Barriers to Participation in Clinical Trials Pediatric Oncology

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Barriers to Participation in Clinical Trials
Pediatric Oncology
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• Jeana Cromer, MPH, CCRP
• Director, Clinical Trials Management
• Oncology Programs
• St. Jude Children's Research Hospital
• Comprehensive Cancer Center

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Agenda

• Childhood Cancer Overview
• Regulations and Legislation for Pediatric
  Research
• Ethics of Pediatric Research

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Overview of Childhood Cancer
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Background

• 1 million diagnosed with cancer annually in the
  USA
• lt1 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

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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/CAFF2007PWSecu
  red.pdf.

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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

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Common Types of Childhood Cancer

• Leukemias - ALL and AML
• Cancers of the central nervous system Brain
  tumors
• Neuroblastoma
• Sarcomas osteosarcoma, Ewings, soft tissue
• Lymphomas Hodgkins lymphoma, non-Hodgkins
  lymphoma
• Liver Cancers hepatocelluar, hepatoblastoma
• Kidney tumors Wilms, clear cell sarcoma
• Retinoblastoma
• Germ Cell Tumors
• Other Rare Tumors melanoma, adrenocortical,
  nasopharyngeal carcinoma

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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

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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

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Regulations and Legislation
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Regulatory Approvals (FDA-CDER) 1979-2004

• gt100 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

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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

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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

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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

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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

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FDA Principles

• Adequate labeling
• Safety
• Efficacy

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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

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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.

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Ethics of Pediatric Research
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Challenges for Pediatric Oncology Drug Development
Impact of Treating Childhood Cancer Lives Saved

• Most children with cancer enrolled on clinical
  trials but
• Very small patient populations
• Studies may be difficult to enroll, long time to
  complete

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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

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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

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

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Pediatric Ethics

• BENEFICIENCE
• RESPECT FOR PERSONS
• JUSTICE

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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)

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Questions in Pediatric Ethics

• Should a particular therapy be given?
• BENEFICIENCE
• Who should make a consent decision?
• AUTONOMY
• The answers may be incompatible

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Consent, Assent, and Permission

• Consent
• An adults voluntary agreement, based upon
  adequate knowledge and understanding of relevant
  information/legal capacity/sufficient
  understanding
• Assent
• A childs affirmative agreement
• Permission
• A parents or guardians agreement

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Limits of Parental Authority

• Bests Interests of the Child
• reasonable range of options
• not always separable from family interests
• Parental Incompetence
• Neglect or Abuse

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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 pediatricians 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

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Purposes of Assent

• Provide information to the young person
• Offer shared decision making with the parents
• Honor the young persons dissent

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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

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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

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Key Concepts for Children to Understand about
Research Participation

1. What is required of them
2. Duration of their participation
3. Personal risks and benefits
4. Voluntariness
5. Freedom to ask questions

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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

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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

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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)

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