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 yearRef: 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

• 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 “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

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:– 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

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

Impact of Treating Childhood Cancer: Lives Saved

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

• 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 Protection of Human Subjects:

OHRP FDAApplies to:

*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

Increasing Risk

Minimal Risk Greater than minimal risk

Special

Decreasing Prospect of Benefit

Prospect of direct benefit

Section 404 Section 405 Section 407 No direct

benefit Section 404 Section 406

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

1. What is required of them

2. Duration of their participation

3. Personal risks and benefits

4. Voluntariness

5. 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)