Cancer Clinical Trials in Special Populations

1
Cancer Clinical Trials in Special Populations

• Gregory H. Reaman, MD
• Professor of Pediatrics
• The George Washington University
• School of Medicine and Health Sciences
• Chair, Childrens Oncology Group

2
What Makes Children (with cancer) Special?

• Vulnerable population with life-threatening
  disease
• General ethical principles that apply to research
  in children embodied in Subpart D of Code of
  Federal Regulations
• Risks must be justified by the anticipated
  benefit
• Benefit Risk relationship at least as favorable
  as current alternative therapies
• Risk-adapted clinical trials

45 CFR46.405 research involving greater than
minor increase over minimal risk must offer the
prospect of direct benefit.
3
Vulnerability

• Developmental association with normal physiology
• Age and cognitive abilities
• Consent and assent
• Compliance
• Dissonance at emancipation

4
Progress in Pediatric Oncology

• Success achieved through multi-center,
  multi-disciplinary clinical and applied research
• Systematic application of the principles of
  evidence-based medicine to a national clinical
  trials infrastructure
• Infrastructure strengthened by the unification of
  the pediatric cancer clinical trials groups

5
Benefits of Pediatric Clinical Trial Participation

• Access to collective wisdom of leading experts in
  the field
• Access to state-of-the art therapies and
  technologies
• Access to translational research and
  discoveries-prognostic classification and
  risk-adjusted therapy
• Access to late effects studies

6
The National Childhood Cancer Mortality Rate and
the Pediatric Cooperative Groups
7
Pediatric Cancer Research

• Unique (academic medical center/hospital based
  vs. private practice) system of care delivery
  historically linked to highly effective clinical
  research model
• Enhanced requirement for correlative biologic
  investigations etiology, therapy development,
  target identification/validation
• Strong collaboration/integration with
  NCI-designated Comprehensive and Clinical Cancer
  Centers and Intramural Programs
• Heterogeneity of diseases and biologic/molecular
  sub-classification (risk-group assessment) impact
  on study accrual requirements and increased
  collaboration COG

8
Childhood Cancer Survival Data
9
Pediatric Cancer Therapeutic Research

• Future Progress from Biologic Discovery and
  Translational Research
• Genomics/Proteomics Molecular targets
• Drug discovery
• Etiology/Genetic Epidemiology
• Prevention (Gene Environment Interactions)

10
Challenges in Pediatric Cancer Research
11
Clinical Challenges in New Cancer Drug Development

• Relatively low cancer incidence unfavorable
  market forces
• Unique pediatric cancers
• Development (age related)
• Changes in organ function absorption,
  distribution and clearance
• Other pK and pD differences
• Optimism Pediatric exclusivity PREA - BPCA

12
Critical Criteria for Selecting New Agents

• Novel mechanism of action
• Favorable toxicity profile
• pK considerations (e.g. pharmacologic sanctuary
  sites)
• Measurable endpoints correlation of pK and
  outcome

13
Prioritization of Agents for Pediatric Development

• Sound rationale
• Compelling pre-clinical data (in vivo, in vitro
  pediatric models)
• Preliminary adult experience
• Drug availability and long term development plan
• Disease-specific scientific agenda

14
The Adolescent and Young Adult Gap

• 64 of pediatric cancer patients between 15-21
  not seen at a pediatric center
• 60 of eligible patients age 15-21 are not
  entered on open clinical trials
• Age related survival differences (15-19, 19-21,
  21-25, 25-30) exist for nearly every cancer type
  most commonly seen in children and adolescents
  ALL, Ewing, Rhabdomyosarcoma, Osteosarcoma

15
Age-Specific Prognosis
SEER 1999
16
Case 1

• 16 yo girl of African American/Mexican American
  descent
• 3 year h/o primary tumor in R pelvis (synovial
  cell sarcoma) previously CR following Ifos/Adria,
  XRT, surgery
• Refused to come for multiple follow-up
  appointments/scans

17
Case 1

• Developed RLE swelling while incarcerated,
  presented to outside hospital
• CT finally done within one week of scheduled
  release date

18
Case 1

• CT massive abdominal tumor with loculated fluid
  collections multiple pulmonary metastases

19
Case 1

• Physical exam
• Thin female, in no distress
• Vitals normal, KPS 90
• Chest unremarkable
• Abdomen distended, mild discomfort on palpation,
  firm RUQ but o/w soft with ?fluid wave
• Massive edema RLE to groin 3 pitting LLE to
  knee

20
Case 1

• Counts normal
• Coags normal
• CMP normal
• Room air oxygen sat 99-100
• Pregnancy test negative
• Not on any medications

21
Would You Offer an Early Phase Clinical Trial
to This Patient?
22
Is this Patient a Candidate for a Clinical Trial?

• We dont have great drugs for recurrent,
  metastatic synovial sarcoma
• Disease is not resectable
• Performance status excellent
• Organ system function is excellent
• Ethnic groups and representation in clinical
  trials

23
Any Issues Here?

• Patient is a minor
• Patient represents an ethnic minority
• Patient is a female of child-bearing potential
• Patient/parent are not medically sophisticated
• Adherence a challenge in past

24
What Makes a Person Part of a Special
Population?

• Age
• Race and ethnicity
• Gender
• Income
• Insurance status

25
What ELSE?

• Rural environment
• Abilities/disabilities
• Physical
• Cognitive
• Educational
• Sexual orientation
• Demographic and social characteristics that are
  different from the majority

26
Health Disparities

• Unequal access to health care for segments of a
  population
• inferior health outcomes
• unequal burden
• morbidity
• quality of life
• survival

27
The burden of cancer is too often greater for
the poor, ethnic minorities and the uninsured
than for the general population.
NCI Center to Reduce Cancer Health Disparities
28
Lets Go Through the Specific Issues

• Patient is a minor
• Any track record for clinical trials in pediatric
  oncology?
• Childhood cancer uniformly fatal in 1950s/early
  1960s
• Overall survival data gt78
• Most progress through multicenter clinical trials

29
Toxicity and pK

• In some cases there are very legitimate reasons
  to be concerned about toxicity issues
• However, MTD usually higher in children
• pK in children may or may not be similar to
  adults
• Teensgt50 kg often very much like adults

30
Recent History

• Phase I studies of IGF1 inhibitors (anti-IgF1r)
• Not initially conceived with sarcomas as main
  target tumor
• Patients with Ewings and other sarcomas with
  objective responses in Phase I
• Major shift in drug development programs in this
  area

31
The Law

• Pediatric Research Equity Act of 2003
• Provides legislative authority for FDA to require
  companies to do pediatric testing for drugs and
  biologics
• Best Pharmaceuticals for Children Act (BPCA) and
  Pediatric Rule provides patient exclusivity
  incentive
• Pharma a bit more anxious to acquire pediatric
  data than previously

32
If You Are Going to Enroll Minors

• Federal Regulations
• CFR Section 46, Subpart D
• Intervention gt minimal risk to child
• must either be of DIRECT BENEFIT to child or
• risk of intervention must be that of available
  alternative
• If research yields only generalizable knowledge
  about childs disease, must be only MINOR
  increase over minimal risk

33
If You Are Going to Enroll Minors

• Consent
• Parental consent for lt18 year olds
• Both parents for research without direct benefit
• Age of majority state regulated
• Adolescent assent
• Childs assent

Local Context Responsibility
34
Correlative Studies in Minors

• Serial tumor biopsies of gtminimal risk, no direct
  benefit
• Not permitted unless making clinical decisions
  for patient on the basis of your findings
• Not permitted even if parent agrees
• Use surrogate tissues

35
Reasonable Approaches Other Than Integrated
Trials

• If endpoint is MTD of cytotoxic agent
• Stepwise cohorts with minors enrolled one dose
  level just behind adults
• Two-part study with minor portion opening as
  adult portion closes
• If agent unlikely to have an MTD
• PK (or someday PD) based study for minors

36
Patient is Incarcerated

• Autonomy in Prisons
• Are increased access to medical care
  opportunities to interact during study-related
  activities undue inducement?
• 45 CFR 46.305 and 45 CFR 46.306
• Only permits participation in studies with no gt
  minimal risk

37
Incarcerated Patients

• Early phase clinical trials prohibited
• August 2006 IOM report
• Prisoners have been exploited in the past,
  carrying a heavier burden of risks than the
  general population, however . . .. responsible
  research has the potential of improving health
  and well being of prisoners . . ..
• Rec Later phase trials could be possible as
  long safeguards in effect

38
Protecting Women

• DES and Thalidomide
• 1975 the fetus defined as a vulnerable person
• Need to protect the unborn
• Most certain way to protect a fetus do not
  permit women of childbearing potential on
  clinical trials

39
Protecting Women and Missed Opportunities

• Potential information from early phase clinical
  trials
• Specific dosing requirements for women
• Identification of drugs that are particularly
  effective in women

40
NIH Policy

• Applications for grants that involve human
  subjects are required to include minorities and
  both genders in study populations so that
  research findings can be of benefit to all
  persons at risk of the disease . . .

41
NIH Policy

• Whenever there are scientific reasons to
  anticipate differences between men and women with
  regard to the hypothesis under investigation,
  applicants should include an evaluation of these
  gender differences in the proposed study

42
The Issue of Pregnancy Prevention
43
Representation of Minorities in Clinical Trials
Christian and Trimble, 2003
44
NIH Policy

• Applications for grants that involve human
  subjects are required to include minorities and
  both genders in study populations so that
  research findings can be of benefit to all
  persons at risk of the disease . . .
• So why are we still not enrolling minorities on
  studies?

45
NCI Cooperative Group Studies

• Enrollment on Cooperative Group trials for
  patients with breast, colorectal, lung and
  prostate cancers 2000-2002 reviewed
• Total participants overall increased
• Representation of minorities decreased

Murthy et al, 2004
46
Barriers to Enrollment of Minorities on Clinical
Trials

• History
• Lack of understanding
• Awareness
• The Fear Factor
• Access
• Uneven/Unequal Recruitment

47
(No Transcript)
48
The Uninvited

• Data from Wendler paper suggest that Hispanic and
  Black patients are NOT less likely to participate
  in trials when trials are offered
• How do we go about inviting the uninvited?

49
What About Language?

• Informational discussion
• Consent document must be in a language understood
  by participant per 21 CFR 50.20
• Practical/financial constraints
• Ongoing information sharing

50
Increasing Participation

• Building trust
• Trial center/community relations
• Patient advocates and trained staff
• Providing funding
• Fund programs in underserved areas
• Provide support for trial related expenses

51
Increasing Participation

• Address uninsured/underinsured issues
• Does your institution accept public aid insurance
  plans?
• What are the laws in your state regarding
  coverage of clinical trials expenses by insurance
  plans?
• Accountability in Cancer Centers
• Appropriate definition of accrual goals
• Reporting on inclusion

52
Enrolling When Low Literacy is an Issue

• Considered a vulnerable population
• Specific issues re witness and other safeguards
  per 21 CFR 50.27(b)(2) and 21 CFR 56.111(b)
• Beyond the regulations
• Alternative formats for educational/consent
  materials

53
Taken Together . . .

• Its a lot of work to conduct clinical research
• Its even more work to conduct inclusive clinical
  research

54
Importance of Inclusivity

• Basic clinical trials methodology study
  population should be representative of overall pt
  population to be useful in clinical
  decision-making
• How will we know how to treat our patients if we
  do not include them in our trials?
• Good Science

55

• Of all the forms of inequity, injustice in
  health care is the most shocking and inhumane.

Dr. Martin Luther King, Jr