FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY SUBCOMMITTEE
OF THE
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
The Ballrooms
The Hilton Hotel
ATTENDEES
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)
STEVEN E. EBERT, PHARM.D.
Department of Pharmacy
MARY GLODE, M.D.
Professor of Pediatrics
The Children's
University of
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)
ROSELYN EPPS, M.D.
Chief, Division of Dermatology
Children's
THOMAS TEN HAVE, PH.D.
Department of Biostatistics and
Clinical Epidemiology
University of
ROBERT STERN, M.D.
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
DAVID DANFORD, M.D.
Associate Professor of Pediatrics
University of
ATTENDEES (Continued)
SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)
(Continued)
ROBERT FINK, M.D.
Chairman, Department of Allergy and Pulmonary Medicine
Children's
NORMAN FOST, M.D., M.P.H.
University of
RICHARD GORMAN, M.D., FAAP
Pediatrician
Pediatric Partners
VICTOR SANTANA, M.D.
Associate Professor
Dependent of Hematology/Oncology
St. Jude's
Children's
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
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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.