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Current Controversies in Pediatric Research Ethics: Day One Notes

July 22, 2005

The following are unedited notes taken by conference participants. They are designed for information purposes only.

 

The following are unedited notes taken by conference participants. They are designed for information purposes only.

Welcome and Introduction

Treuman Katz, President and CEO
F. Bruder Stapleton, MD, Pediatrician-in-Chief
Children’s Hospital and Regional Medical Center

Douglas Diekema made opening remarks and introduced hospital President and CEO, Treuman Katz.

Mr. Katz welcomed the conference participants and spoke of the importance of pediatric bioethics for the future of Seattle’s Children’s Hospital and other organizations at a national and international level.

Katz said, “It is both a privilege and an obligation for Children’s Hospital and Regional Medical Center to develop the first pediatric bioethics center. Our task is to develop and sustain the Center to promote policies, best practices, and standards for pediatric bioethics.”

Katz thanked the Northwest Congressional Delegation for its support in securing funding to establish the Center and recognized the Board of Trustees for helping make the Center for Pediatric Bioethics possible. He also acknowledged the leadership and vision of Drs. Bruder Stapleton and Jim Hendricks in making the first Center for Pediatric Bioethics a reality.

Katz then introduced Dr. Stapleton who talked about the ethical and clinical challenges facing the future of medicine.

Overview of History and Review of Pediatric Regulations

Douglas S. Diekema, MD, MPH
Interim Director, Center for Pediatric Bioethics, Children’s Hospital
and Regional Medical Center
Associate Professor of Pediatrics, University of Washington School of Medicine
Adjunct Associate Professor, Department of Medical History and Ethics

Early vaccine experiments are tracked back to 1776 when Jenner inoculated an 8-year-old boy with cowpox and 1855 when 12-year-old Joseph Meister was given a Rabies vaccine in an attempt to save his life.

The Prussian Ministry of Religious, Educational and Medical Affairs issued the first directive on human experimentation in 1900. “…Medical interventions for purposes other than diagnosis, therapy, and immunizations are absolutely prohibited…if…the person in question is a minor or is not fully competent on other grounds or the person concerned has not declared unequivocally that he consents to the interventions.”

The Nuremburg Code was established in Germany in 1949: “The voluntary consent of the human subject is absolutely essential.” Children were excluded from all research.

In 1961, the Nuremburg Code was not considered pertinent to Harvard University researchers. Harvard researchers felt that they had a moral sense that differentiated them from previous generations and prevented the need for codes, rules, and regulations. Many research studies were conducted in the United States, including Human Radiation Experiments at the Fernald School in Waltham, MA. There, seventy-four “mentally retarded” children were fed radioactive calcium and iron in oatmeal to determine the absorption of those nutrients.

The National Commission for the Protection of Human Subjects of Biomedical Research was established in 1974.

The twin pillars of protection in research were defined as:

  • IRB Review of benefits and burdens;
  • Informed consent/parental permission/child assent.

Our ethical principles in research include:

  • Respect for persons;
  • Beneficence and “Do No Harm”;
  • Justice.

Of the many conflicting views regarding children as research subjects, the core issues are whether children need to be protected as vulnerable persons or whether they should be viewed as humans who are social beings and ought to contribute to the good of others.

The IRB review of all human subjects research has helped to define the parameters of research, the definition of children, state laws, and federal regulations for research with children.

Ethical Conduct of Clinical Research Involving Children: The IOM Report

Bonnie Ramsey, MD
Professor and Vice Chair for Research, University of Washington School of Medicine
Director, Therapeutic Development Network Coordinating Center and Co-Director, Clinical Research Center

Institute of Medicine (IOM) Report (executive summary in notebook)

Children are on a seesaw while we try to maintain a delicate balance between clinical benefits and scientific knowledge vs. patient safety, informed consent, and assent in a vulnerable population.

The federal government directed the IOM to review and report on the federal regulations governing research on children. The IOM study committee included pediatricians, ethicists, public policy makers, and child advocates, representing a wide variety of perspectives.
The study committee engaged in a process that included a comprehensive literature review, public forums, committee discussions, draft reports, outside reviews, and finally a public release of the report in 2004.

Overarching themes:

Well-designed and well-executed clinical research involving children is essential to improving the health of children and future adults in the US and worldwide.

Children should not be uniformly excluded from research as a group.
A robust system for protecting human participants in research in general is a necessary foundation for protecting child research participants in particular. All human research is subject to a responsible human research participant protection program (HRPPP) under federal oversight.

Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research.

Composition of IRBs – IRBs that review clinical research involving minors should have adequate expertise in child health research. At least three members of the IRB must have such expertise.

In addition to the three overarching themes, the IOM was charged with looking at the federal regulations to determine and evaluate several areas:

  • Assess appropriateness of regulations for children of different ages;
  • Evaluate compliance with federal regulations;
  • Consider definition of minimal risk with respect to healthy or ill children;
  • Consider unique roles and responsibilities of IRBs involved in the review of pediatric studies;
  • Examine the appropriateness of payments to parents or children related to research;
  • Review assent.

The committee’s findings helped clarify the definitions of terms such as “benchmark”, “minimal risk”, “condition”, and “minor increase over minimal risk”.

Implications:

  • Can healthy children be normal volunteers in pharmacokinetic studies of drugs approved for adults?
  • Can children with life threatening disorders participate in Phase 1 or 2 studies of new therapies (i.e., gene therapy or new antibiotics)?
  • What happens when IRBs disagree on the risk category for multi-center trials?

Since the IOM report was released in 2004, the 407 Review Process has been improved in the following areas:

  • Guidance was provided for IRBs and investigators on use of the 407 process, guidelines, timelines, how to apply, etc.;
  • FDA Pediatric Advisory Committee was established with a permanent ethics subcommittee to review IRB referrals.

Swinging on the Pendulum: Changing Views of Justice in Research with Children

Anna Mastroianni, JD, MPH
Assistant Professor of Law and Public Health Genetics, University of Washington School of Law
Greenwall Foundation Faculty Scholar in Bioethics
Past Associate Director of the White House Advisory Committee on Human Radiation Experiments

Mastroianni suggests that organizations consider policy developments in pediatric research over time through the lens of justice. The Belmont Report defines justice as fair distribution of risks and benefits as it relates to subject selection.

Research in children prior to 1966 has a history of using convenient populations, including children of researchers and poor or orphaned children. There were no research policies passed before 1966 that directly addressed children.

Research Studies “Scandals and Exposés”:

  • Henry Beecher, NEJM (1966);
  • Willowbrook State School for the Retarded, NY (1956-1972);
  • Institutionalized children with mental disabilities injected with hepatitis serum and studied;
  • The Fernald School for the Mentally Retarded;
  • Jewish Chronic Disease Hospital, Brooklyn, NY (1963);
  • Tuskegee Syphilis Study (1932-1974).

The commonalties between these studies include:

  • Failure of informed consent;
  • Using vulnerable populations;
  • An unfair distribution of risks and benefits.

The National Commission for the Protection of Subjects of Biomedical and Behavioral Research (1974-1978) was charged with recommending to the U.S Department of Health Education and Welfare (DHEW) guidelines to protect rights and welfare of human subjects, particularly those with disabilities, and to develop principles to govern ethical conduct of research.

The shift in perception from protection to access occurred in the 1980s and 1990s based on advocacy efforts driven by AIDS and cancer groups. The perception was that research was cutting-edge therapy. The women’s health movement pushed to have more women accepted in clinical trials.

The policies shifted to meet the needs of this new focus on inclusion. These policies included fast tracking drug approval processes, stronger federal research funding, and the approval of emergency research. Diversity initiatives were established to include new groups including women, racial and ethnic groups, and children.
In 1979, pediatric labeling was required in pediatric trials, including the wording “safety and effectiveness in pediatric patients have not been established.”

We now recognize that research inherently carries risk and is not always beneficial. The question today is: How is it possible to ensure equitable access to benefits while protecting the interests of patient-subjects? New “scandals” are emerging. The Office of Human Research Protections (OHRP) has shut down programs at some major research institutions and there have been a number of Congressional inquiries and reports. There is also increased legal attention focused on research.

Children’s policies have encouraged more research and have provided protection from risk. But there is still a lack of subgroup analysis. In addition, the patent extension is losing steam. Our other outstanding issues today include the quality of informed consent (particularly regarding research taking place in the therapeutic context), overburdened oversight, and conflicts of interest.

In conclusion, undermined trust will result in less-willing subjects. Research is a privilege not to be exploited or presumed. We need to move from “compliance” to “conscience.”

Research and Innovative Therapy: Failure To Do Research Is Unethical

Norman Fost, MD, MPH
Professor of Pediatrics, University of Wisconsin
Director, Program in Medical Ethics, University of Wisconsin
Former Chair, American Academy of Pediatrics National Committee on Bioethics
Recipient, William G. Bartholome Award of the American Academy of Pediatrics for Excellence in Ethics

Differences Between Research and Innovative Therapy

The traditional view is that we need a reason for distinguishing “experimentation” from “treatment.”
The critical ethical distinction is that the physician serves as a double agent.

In innovative therapy, the physician’s primary concern is the interest of the patient. In research, the physician’s primary concern is to benefit society.

Historical examples - physicians/investigators as double agents:

  • In 1830, Dr. William Beaumont started as a doctor caring for a patient, Alexis St. Martin (Wisconsin). He then became involved in research and drafted the patient into the US Army so that he could continue to study St. Martin and confine him to the stockade if necessary.
  • Beaumont went on to write Beaumont’s Code, one of the first written policies about standards and protocols in research.

Other examples include:

  • Nuremberg Trials: Nuremberg Code;
  • Southam: Injected cancer cells in patients without their knowledge;
  • Hopkins: hernia study in infants;
  • Texas: placebos vs. birth control pills;
  • Beecher exposed all this in the NEJM in 1966;
  • 1966: IRBs were created;
  • 1971: Bernard Barber’s study of IRBs found most were not working well. As a result, Senator Kennedy held hearings;
  • Led to the creation of the National Commission and new federal regulations;
  • IOM study committee reviewed federal regulations and made recommendations for change.

Theoretical reasons why being a research subject is likely to be less dangerous than being a patient.

Alleged distinctions - MYTHS

  • Research involves trying new interventions of unknown benefit and risk while standard treatment in the doctor’s office offers known benefits and risks.
  • Standard prescriptions have known benefits and risks. In fact, 80 percent of pediatric prescriptions have never been tested on children and many clinical trials exclude women and children.
  • Risks of Standard Practice: In NICUs, for example, exchange transfusions in children with jaundice resulted in children dying from shock or infection. With PKU screening, where most of the children had false positive tests, they were put on a restrictive regiment and died as a result.
  • Whether or not an intervention is a research or standard practice is an objective question. Intent can be determined by a series of simple questions. “As long as you promise not to learn anything from what you are doing, you don’t have to go through an IRB.
  • Litmus tests: Reliance on intent relies on the integrity of the physicians, whose potential conflicts of interest are at the root of the need for external review. For example, many doctors are now doing “quality improvement studies” because these are exempt from IRB approval.
  • Reimbursement as criterion of whether or not intervention is experimental.
  • Research is more tightly regulated than practice because experimental interventions raise more questions.
  • Research is riskier.
  • Research is risky in theory.
  • Research must be reviewed by funding agency.
  • Researcher must have credentials.
  • Researcher must do a literature review.
  • Institutional review for human subjects.
  • High standards for written consent.
  • Carefully monitored for adverse events.
  • Data monitoring committees monitor research.
  • Research is riskier - actual risks.
  • Practice setting (60,000 –90,000 preventable deaths per year).
  • Research setting (few documented deaths).
  • Why is research more tightly regulated?
  • History of widespread egregious unethical research.
  • Because it can be – the nature of the research is limited and well-defined.
  • The researcher as a double agent – conflicts of interest.
  • Advancement of knowledge.
  • Personal benefits (salary, benefits).
  • Practicing physician also has conflicts.
  • There may be a congruence of interests in research.
  • Unclear whether these conflicts play out more commonly in a research setting or standard practice (doctor’s office).

Benefits of being a research subject:

  • Review, monitoring, consent;
  • Free care not otherwise available;
  • Indirect benefits, money, incentives;
  • Present patients are beneficiaries of prior research;
  • Press accounts blur the distinction between therapeutic and non-therapeutic research.

Physicians may ask, “Why do I have to have permission to give a new drug to half my patients but I don’t need any permission to give a new drug to all my patients?”

Summary & Conclusions

History (abuses and unethical research) justified the creation of regulations and rules and, eventually, a common rule was created. Regulations, protocols, and policies have changed over time and should continue to do so. Regulated research has reached a point of diminishing returns.

Panel Discussion

Facilitated by Douglas Diekema, MD, MPH
Norman Fost, MD, MPH
Anna Mastroianni, JD, MPH
Lainie Friedman Ross, MD, PhD
Bonnie Ramsey, MD

Migration of research to underdeveloped and third world countries?

It’s where the diseases are most prevalent (i.e., AIDS in Africa). To develop an effective vaccine, treatment, or cure, you need to go to where the disease is rampant. To exploit populations in third world countries in order to benefit people in the U S or to benefit drug companies is not, in and of itself, unethical. The question is: Are the results of the clinical trial or research study ever going to create a benefit, in terms of health, to the people in that country?

Role of insurers and payment for subjects who are enrolled in research studies or clinical trials?

This affects the cost to the institution conducting the research. Oncology drugs are an example of this. For patients in a study, their insurance company will be billed first. If they don’t pay, then the research institution may have to pay. Do we tend to exclude people who can’t pay or don’t have insurance in research trials?
In terms of access, informed consent can be challenging for people who may not speak or read English. How do we account for the additional costs to provide translation to non-English speaking patients in research?

Historically, minority populations have been over-represented in medical research. We need to determine whether the goal is access or protection. In some institutions, the consent form is available in multiple languages, but there is also a cost for translation. Informed consent really goes beyond just filling out and signing a form. People need to fully understand the research, risks, benefits, and process. If you are going to reach non-English speaking populations, you need to go beyond just translating the consent form.

The Ethical Origins of the Regulations on Research with Children

Albert R. Jonsen, PhD
Emeritus Professor of Ethics in Medicine, University of Washington School of Medicine
Recipient, Lifetime Achievement Award, American Association of Bioethics and Humanities
Author, The Birth of Bioethics; A Short History of Medical Ethics; The New Medicine and Old Ethics

An article in the New York Times on July 17th reports on AIDS drug tests involving foster children and charges of racism. The article talked about studies done in the 1980s when no drugs had been tested on children and most children presenting or born with HIV were in foster care. Investigations now look into whether children were harmed during that time although there is little evidence that the trials were successful. The investigation is the result of a story on the internet based on a single incident.

Frequently, discussions of ethics arise from this sort of episode, whether verified or not. We are in a field of crises.

National Commission recommendations for children came out of crises like Willowbrook. Children’s research has been considered in relationship to Willowbrook. In the early part of the 20th century, research was being done in institutions such as orphanages and around such issues as communicable or infectious disease. Dr. Jonsen cited the example of whooping cough, now rare and treatable, but in 1910, serious and prevalent without therapy. He also noted similar issues around diphtheria.

Such diseases lead to an urgency around research but, at the same time, there was a powerful antivivisection movement in the US, largely fueled by William Randolph Hearst and the Hearst newspaper empire. Newspapers promoted the idea that researchers were infecting children with lethal diseases, further influencing the effort to limit research on children. He noted that there is an “aura of horror” that has long surrounded the issue of research with children.

Dr. Jonsen spoke about the issue of ethics being considered within the “cool, calm moment.” Paul Ramsey gave a series of invited lectures at Yale in 1970 and published the collection in a book, Patient as Person, in which he attempted to analyze ethical issues, including research on children.

He and Richard McCormick, a Jesuit priest and professor of therapy, were invited to debate whether research on children was ethical before a congressional panel, the National Commission for the Protection of Subjects, in 1975. Ramsey’s position was one based on strong principles. He called it a “sanitized form of barbarism” and insisted children should never be the subject of research. McCormick took the position that children are participants in the human community and it is reasonable to include them in non-risky research.

While there were very convincing arguments on both sides, Dr. Jonsen (who served on the Commission) noted that the group “split the difference” and designed a “Casuistic Calculus” which outlined when and how children should be included in research.

Casuistic Calculus:

  • Minimal risk research is acceptable given appropriate assent of subject, permission and participation of guardian (not proxy consent), and peer and institutional review.
  • More than minimal risk must anticipate direct benefit to the subject or, if not direct benefit, minor increase over minimal can be justified if risk is commensurate with subject’s experience.
  • Otherwise, more than minimal risk can be tolerated only in grave situations and with national review.

The commission defined risk, assent, permission, etc. and established the foundation for decision-making in the “practical world.”

Genetic Issues in Pediatric Research

Wylie Burke, MD, PhD
Professor and Chair, Department of Medical History and Ethics, University of Washington School of Medicine
Adjunct Professor of Medicine and Epidemiology

Goals of genetic research:

  • Identify gene variants associated with health outcomes;
  • Define gene-gene/gene-environment interactions;
  • Determine biological mechanisms of disease;
  • Develop & assess interventions.

Methodologies:

  • Family Studies;
  • Collections of biological samples and databanks incorporating genetic, clinical, and exposure data;
  • Assessment of interventions.

Issues:

  • Recruitment of family members;
  • Use of stored samples for purposes beyond original study;
  • Disclosure of research results;
  • Border between clinical care and research.

What is the need for family studies?

Familial aggregation is often the first indicator of genetic risk. Also, most gene discovery is based on linkage studies within families.
How do researchers recruit family members? Is it okay for a researcher to have identifying information of potential subjects? Who should make the first contact? Will confidential information be revealed during the recruitment process?

Autonomy is the fundamental principle. An individual has the right to self-determination and informed consent in research.

From the pediatric perspective, questions arise regarding coercion when dealing with a parent and child. There should be heightened scrutiny of potential risks. Will a child’s privacy be breached? Does health information gained throughout the study confer a risk? Is there a compensating benefit?

There is often a need for large databases. They offer sufficient power to study rare gene variants and multi-factorial diseases. Large databases require both clinical and personal information, but they can be more valuable if on-going follow-up and recruitment into related studies are possible.

Recruitment and retention of human subjects raises the problem of “blanket consent.” Can a participant consent for studies not yet described? How many choices should be offered at initial recruitment? Should periodic re-consent be required?

The nature of databases:

  • What is included and what privacy protections are in place?
  • How are data elements separated for sharing?
  • Should anonymized data be periodically downloaded for sharing?

Another issue around parental consent for their children involves longevity of the consent. Can a parent consent for the inclusion of pediatric samples in a permanent database? We should assume the need for re-consent in adulthood and consider options for future sample removal.

Most genetic studies involve a collection of genetic information with proven or potential health significance. When should individual results be provided to the participants? Participants have a right to know and the information may provide medical or other benefits. On the other hand, participants have the right not to know. There may also be the potential for harm when results do not provide benefit and could stigmatize. Lastly, it may add unnecessary costs to research.

It is the responsibility of researchers to ensure the safety and well-being of human participants in research?

Nuremberg Code
Belmont Report
Helsinki Declaration

The National Bioethics Advisory Committee Guidelines for Disclosure:

  • Findings are scientifically valid and confirmed;
  • There are significant health implications;
  • A course of action to ameliorate health concerns is readily available.

The legal considerations:

  • Federal regulations do not explicitly address result disclosure;
  • HIPPA may confer a right of access for covered entities;
  • NBAC appears to define the current “standard of care”.

What are the contrasting goals of medicine and clinical trials?Medicine concerns itself with providing individual patients with optimal care, while clinical trials are interested in answers to scientific questions in order to produce generalized knowledge. The potential conflicts include difficulty in accruing adequate numbers of subjects, the need for risky procedures to obtain study data, and the eligibility of subjects to remain in a study after a change in clinical status.

Some “red flags” indicating the need to monitor for conflict:

  • Incentives or encouragement offered to promote recruitment;
  • Patient seeks advice from the health care team regarding study participation;
  • Study involves invasive or otherwise risky procedures.

How old does a child need to be to distinguish the difference between clinical care and research? Information must be provided to parents with general information about the purpose of the clinical research. The researchers must use specific measures to distinguish research from clinical care.

Issues raised by genetic research are not unique, but they are often viewed as uniquely powerful and personal. Genetic research offers powerful opportunities for new knowledge.

Central IRBs

Erik Kodish, MD
F.J. O’Neil Professor and Chair, Department of Bioethics, Cleveland Clinic Foundation
Editor, Ethics and Research with Children: A Case-Based Approach

Dr. Kodish discussed the ethical imperative to conduct clinical trials, specifically in childhood cancer, and the current policy goals of protecting subjects and enhancing access to clinical trials. He shared the idea that pediatric research is a crossover between pediatric expertise and expertise in the specific science (i.e., cancer). He commented that if IRBs are to protect the subject, weigh the risks to the subject, and the benefits to society, the crossover of expertise is required.

He shared the results of a study by the Association of American Medical Colleges (AAMC) in which he notes that most medical schools are unconvinced that central IRBs are a reasonable alternative.

The issue of local context was discussed. While some say there is no such thing as local context, and that the protocol itself is what should be reviewed, others disagree. Another issue to resolve is control of the study; and IRBs and investigators need to negotiate in order to enable successful outcomes.

Some legal issues were discussed regarding accepting central IRB direction and the liability for individual organizations if they do so. Dr. Kodish suggested that investigators and institutions should always consider “doing the right thing” as a guide.

The roles of parents and community members within IRBs were discussed as well as whether those individuals would subjugate either their own opinions or the need to protect the child when influenced by the investigators or other IRB committee members.

A representative from the audience commented that the IRB, whether central or not, is only as good as the people on the committee who should be trusted to do the right thing. In light of this, Dr. Kodish noted that informed consent is enforceable, but does very little to protect children from research risk. Investigator integrity is the best way to protect the child, but that cannot be measured. A member of the group commented on the complexity of the COG packets and noted the consistency of the protocol and consent. She said consistency helps communicate effectively with the users – patients and families. Dr. Kodish agreed, noting that when parents are approached to participate in research, they are usually in a stage of turmoil and grief, with their child having been newly diagnosed or involved during a relapse. He said the needs of patients and families should always come before the desire of the investigator.

Dr. Kodish commented that a benefit of a central IRB is to enable the study of “orphan” diseases that may go unserved by individual organizations.

Pediatric ethics always must, and does, consider what is in the best interests of the children, says Dr. Kodish, whenever and wherever research is considered or conducted. Whether commercial or privately funded, the IRB should be weighing risk and benefit. He also suggested that IRBs should be looking at payment to physicians as well as to subjects.

Ethics & Publications: An Editor’s Perspective

Dimitri Christakis, MD, MPH
Associate Professor of Pediatrics, University of Washington
Associate Editor, Archives of Pediatrics and Adolescent Medicine

  • Published research is critical to the advancement of science.
  • Ethical oversight in publishing is considerably less than in the traditional practice of medicine.

An editor’s perspective on some key ethical challenges:

  • Maintain the integrity of the science;
  • Protect human subjects;
  • Publish “notable” research for both the scientific community and the general public;
  • Publish well-done research.

Seven key factors that determine whether to accept for publication:

  • Authorship: too many authors undermine the integrity of the project; ask if each author truly contributed to this paper;
  • Duplicate publication: more than 40% of articles get published more than once. Journals try to avoid duplicate publication and reviewers watch out for articles that are similar to others;
  • IRB approval: Articles published in the Archives must have IRB approval. Some researchers seek it after the fact, then resubmit if it is granted;
  • Non-publication: Most common reasons why articles do not get published:
    - Poorly presented science: it could be a good idea or hypothesis but poor data, analysis, or presentation;
    - Publication bias: studies that are positive have a higher likelihood of publication than those that are negative;
    - Suppressed results: the study suppresses results and significant findings (e.g. anti-depressants in adolescents);
    - Editorial discretion: articles that do not maximize the impact factor for the scientific community or public;
    - Authorial discretion – authors don’t submit for a variety of reasons (most say “they don’t have time”).
  • Sponsorship: Approximately 30% of current studies are sponsored by pharmaceutical companies. Journals require a conflict of interest statement and full disclosure. Some Journals will not publish studies sponsored by pharmaceutical companies; other Journals hold sponsored studies to a higher standard;
  • DATA analysis: done on an honor system. Editors and reviewers assume that the authors have run the numbers and analyzed the data using fair and scientifically accurate methods.

New RCT registry for Random Control Trial studies is available at www.clinicaltrials.gov. All RCT studies are supposed to be registered.

In conclusion, Dr. Christakis noted that the publication of most of the studies depend on the persistence of the author. The message is to try, try, and try again.

Minimal Risk Research

Norman Fost, MD, MPH Professor of Pediatrics, University of Wisconsin
Director, Program in Medical Ethics, University of Wisconsin
Former Chair, American Academy of Pediatrics National Committee on Bioethics
Recipient, William G. Bartholome Award of the American Academy of Pediatrics for Excellence in Ethics

“The Problems with Minimal Risk Are More than Minimal”

The oldest law is Battery - no non-consensual touching. Children cannot give consent. Therefore, we cannot touch them…

Unless there is a reasonable prospect of benefit:

  • Ordinary care;
  • Therapeutic research.

If no benefit, then no touching without consent:

  • Ramsey “unjustified violence”;
  • McCormick: Children would consent if they could;
  • Gaylin: parents should be able to rear their children to be altruistic.

National Commission (1980)

It is not in the interests of children as a class to have no research. It is not in the interests of adults as a class either.
Allow studies to be done if there is “minimal risk”:

  • New concept;
  • Parents not restricted.

Minimal Risk: “the probability and magnitude of harm or discomfort are not greater than those encountered in daily life…”

Problems with “Minimal Risk” law:

  • Definition of “daily life”;
  • Whose daily life? – Baghdad or Boca Raton;
  • If child plays hockey or chess;
  • Willowbrook study – what is the risk of hepatitis infection in this environment? The study could be viewed as therapeutic;
  • Local standard has some merit;
  • Risk may vary in different locations based on expertise of the researchers/physicians;
  • Problem: “Routine medical or psychological tests”;
  • Some specialists claim that small bowel biopsy/kidney biopsy were routine in their practice;
  • Commission intended this to refer to “healthy children” but did not write that;
  • Investigator could claim risk was minimal for healthy child versus probability of harm or risk to the child as a result of the study;
  • Problem: Inconsistencies from IRB to IRB in terms of what constitutes “minimal risk”.

What’s wrong with inconsistency?

  • Low risk research is thwarted: not good for children as a group;
  • Risky research is tolerated: not good for individual subjects;
  • Leads to mistrust in ethics as driving the process;
  • It would be like the definition of “cruel and unusual punishment” varying from state to state or prison to prison;
  • Might lead sponsors to “shop” for a tolerant IRB.

What’s good about inconsistency?

  • May be within range of acceptable conduct;
  • “A foolish consistency is the hobgoblin of little minds”;
  • Stimulates debate – challenges IRBs that are too strict or too lenient;
  • Factor factors may be relevant;
  • Minor increment over minimal rule: “likely to yield generalized knowledge about the subject disorder or condition which is of vital importance to the amelioration of the subject’s disorder or condition”; the intervention or procedure presents experience to subjects that are “reasonably commensurate.”

Summary

  • Minimal risk rule is vague. The ordinary life standards are hopelessly vague.
  • Routine test standard could be applicable if clarified to mean healthy children.
  • The routine test standard could be applied more consistently as guidelines.
  • Local variation should not be prohibited.

Should We Provide Greater Protection to Healthy Children?

Lainie Friedman Ross, MD, PhD
Associate Professor, University of Chicago
Assistant Director, MacLean Center for Clinical Medical
Author, Children in Medical Research: Access versus Protection; Children, Families and Health Care Decision-Making

Human Subject Protections: The Code of Federal Regulations and Federal Policy for the Protection of Human Subjects were developed based on the reports of the National Commission.

Research not involving greater than minimal risk: HHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented and only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

What is minimal risk?

Minimal risk is defined in the National Commission’s report, Research Involving Children, as “the probability and magnitude of physical or psychological harm that is normally encountered in their daily lives or in a routine medical or psychological examination.”
Minimal risk is defined in the Common Rule as “the probability and magnitude of harm or discomfort anticipated in the research are not greater, in and of themselves, than those ordinarily encountered in daily life.”

Comparing and Contrasting the National Commission’s Recommendations and Federal Regulations.

What does the exclusion of healthy children mean? The National Commission includes the words “of healthy children”; the Federal Regulations do not.

What does “ordinarily encountered in daily life” mean? Does this mean that children who are exposed to greater risks in their daily lives are allowed to be exposed to greater risks in research?

A research procedure involving minimal risk is one in which the probability of physical or psychological harm is no more than that to which it is appropriate to intentionally expose a child for education purposes in family life situations.

A “minor increase over minimal risk” is not defined in the Federal Regulations, nor is it defined in the National Commission’s reports from which the regulations are derived. How this phrase is interpreted varies greatly.

Must you have the “disorder or condition” or can you merely be “at risk” for the said “disorder or condition”?

Who is at risk? What is their level of risk? Why do we protect healthy children more than children with a disorder or condition (or children at risk for a disorder or condition)?]

Should we make the distinction?

Support:

  • It is appropriate because the research must be related to the specific disorder;
  • The children have benefited from research done on similarly situated children in the past.

Reject:

  • Sick children are more vulnerable and deserve better protection;
  • The sick children have stronger relationships with their doctor and can feel pressured to join research studies;
  • Justice may demand that we protect sick children because it is unethical to place further burdens on already burdened individuals.

The solution:

Either allow all children to be exposed to a minor increase over minimal risk or prohibit all children from participating in research that poses more than minimal risk.

Does this mean that all studies must include both healthy children and children with a disorder or condition? No. There may still be times when we want to do research only on children with a “disorder or condition” or vice versa.

Dr. Ross stated she believes that if children are going to participate in research that does not offer the prospect of direct benefit, and there are strong utilitarian reasons to permit them to do so, then the double standard must be revised.

Assent from Children: The Children’s Oncology Group Experience

Eric Kodish, MD
F.J. O’Neil Professor and Chair, Department of Bioethics, Cleveland Clinic Foundation
Editor, Ethics and Research with Children: A Case-Based Approach

Ethical considerations:

  • Informed consent in pediatrics is a misnomer. Informed consent in pediatrics equals parental permission and assent of the child.
  • Assent means that the child is aware of the condition or disorder, understands what to expect, understands the procedure or treatment, and expresses support for participation in the study.

Does silence equal acquiescence? No.

At the Cleveland Clinic Oncology Group, they collect data about the informed consent process for families with children who have been newly diagnosed with Leukemia.

The group looked at:

  • Videotapes of informed consent conferences (ICC) with parents & children;
  • Observers’ checklists;
  • Parent interviews after the ICC.

They found that the presence of a child over age seven limited the amount of frank discussion in the conference.

They found that clinicians displayed variability in the approach used during the ICCs with parents and children.

They recommend that broader empirical research is needed on the assent process, including interviews with children.

Review of the COG assent policy – developed and adopted by the Children’s Oncology Group in Cleveland in January 2005.

  • Provide information to children;
  • Inclusion of children in decision-making process about research, clinical trials, or studies;
  • Integration of family decision-making process;
  • Assent as a process over time;
  • Benefit-based waivers of assent should rarely be used;
  • Capacity-based waivers of assent can be used;
  • Determine capacity to assent by asking the child why he or she assented or not;
  • Documentation of assent in the chart – clinicians and investigators must justify what they did and why in order to obtain assent;
  • The role of adolescents in decisions about research;
  • Resolving disagreements with children about research participation;
  • Defining, understanding, and improving assent;
  • Train research staff to talk with children and families about assent.

A Developmental Approach to Child Assent

Robert M. Nelson, MD, PhD
Associate Professor of Anesthesia and Pediatrics, University of Pennsylvania
Member, Subcommittee on Research Involving Children of the Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protections

At what age (or developmental capacity) should assent from a child be required for non-beneficial research?

There is some debate regarding the ability of children to make informed decisions. The debate hinges on the degree to which “assent” is understood as “consent.”

If assent means a preference to participate, then assent should not require the same understanding as consent.

Data shows that children over the age of eleven have the ability to comprehend important aspects of research. Younger children can only reason in terms of tangible objects (e.g., blood draw). These findings only demonstrate that younger children struggle with the customary approach to consent.

“…the scope of children’s research decision-making should be based on the principles of respect for autonomy and non- maleficence. These principles imply that the threshold for assent should be fixed at fourteen years of age and a dissent requirement should be adopted for all children in the context of non-beneficial research.”

Beginning with the principal of respect for autonomy, assent should reflect capacity for autonomous decisions. The concept of altruism is essential for appreciating the reason for participating in non-beneficial research. What are the differences between dissent and assent, if any?

The developmental capacity for assent follows from our concept of what child assent is meant to accomplish.

What are the implications (for child assent) of linking assent with parental permission?

“The role of the parent or guardian as the proxy decision-maker for his or her child’s participation in clinical research is one of protection and, as such, differs from that of the adult subject whose role is one of self-determination.”

Autonomy or self-determination is not an appropriate model for understanding either parental permission or child assent.
Respect for persons incorporates both treating individuals as autonomous agents and protecting persons with diminished autonomy. Respecting children includes respecting parental permission (within limits) and child consent (not as a right, but a benefit).

The elements of assent:

  • Help the child achieve a developmentally appropriate awareness of their condition;
  • Disclose the nature of the proposed intervention and child’s likely experience;
  • Assess the child’s understanding;
  • Solicit the child’s willingness to participate.

Child assent and parental permission should be understood together.

What might a developmental approach to child assent look like?

There is likely a lower age at which dissent (or assent) is not possible. Should the age of assent be set at when a child understands when something is being done against his or her wishes? Or when a child can appreciate being used for another’s purpose?

By grounding child assent in respect for children, we incorporate the obligations of parents to protect and nurture their children. 

About Seattle Children's Hospital

Consistently ranked as one of the best children’s hospitals in the country by U.S. News & World Report, Children’s serves as the pediatric and adolescent academic medical referral center for the largest landmass of any children’s hospital in the country (Washington, Alaska, Montana and Idaho). For more than 100 years, Children’s has been delivering superior patient care and advancing new treatments through pediatric research. Children’s serves as the primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine. The hospital works in partnership with Seattle Children’s Research Institute and Seattle Children’s Hospital Foundation. For more information, visit http://www.seattlechildrens.org.

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