Barriers to Participation in Clinical Trials Pediatric Oncology

1. Barriers to Participation in Clinical Trials Pediatric Oncology

2. 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. 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 2003. Vol 21 pp1066-1073

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 2007. Atlanta, GA: American Cancer Society. Retrieved December 26, 2007, from http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf.

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% (1975 -1977) to 79.6% (1996-2003) • Significant advances in treatment and supportive care • Clinical trials research SEER Cancer Statistics Review, 1975-2004

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 1975-1995, National Cancer Institute, SEER Program. NIH Pub. Nol 99-4649. 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 1975-1995, National Cancer Institute, SEER Program. NIH Pub. Nol 99-4649. 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 2003. Vol 21 pp1066-1073

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) - 2002 • Pediatric Research Equity Act (PREA) - 2003 • 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. 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 http://www.newyorker.com/archive/2005

24. 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 Regulatory Framework: Pediatric Research FDA OHRP 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 • Consent • 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)