically seem to me to be
especially important to consider when the endpoints are developmental
and may take some substantial period of time for the impact of the agent
to be expressed. So I would say that one of the criteria would be use of
the agent during developmental time frames or life stages and concern
for uncertainty about the impact of those exposures across the course of
development.

DR. CHESNEY: Dr. Glode.

DR. GLODE: So my criteria for these topical products would be, first, is
there evidence of systemic absorption of the product. Secondly, is there
evidence beyond pharmacologic absorption of systemic effect of any kind,
and third, are the other formulations that are systemically administered
associated with serious and/or life-threatening complications. And if
the answer to those questions are all yes, then that\'s the population
that deserves long-term studies I think.

DR. CHESNEY: Yes.

DR. GORMAN: I\'d like to echo what Dr. Glode said because I think those
are the parameters, and the outcomes with the systemic absorption and
systemic effects have to be severe and pose a public health challenge.
If I remember Dr. Wingo\'s data correctly, there are about 20 cases of
lymphoma in adults per 100,000, and if 20 percent of Americans have
atopic dermatitis, and if they\'re all exposed to this drug class, and
if it just increases the relative risk by a 2-fold effect, which might
be hard to determine statistically, that increases the burden of
disease, from the back-of-the-envelope calculations, by 25 percent in
the American population, which I think is a substantial increase in
risk. So if everybody in the 20 percent got it and got a 2-fold increase
in their rate of lymphoma, that would increase the total number of
lymphoma cases in the United States by 25 percent. I think that\'s a big
number.

DR. CHESNEY: I think the question is in what situation should we require
such studies. Dr. Rabkin pointed out the difference between lymphoma
being life-threatening and skin cancer not necessarily being
life-threatening. So I think a criterion would be that there is a signal
for a life-threatening event which would, for me, precipitate the
requirement for a more comprehensive study.

Dr. Fink and then Dr. Andrews.

DR. FINK: I think since widespread usage and long-term risk are
important, I would almost raise the question that this is one drug or
one class of drugs where there\'s that concern. There are many new
bioengineered agents coming into use and we\'re reaching a period of
very rapid drug development, and it would almost strike me that it may
be more cost effective to look at undertaking some NIH
federal-sponsored, large-term pediatric population studies looking at
all risks rather than separating them out drug by drug because it may be
environmental risks, it may be drug-related risks, but we\'re clearly in
a very rapid period of evolution both in terms of pharmacotherapy and
potentially changes in the environmental risks.

DR. CHESNEY: I had that same thought earlier today, and I think wasn\'t
original. Has Dr. Alexander not been a proponent of long-term childhood
studies such as the Women\'s Initiative?

DR. RABKIN: There actually is in the planning phases implementation of a
very large cohort of children to be followed from birth, actually prior
to birth, with cancer being one of the important endpoints. But that
still may not be powerful enough to detect a side effect of these
medications if they\'re not used as frequently as the manufacturers
hoped.

DR. CHESNEY: Could you tell us a little more about that study? It\'s to
look at all life events?

DR. MATTISON: We\'re about 2-and-a-half to 3 years into what\'s thought
to be about a 6-year planning phase of a study that\'s called the
National Children\'s Study that would enroll about 100,000 families. It
was mandated that NICHD begin planning this in the Child Health Act of
2000. The goal is to look at environmental influences on children\'s
health, growth, and development. There are, in designing the study,
substantial concerns by various working groups about pharmaceutical
exposures and their impact. As I say, it\'s in its planning phases right
now.

There is an advisory committee that\'s providing recommendations to
NICHD and to the other federal agencies that are participating in this,
and there\'s substantial discussion about even with a sample size of
100,000, how useful this would be for ascertaining exposures that are
associated with cancers given that it\'s likely that this will be some
sort of a representative sampling of folks around the United States.

But there are current discussions going on with NCI about the role that
this study could play either as a control cohort or as a cohort to look
at specific biomarkers in association with exposure.

All of the information about the study is publicly available. There is a
public web site called the nationalchildrensstudy.gov, and the current
hypotheses that have been proposed by the working groups and other
organizations are there, as well as minutes from all the meetings.

DR. CHESNEY: Thank you.

Dr. Ten Have.

DR. TEN HAVE: One more aspect of the criteria for launching these
studies may be better animal studies that try to approximate patient
reality better. Somebody mentioned that none of the animal studies have
been done on young animals. That may be one criterion.

Another one may be lower doses, longer duration trials in animals, again
to try to approximate more what\'s happening in clinical reality.

DR. CHESNEY: Any other suggestions for question 3?

(No response.)

DR. CHESNEY: On to question 4.

DR. CUMMINS: Is there a role for cancer registries and/or the SEER
program in this long-term follow-up project? Please discuss how one
might utilize existing registries or programs.

DR. CHESNEY: Dr. Andrews.

DR. ANDREWS: I think the answer is obvious. If there is to be a study
looking at exposures in lymphoma, then the State registries could play a
key role. The SEER program, I don\'t think, allows you to actually do
the linkage. I think that has to be done at the State level. So one
could identify the patients and exposures through some mechanism,
whether it\'s through an automated database or through patient
recruitment, and link that information with cancer registries for
ascertainment of lymphoma.

DR. EPPS: I agree.

DR. CHESNEY: Any other comments about that? Dr. Fink.

DR. FINK: A concern I guess I would have with the use of the registries
is they may be helpful, but again going back to some of the data from
the asthma field, there have been several nice studies that showed that
only about 10 percent of 30-year-olds who had pediatric asthma recall
that they had asthma as a child. I\'m not sure, if you use a registry
approach, what the likelihood is of recalling atopic dermatitis or use
of a calcineurin agent for making that association.

DR. ANDREWS: I would agree. I wouldn\'t start with identifying cases
from the registry because I think recall would be hopeless here. I would
identify people exposed first and use their exposure status and their
identification to then identify reported cases of lymphoma because we
know there is close to 100 percent ascertainment of lymphoma in these
cancer registries. So it would be some kind of a longitudinal study
where the registries are used to ascertain the outcome.

DR. FINK: Okay, but that\'s a big registry to take on people who use the
drug. That doesn\'t exist currently.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I think the registry doesn\'t exist as a registry, but I
think the prescription databases, if available, could provide you with
those numbers that could then be linked 40 years later to the cancer
registries.

DR. CHESNEY: Dr. Santana mentioned before he left, if it was pertinent
to bring up, the ‑‑ I forget now how you all describe this where you put
the label on and you require the physician to register, that process. He
said he wondered if that was a situation where physicians using these
drugs would have to be registered and the patients have to register.
Could you review that policy for those who might not have heard it
yesterday? Obviously I didn\'t remember the details.

DR. WILKIN: Well, there is such a program for thalidomide which is a
systemic, very potent teratogen where physicians must take certain CME
types of courses and make assertions that they understand the
pharmacology of thalidomide, the teratogenic risk, that they understand
the risks of getting pregnant and how those risks might be minimized
with counseling. And then pharmacies I believe register, and there\'s a
controlled distribution. The thalidomide goes to the pharmacy and only
specific pharmacies. Again, the physician would direct a patient to go
to a specific pharmacy to pick it up. There\'s a program embedded in all
of this of getting pregnancy tests in a timely manner in women of
childbearing potential. So those are the kinds of things that could be
done if that\'s responsive to the question.

DR. CHESNEY: That would certainly allow registering of every patient who
used it, but it seems that it might be a bit extreme.

Dr. Fost.

DR. FOST: Thalidomide is a drug with virtually a 100 percent incidence
of an extreme adverse effect if used improperly. So that sort of
intensive monitoring is warranted by the severity. Here where you don\'t
even know ‑‑ to invest that sort of effort in something that may produce
‑‑ well, you don\'t know what it will produce and it may take you 20
years to find out. There are hundreds of drugs you\'d want to ask that
kind of question about.

DR. CHESNEY: I agree. I just wanted to bring it to the table on his
behalf.

Dr. Rabkin.

DR. RABKIN: Just to mention an alternative model for investigating
pharmacoepidemiologic associations is to take advantage of preexisting
healthcare networks that already have computerized records of
prescriptions and also track health outcomes. So that\'s something that
a number of pharmacoepidemiologic research groups have been able to
investigate with fairly large patient populations.

DR. CHESNEY: Thank you for bringing that up. The Kaiser Permanente group
was mentioned yesterday as an example of that.

Other suggestions for question 4?

(No response.)

DR. CHESNEY: Is that enough? Okay.

Moving on to the first part of question 5, Dr. Cummins, maybe we could
just ask for any more specific suggestions about other studies that
would be recommended.

DR. FOST: Could we just go back to 4 just to add to Dr. Rabkin\'s
suggestion?

DR. CHESNEY: Yes.

DR. FOST: What\'s the extent of the use of the calcineurin inhibitors in
Europe in countries where they have integrated databases, medical
databases?

DR. CHESNEY: Dr. Salmon.

DR. SALMON: I have to say I can\'t answer that question either on a
national level or across Europe. I suspect the records are available,
but I\'m afraid I don\'t have them.

DR. CUMMINS: The first part of question 5 is what other studies would
you recommend, for example, animal studies.

DR. CHESNEY: Other studies that people would recommend that haven\'t
already been brought? Dr. Stern.

DR. STERN: Well, I do think that the amount of animal
photo-carcinogenicity experiments that have been done for these
compounds compared to the likely magnitude of risk represents an
imbalance that could be easily corrected, and I think there are a number
of designs that can look at simultaneous and sequential exposures with
appropriate controls and at least in some models ‑‑ you can\'t predict
extent, but at least predict direction or how much to be concerned would
either help to increase our concerns or perhaps even allay our concerns
about the use of these in various ways, including controlling for age of
animals and levels of exposure and chronicity.

DR. CHESNEY: I think many people picked up on that.

Dr. Wilkin.

DR. WILKIN: Perhaps Dr. Stern can give us a few more pieces of
information on this. We thought about this internally. The rodents, in
which we look at this model, are essentially nocturnal animals. So this
is sort of a very artificial thing that happens to them. I\'m not sure
that over time they have all of the evolutionary adaptive advantages in
their immune system. In other words, if we got a negative response, what
would that tell us, I mean, a negative signal that the calcineurin
inhibitor wasn\'t doing something?

DR. STERN: I don\'t do mouse work and I don\'t recall ‑‑ and perhaps you
do ‑‑ for the calcineurin inhibitors, if they\'ve ever been tried
systemically in mice with photo-carcinogenicity. I\'m not aware of that,
if there are positive responses.

I guess what I would look for is, first, I\'d look and see if there\'s a
positive animal model of exposing the animal, giving them either placebo
or systemic doses of calcineurin inhibitor and seeing if there\'s an
increase in subsequent skin cancer risk, kind of the human model in
transplantation. If it hasn\'t been shown, I\'d try that experiment. If
that were negative, I\'d go home and take back all my comments.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I\'d like to suggest a varicella study. I think dogs are
susceptible to varicella. There\'s also a vaccine in dogs for that. I
would like to see if when this agent is used topically on dogs, whether
the death rate from varicella or the breakthrough rate for immunized
dogs changes.

DR. CHESNEY: Dr. Fink.

DR. FINK: This wouldn\'t really be an animal study, but it might be
interesting to try and look at, in a small number of young patients, if
this drug is going to be used, whether local application of it affects
their immune response to vaccinations since that is taken up by
localized lymph nodes. I don\'t know how feasible that is, but it would
strike one as something worth looking at.

DR. CHESNEY: I was very intrigued by Dr. Hill\'s comment that there may
be drainage to the local nodes, and I wondered about the feasibility of
looking at the local nodes in animals. I have no idea how to do it, but
to see if the lymph nodes near a localized area of application look
different than nodes at another site or whether it would be possible to
label the drug and see how much of it went to nodes and how much went
elsewhere in terms of additional studies.

Dr. Rabkin.

DR. RABKIN: We\'re I think several steps away from the question about
what the goal is, though, because even if you do note differences in the
local lymph nodes, it may not be relevant to question as to whether this
increases risk of systemic lymphoma.

DR. CHESNEY: I agree, but it was a great idea and I just wanted to say
it.

(Laughter.)

DR. CHESNEY: Other comments about additional studies that could or
should be done?

(No response.)

DR. CHESNEY: Have we been of any help with these questions? I feel like
they were very difficult and complex to try to answer in a short period
of time.

DR. WILKIN: Yes. I think we\'ve heard a lot of important suggestions
today.

I would like to make just a couple of comments. Originally we started
out with the first part of question 1 and not the second part, and it
was really a lead-in to these long-term studies. We had planned this
session of the advisory committee to talk about uncertainty and how to
study for it. I don\'t know that the FDA group really came with the
preparation to talk about risk management per se.

And the other part that we missed today is I think we might have heard a
somewhat different portrayal of the actual risk if industry had had an
opportunity to go over the data. So I think we\'re going to take all of
the information we\'ve heard, discuss it with the two industries that
currently are involved. Who knows? Maybe there\'s an opportunity for
this group to get a refresher course in what happens at the cellular
level and also in dosimetry.

I guess that\'s one of the other important points today that we had sort
of thought about but maybe not articulated in such succinct terms as Dr.
Stern, that this is largely a question of dose and duration. And if
you\'ll permit me one more quote, Paracelsus did say that whether a
substance is toxic or not depends on what its dose is. We have a lot of
topical products that have, frankly, been developed from fairly toxic
drugs given systemically. Just as an example, 5-fluorouracil is used on
the surface of the skin. I can guarantee that the side effect profile is
nowhere close to what we see with systemic 5-fluorouracil. We have
active agents in topical products for which industry has never developed
a systemic-form product simply because of toxicity concerns. So I think
there\'s an enormous dose aspect to all of this.

We even have a retinoid in a product which is largely going to be used
in the setting of pregnancy. It\'s used for melasma and melasma is
virtually a physiologic sign of pregnancy and we know that retinoids
given in much higher amounts are actually going to lead to
teratogenicity.

So I think one of the things that we always want to be careful about ‑‑
and I think I heard the word \"scare\" maybe once or twice ‑‑ is I think
we want to make an important distinction when we are working on risk
management to carefully define the line between pharmaco fear mongering
or scaring and conveying uncertainty. I think that\'s something that we
also heard the conveying of uncertainty from the committee. And I think
we\'re going to work hard internally, and we may come back and find out
from your group if we got it right. But we want to make sure that we
haven\'t crossed over beyond into the crying wolf because crying wolf
undermines every precaution and warning and all of the other, if you
will, advisory or hortatory things that FDA puts in all of our
medication guides and healthcare provider letters and all these sorts of
things.

So I think we want to be very careful. We don\'t want to be overly
careful. I mean, we want balance is basically what I\'m saying. Dr. Fost
actually mentioned that when thalidomide was brought up. He said this is
not thalidomide I think, something to that effect, that we need to think
of a measured communication response for the information we have got.

So I think the committee has worked very hard today, given us a lot of
good information. You\'ve not only wrestled with the science, but
probably you\'ve wrestled with the even greater difficult issue of
societal values, that is, how much do we want to know things, how much
are we willing to spend, subject kids to different sorts of things to
learn about them. It\'s a difficult area when we\'re working with
uncertainty, and we\'ll be working with the companies and we may well
come back to you to see if we\'ve been able to convey the uncertainty in
an appropriate manner.

Thank you.

DR. CHESNEY: Thank you very much for putting it in the broader
perspective. I think we realize that when we come, you ask us to look at
something very focused, and we don\'t have necessarily the perspective
that you do. But we thank you for bringing it to us.

I also want to thank you for educating us in ancient mores.

I also have a comment that if anybody on the panel needs a cab and
didn\'t sign up there will be a desk in the lobby that\'s got an FDA
label on it and they will help find a cab.

I thank everybody on the panel very, very much for all your comments. I
think it was a very informative session. Thank you.

(Whereupon, at 2:55 p.m., the subcommittee was adjourned.)