# Presentation: 261429

## Quick overview:  Ethics of Phase I studies in children with cancer 

- Susan B. Shurin, MD
- Professor of Pediatrics and Oncology
- Case Western Reserve University
- Cleveland OH

## Why do investigators perform Phase I studies?

- Test scientific hypotheses
- Develop new therapeutic agents to improve therapies.
- Advance their own careers: publication, acclaim, promotion, recognition
- Reap economic rewards: personal, institutional (program development)

## Why do corporations sponsor new drug development? 

- Products for the marketplace
- Part of the business plan
- Scientific research arm depends upon bringing drugs from bench to bedside
- Individual scientists have same motivations as clinical investigators

## Why do patients participate in Phase I studies?

- To maintain hope and optimism
- 85% of participants hope for possible therapeutic benefit
- 11% participate on advice of physicians
- 4% because of family pressure
- Altruistic feelings, while present, are not major motivators

## Basic principles of human subject research ethics

- Respect for autonomy
- right of subject to make choice, assume risks
- avoid excessive paternalism
- Beneficence
- maximize benefit, minimize harm
- Justice
- fair distribution of burdens and benefits of research

## Autonomy in Pediatric Phase I studies

- Subjects are especially vulnerable
- Decision to participate is proxy
- Hope being maintained may be that of the family, not the child
- Paternalism is more complicated, since coercion may come from the parents
- Personal costs (being away from home, pain) are not born by the decision-maker

## Informed consent for Phase I Adult Oncology Trials

- Disclosure:  the fact that the study aim is determination of toxicity and dose is usually disclosed
- 93% of participants say they understand most (60%) or all (33%) of the information provided
- Only 33% can state that the purpose of the trial is dose-finding and toxicity

## Autonomy and Informed Consent

- Autonomy (protection of right to chose freely) depends heavily upon having an awareness of what is being chosen
- The fact that hope is a major motivator for participation may impact autonomy more than lack of disclosure by investigators
- Autonomy includes the right to make unique personal decisions others may deem wrong

## Beneficence in Phase I Pediatric Oncology Trials

- Failure to gain data on children deprives children as a class of the medical benefits generated through research
- Minimizing harm is especially important when direct benefit to a vulnerable subject is not anticipated
- Issues of extra procedures and pain are particularly crucial here

## Justice in Phase I Pediatric Oncology Trials

- Fair distribution of benefits of research requires a fair distribution of the burdens of research
- Children are different from adults in drug metabolism, pharmacokinetics
- Pediatric tumors are different from adult tumors, and results cannot be transferred
- Children must participate in drug development if they are to benefit

## Tissue biopsy in Phase I trials of targeted therapies 

- With targeted therapies, knowing the characteristics of tissues and the distribution of drug in tissue is equivalent to knowing pharmacokinetics of more standard agents
- The MTD is likely to be irrelevant when a targeted agent is used
- Tissue biopsy may be essential to determine whether the drug can ever be useful

## Downsides to tissue biopsy

- Invasive
- Potentially painful
- Carries some risk to the patient
- Offers no benefit to the patient
- Increases the cost of the study

## Moral imperative of clinical trials

- Answer the question to validate the contributions of all participants in this study
- Protect future subjects/patients from unnecessary risk and toxicity and lack of benefit (if more subjects are needed because of insufficient information on some, harm is shifted)
- Preserve the integrity of the science

## “Elective” biopsies for targeted agents?

- Omitting a biopsy which is scientifically necessary  implies that the agent is being given because the investigator expects it to benefit the patient.  This masks awareness of choice, and fails to respect autonomy.
- If the class of children will be deprived of benefits generated through research, it is not beneficent.
- If other subjects bear an unfair share of the burden of answering the question, it is unjust.

## Imperatives in Study Design

- Extremely stringent study design and conduct
- Minimize risks, discomforts, and maximize benefit of information gained
- Ensure truly informed consent -- we need to work on communication
- Publish the results

- “Patients are free to maintain unwarranted optimism about their prospects, but the research system is not free to exploit this vulnerability to advance its own ends.”                Rebecca Dresser, *When Science Offers Salvation.  Patient advocacy and research ethics. *2001.

## Design of Phase I Oncology Studies

- Subjects typically have advanced disease
- Goal of the study is to determine toxicities and MTD of investigational drug
- Probability of direct benefit to patient is very low (4-6% response rates overall)
- Toxic death rates <0.5% overall
- Children are not enrolled until adult MTD has been determined

## Alternatives to Phase I agents

- Alternative therapies:  herbal, other non-traditional approaches (claims do not need to be substantiated, but these offer hope)
- Non-experimental but unproven drugs in common medical use
- Palliative care must be given regardless of whether other attempts to treat disease are offered to children with advanced disease.