Pediatric Oncology Pediatric Oncology Subcommittee of ODACSubcommittee of ODAC

Report of Meeting

October 20, 2005

Pamela J. Haylock, RN, MAConsumer Representative

presenting on behalf of

Gregory H. Reaman, MD Subcommittee Chair

Subcommittees

Subcommittees are advisory to the “parent” committee do not directly advise FDA

Parent committee reviews subcommittee recommendations; advises FDA

At least 2 members of parent committee serve on the subcommittee

No charter or official roster

Pediatric Subcommittee to ODAC BPCA– Sec 15

Evaluate and to the extent practicable, prioritize new and emerging therapeutic alternatives to treat pediatric cancer

Provide recommendations and guidance to ensure that children with cancer have timely access to the most promising new cancer therapeutics

Advise on ways to improve consistency in the availability of new therapeutic agents

Pediatric Subcommittee Pediatric Subcommittee Members & Consultants for Members & Consultants for the October 20, 2005 the October 20, 2005 MeetingMeetingFrom ODAC: Gregory H. Reaman, MD,

ChairpersonPediatric Oncology & Chair, COGProf Pediatrics, GWU, School of MedicineWashington, D.C.

Pamela Haylock, RN, MAConsumer Representative to ODACOncology Consultant & Doctoral StudentUTMB Graduate School of Biomedical SciencesGalveston, TX

Consultants

Jeffrey Barrett, PhDAssoc. Prof, Pediatrics, Children’s Hospital of Philadelphia

James Boyett, PhDDept. BiostatisticsSt. Jude Children’s Research Hospital, Memphis, TN

Jerry Finklestein, MDJonathan Jacques Children’s CA CenterLong Beach, CA

Michael Link, MDStanford, School of MedicineDivision of HematologyStanford, CA

Charles Reynolds, MDChildren’s Hosp of LA/USCLos Angeles, CA

Victor Santana, MDDept Hematology OncologySt. Jude, Children’s Research Hospital, Memphis, TN

Consultants

Cindy Schwartz, MD Rhode Island Hospital Dept. Pediatrics - Hem/Onc Providence, RI Malcolm Smith, MD, PhD Head, Ped Section, CIB CTEP, NCI Clinton Stewart, PhD

St. Jude Children’s Research Hospital Memphis, TN

Thomas Walsh, MDChief, Immunocompromised Host Section, NCI

Naomi Winick, MDDept. Pediatrics – Hem/OncUT, Southwestern Med CtrDallas, TX

Consultants

Marilyn S. Eichner – Rockville, MDPatient Representative

Cathy A. O’Connell – Belchertown, MAPatient Representative

Eugene Sun, M.D.Industry Representative

Global Pharmaceutical DevelopmentAbbott Laboratories, Abbot Park, IL

FDA Participants Richard Pazdur, MD

Director, Office of Oncology Products Karen Weiss, MD

Deputy Director, Office of Oncology Products Patricia Keegan, MD

Director, Div of Biologic Oncology Products Robert Justice, MD

Acting Director, Division of Oncology Drug Products Ramzi Dagher, MD

Medical Team Leader, Division Oncology Drug Products

FDA Participants

Joseph Gootenberg, MDMedical Team Leader, Divsion of Pediatric Drug Development

Lisa Mathis, MDActing Director, Division of Pediatric Drug DevelopmentOffice of Counterterrorism & Pediatrics

Martin Cohen, MDMedical Officer, Division of Oncology Drug Products

Jeff Summers, MDMedical Officer, Division of Biologic Oncology Products

Anne Zajicek, MD, NIH Victoria Ferretti-Aceto, PharmD, Executive

Secretary

Pediatric InitiativesPediatric Initiatives

Pediatric Research Equity Act, December Pediatric Research Equity Act, December 3, 20033, 2003

Best Pharmaceuticals for Children Act, Best Pharmaceuticals for Children Act, January 4, 2002January 4, 2002

Both laws are intended to support Both laws are intended to support and encourage drug development in and encourage drug development in the pediatric populationthe pediatric population

Pediatric Research Equity Pediatric Research Equity ActAct

(PREA)(PREA)

One of two laws intended to promote the study One of two laws intended to promote the study of drugs and biologics in pediatric patientsof drugs and biologics in pediatric patients Studies prevent pediatric patients from Studies prevent pediatric patients from

being a “study of one” being a “study of one”

Studies in the pediatric population are Studies in the pediatric population are REQUIRED, REQUIRED, but only for the indication that was but only for the indication that was studied in adultsstudied in adults

Best Pharmaceuticals for Children Act (BPCA)

In pediatric oncology prioritize new drugs for study assure timely access to new

treatments develop pre-clinical models of

pediatric cancers

Why both PREA and Why both PREA and BPCA?BPCA?

Distinction between the scope of studies Distinction between the scope of studies requested under BPCA and required requested under BPCA and required under PREAunder PREA

PREA specific to indication in submissionPREA specific to indication in submission BPCA can ask for “off-label” indicationsBPCA can ask for “off-label” indications

Open Public Hearing Open Public Hearing SpeakerSpeaker

Sadhana Dhruvakumar

Director, Medical Products Testing

People for the Ethical Treatment of Animals

Animal Use in Drug Development

Questions from NIH to the Pediatric Subcommittee of the

Oncologic Drug Advisory Committee

What type of prioritization process should be used for deciding which off-patent drugs should be studied? What is the definition of health

benefit? Number of patients affected Lack of other drugs that treat the disease Severity of the disease

Questions

Are there other drugs that should be studied? Antineoplastics Supportive Care

Anti-emetics Anti-infectives Analgesics

Other

Issues in post-marketing studies for clofarabine (Clolar™)

Feasibility of proposed populations (ALL, 1st or 2nd relapse) & primary endpoint (4 mo EFS)?

Design’s likelihood to permit adequate assessment of clinical benefit?

Can data generated in adults support efficacy in pediatric ALL patients?

Issues in post-marketing studies for clofarabine (Clolar™)

Adult populations & primary efficacy endpoints do not permit adequate assessment of clinical benefit. Suggest focus on 1st relapse, known active agents in controlled setting. Remission induction &/or MRD are potential primary endpoints.

It is not plausible that Adult AML data supports efficacy in pediatric ALL patients based on current knowledge of disease biologies

Issues in post-marketing studies for pegfilgrastim (Neulasta®)

Will Amgen’s study in patients with sarcoma treated with VAdriac/IE allow for extrapolation of activity and safety findings across all age groups and different pediatric cancers?

Issues in post-marketing studies for pegfilgrastim (Neulasta®)

Difficulty enrolling this population of patients (esp. younger ages) in these studies

Difficulty administering filgrastim in randomized settings

Competition with other studies where protocols demand growth factors

Issues in post-marketing studies for pegfilgrastim (Neulasta®)

Suggestions:1. Patients serve as own controls2. Randomize for the first cycle3. Consider studies in patients with

rhabdomyosarcoma & neuroblastoma to enhance age range of subjects

Issues in post-marketing studies for palifermin (Kepivance®)

Suitability & feasibility of need for dose escalation;

Need for pharmacokinetic data Choice of patient population

(homogenous Vs heterogeneous r/t underlying disease, source of stem cells, cytotoxic regimen, etc.)

Issues in post-marketing studies for palifermin (Kepivance®)

Need data from pediatric populations: Suggest decreasing # of doses tested in dose

escalation portion Consider evaluating other schedules Suggest study in pts with acute leukemia

receiving allogeneic transplant would be useful, feasible

Population could be both autologous & allogeneic transplant recipients

Use adult PK data as a guideline for when/how to sample, but only as a framework for ped dosing

Ongoing studies of Ongoing studies of vincristine & actinomycin-vincristine & actinomycin-DD Approach to safety/efficacy & PK data Are there additional data that should be

collected? Could frequency of toxicity be

minimized with dose cap? Would dose-capping cause underdosing

& subsequent lack of efficacy Application of mathematical models for

dose finding?

Ongoing studies of Ongoing studies of vincristine & actinomycin-vincristine & actinomycin-DD

VCR: difficult to quantify toxicity Lack of standard assessments &

scoring for peripheral neuropathy Required tests for measuring or

monitoring?

Off-patent BPCA Process

Could additional labeling data to provide health benefits for pediatric patients r/t off-patent drugs and/or therapeutic drug classes?

Off-patent BPCA Process

Need dose adjustment guidelines for many off-patent drugs, specifically in obese children

Administration methods to decrease toxicity – eg., less frequent dosing intervals

Dose-optimization via systematic methods Tools to measure early toxicity Arbitrary age groups (suggesting 2 age

ranges during first year of life, then 1-5 & 5-10)

Suggested topics for future ODAC Pediatric Subcommittee Meetings

Pain control Symptom management in neonates Drug delivery systems Long term sequelae Orphan drug indications End of life & palliative care Indications waived from the

requirement for conducting pediatric studies

Suggested topics for future ODAC Pediatric Subcommittee Meetings

Role of stable disease as an endpoint Endpoints for pediatric cancer Pre-clinical predictors of clinical

outcomes Re-formulations, rounding off errors Past 7 years (post PREA & BPCA): any

changes in getting drugs to pediatric cancer patients earlier?

Suggested next meeting of ODAC Pediatric Subcommittee:

First quarter 2006