1. Barriers to Participation in Clinical Trials Pediatric Oncology

2. Director, Clinical Trials Management Oncology Programs
Jeana Cromer, MPH, CCRP
Director, Clinical Trials Management
Oncology Programs
St. Jude Children's Research Hospital
Comprehensive Cancer Center

3. Agenda Childhood Cancer – Overview
Regulations and Legislation for Pediatric Research
Ethics of Pediatric Research

4. Overview of Childhood Cancer

5. Ref: Hirschfield, et al JCO 2003. Vol 21 pp1066-1073
Background
1 million diagnosed with cancer annually in the USA
<1% Childhood cancers
170,000 lung cancer per year
175,000 breast cancer per year
179,000 prostate cancer per year
10,000 – 12,000 pediatric cancer patients per year
Ref: Hirschfield, et al JCO Vol 21 pp

6. Childhood Cancer Facts
In 2007, approximately 10,400 children diagnosed with cancer
Approximately 1,545 will die from disease
Leading cause of death by disease in children 1-14 years
American Cancer Society. Cancer Facts and Figures Atlanta, GA: American Cancer Society. Retrieved December 26, 2007, from

7. Childhood Cancer Incidence and Survival Rates
11.5 cases per 100,000 children in 1975
14.8 cases per 100,000 children in 2004
5-year survival rates for all cancers combined 58.1% ( ) to 79.6% ( )
Significant advances in treatment and supportive care
Clinical trials research
SEER Cancer Statistics Review,

8. Common Types of Childhood Cancer
Leukemias - ALL and AML
Cancers of the central nervous system – Brain tumors
Neuroblastoma
Sarcomas – osteosarcoma, Ewings, soft tissue
Lymphomas – Hodgkin’s lymphoma, non-Hodgkin’s lymphoma
Liver Cancers – hepatocelluar, hepatoblastoma
Kidney tumors – Wilms, clear cell sarcoma
Retinoblastoma
Germ Cell Tumors
Other Rare Tumors – melanoma, adrenocortical, nasopharyngeal carcinoma

9. Childhood Cancer Incidence
Incidence of childhood cancer peaks in the first year of life
Incidence is higher for children under 5 years of age and ages 15-19
Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program , National Cancer Institute, SEER Program. NIH Pub. Nol Bethesda, MD, 1999

10. Incidence Varies by Type and Age
The types of cancer in young children under 5 years (neuroblastoma, Wilms, retinoblastoma, hepatoblastoma, ependymoma) are very uncommon in adolescents (years 15-19)
Cancers common in adolescents (germ cell tumors, lymphomas, bone cancers) are rarely diagnosed in younger children
Cancers most commonly diagnosed in adults (lung, breast, colon) rarely occur in adolescents or children
Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program , National Cancer Institute, SEER Program. NIH Pub. Nol Bethesda, MD, 1999

11. Regulations and Legislation

12. Regulatory Approvals (FDA-CDER) 1979-2004
>100 drugs approved for cancer treatment
50 new molecular entities (NME) approved for adult cancers
Only 7 NME submissions for pediatric oncology
2 approved (teniposide and clofarabine)
Ref: Hirschfield, et al JCO Vol 21 pp

13. Key Challenges for Pediatric Drug Development
Historical Lack of Pediatric Labeling
Tragedies in children led to regulations
“Therapeutic Orphans” Children are not “mini-adults” or “little adults”
Small Pediatric Market – limited marketing potential
Difficult Trials
Small #s, difficult outcome measures, need for formulation development (smaller doses, oral formulations)
Ethical and Liability Issues

14. Key Challenges for Pediatric Drug Development
Differences between disease in adult vs pediatric (pathophysiology, PK, organ maturity, etc)
Cannot always extrapolate from adult data
Differences in pediatric age groups
Need to ensure representation from relevant age groups in studies
Challenges with procedures/sampling: blood volumes, diagnostic vs research procedures
Formulations – smaller doses, oral formulations
Ethical considerations: consent, assent, permission

15. General Principles: ICH E-11
Pediatric patients should be given medicines that have been properly evaluated for their use in the intended population
Product development programs should include pediatric studies when pediatric use is anticipated
Pediatric development should not delay adult studies nor adult availability
Shared responsibility among companies, regulatory authorities, health professionals, and society as a whole

16. Pediatric Goals
Provide adequate product information for drugs and biologics that will be used to treat children
Establishment of mechanisms for the safe and effective development of pediatric medications

17. FDA Principles
Adequate labeling
Safety
Efficacy

18. History of Pediatric Regulations/Legislation
FDAMA Pediatric Exclusivity -1997
Pediatric Rule Regulation -1998
Best Pharmaceuticals for Children Act (BPCA)
Pediatric Research Equity Act (PREA)
October 2007: reauthorization of BPCA and PREA

19. What Have We Learned For many products studied:
There was new dosing information, or
It was not effective, or
It had a new pediatric safety issue
Long term safety and effects on growth, learning, and behavior continue to be understudied
Neonates still remain mostly unstudied as to the safety and efficacy of the therapies being used to treat them.

20. Ethics of Pediatric Research

21. Challenges for Pediatric Oncology Drug Development
Impact of Treating Childhood Cancer: Lives Saved
Challenges for Pediatric Oncology Drug Development
Most children with cancer enrolled on clinical trials but
Very small patient populations
Studies may be difficult to enroll, long time to complete

22. Why Involve Children in Research?
Develop treatment for childhood diseases
Retinopathy of prematurity
Cystic fibrosis
Cancer
Data in adults may not be generalizable
May result in over/under dosage of medications
Pathophysiology may be different
Toxicities may be different

23. Why Involve Children in Research?
Consequences of not involving children is research:
Perpetuation of harmful practices
Introduction of untested practices
Failure to develop new treatments for childhood diseases
The Pediatric Gap: New Yorker, 1/10/05

24. Regulatory Framework: Pediatric Research
OHRP
FDA
HHS conducted or supported research
Domestic*
International
45 CFR 46
Subpart A (“Common Rule”)
Subpart B (Fetus, Pregnant Women)
Subpart C (Prisoners)
Subpart D (Children)
Research that involves products regulated by FDA
21 CFR 50, 56
Part 50: Protection of Human Subjects
Subpart D (Children) Interim Rule
Part 56: IRBs
21 CFR 312 – INDs
21 CFR 361 – Drugs used in research
Applies
to:
Regulatory Protection
of Human Subjects:
*Domestic institutions may elect to apply 45 CFR 46 to all of its research regardless of source of support

25. Risk Benefit Categories for IRB Consideration of Pediatric Studies
Code of Federal Regulations Title 45 Part 46 Subpart D and FDA 50.

26. Issues in Pediatric Research
Designation as “vulnerable” adds a layer of protection as well as denying access
Children lack legal capacity to consent
Many are incapable of understanding research
Pediatric trials are more difficult to complete

27. Pediatric Ethics
BENEFICIENCE
RESPECT FOR PERSONS
JUSTICE

28. Principals of Medical Ethics
Respect for person is dominant principle for adult ethics (autonomy)
Beneficence is dominant principle for pediatric ethics (best interests of child)

29. Questions in Pediatric Ethics
Should a particular therapy be given?
BENEFICIENCE
Who should make a consent decision?
AUTONOMY
The answers may be incompatible

30. Consent, Assent, and Permission
An adult’s voluntary agreement, based upon adequate knowledge and understanding of relevant information/legal capacity/sufficient understanding
Assent
A child’s affirmative agreement
Permission
A parent’s or guardian’s agreement

31. Limits of Parental Authority
Bests Interests of the Child
reasonable range of options
not always separable from family interests
Parental Incompetence
Neglect or Abuse

32. Informed Consent vs Parental Permission
Autonomous authorization of adults on their own behalf is more robust than parental permission for children by proxy/surrogate
“…the pediatrician’s responsibility to his or her patient exist independent of parental desires or proxy consent.”
AAP 1995 statement on informed consent, parental permission, and assent in pediatric practice

33. Purposes of Assent Provide information to the young person
Offer shared decision making with the parents
Honor the young person’s dissent

34. Assent: A Clinical Definition
Awareness of the nature of his/her condition
What to expect with tests and treatment(s)
Assessment of understanding (including pressure to accept)
Soliciting an expression of willingness to accept the proposed test/treatment

35. Authority of Assent
Therapeutic studies with direct benefit available only in the context of research: NO
Therapeutic studies with no direct benefit: YES
Non-therapeutic studies: YES

36. Key Concepts for Children to Understand about Research Participation
What is required of them
Duration of their participation
Personal risks and benefits
Voluntariness
Freedom to ask questions

37. Assent/Parental Permission*
The IRB must determine that adequate provisions are made for soliciting the assent of children when in the judgment of the IRB the children are capable of providing it:
Age/Maturity
Intellectual development
Psychological, emotional state
*21 CFR 50.55, 45CFR46.408

38. Assent/Parental Permission*
The assent of the child is not a necessary condition for proceeding with the clinical investigation if:
The capability of some or all of the children is so limited that they cannot be reasonably be consulted
The intervention or procedure holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the clinical investigation
*21 CFR 50.55, 45CFR46.408

39. Pediatric Research: Emerging Issues
Consent at age of majority
Genetic research
Family studies (secondary subjects)
Non-CLIA approved tests (do we share results?, e.g. MRD)