Transcript Slide 1

Barriers to Participation in Clinical Trials
Pediatric Oncology
Jeana Cromer, MPH, CCRP
Director, Clinical Trials Management
Oncology Programs
St. Jude Children's Research Hospital
Comprehensive Cancer Center
Agenda
• Childhood Cancer – Overview
• Regulations and Legislation for
Pediatric Research
• Ethics of Pediatric Research
Overview of Childhood Cancer
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
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.
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
Common Types of Childhood Cancer
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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
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
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
Regulations and Legislation
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
Key Challenges for Pediatric Drug
Development
• Historical Lack of Pediatric Labeling
– Tragedies in children led to regulations
– “Therapeutic Orphans” Children are not “miniadults” 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
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
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
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
FDA Principles
• Adequate labeling
• Safety
• Efficacy
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
What Have We Learned
• For many products studied:
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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.
Ethics of Pediatric Research
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
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
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
Regulatory Framework: Pediatric Research
FDA
OHRP
Applies
to:
Regulatory
Protection
of Human
Subjects:
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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)
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Research that involves
products regulated by FDA
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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
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*Domestic institutions may elect to apply 45 CFR 46 to all of its research regardless of source of support
Risk Benefit Categories for IRB
Consideration of Pediatric Studies
Code of Federal Regulations Title 45 Part 46 Subpart D and FDA 50.
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
Pediatric Ethics
• BENEFICIENCE
• RESPECT FOR PERSONS
• JUSTICE
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)
Questions in Pediatric Ethics
• Should a particular therapy be given?
– BENEFICIENCE
• Who should make a consent decision?
– AUTONOMY
The answers may be incompatible
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
Limits of Parental Authority
• Bests Interests of the Child
– reasonable range of options
– not always separable from family
interests
• Parental Incompetence
• Neglect or Abuse
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
Purposes of Assent
• Provide information to the young person
• Offer shared decision making with the
parents
• Honor the young person’s dissent
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
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
Key Concepts for Children to Understand
about Research Participation
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What is required of them
Duration of their participation
Personal risks and benefits
Voluntariness
Freedom to ask questions
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
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
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)