In this issue

Director's Corner by David G. Poplack, M.D.

Gastrointestinal stromal tumors (GIST)
by Alberto Pappo, M.D.

Turning the Immune System Against Neuroblastoma
by Doug Myers, M.D. and Malcolm Brenner, M.D., Ph.D.

Pediatric Hematology Oncology Subspecialty
Training in the United States
by Lindsay B. Kilburn, M.D. and C. Philip Steuber, M.D.

Regulatory and Ethical Issues in the Treatment of Children
by Bambi Grilley, R.Ph., C.C.R.P., C.C.R.C., C.I.P., Stacey Berg, M.D.
and Cynthia Boudreaux, M.Ed., C.C.R.P.

Human Subjects Protections - International Regulations
Current guidelines governing human subject research have their basis in The Nuremberg Code released in 1947. Developed as a result of the Nuremberg trials conducted at the end of the Second World War, the code was developed to prevent the types of inhumane experimentation conducted by Nazi physicians. The code contains 10 basic points, many of which have been built upon to develop current standards and laws used to govern human subject research. Key points of the Nuremberg Code include:

1. Voluntary consent of the subject is absolutely essential
2. The experiment should be such as to yield fruitful results for the good of society
3. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment
4. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the state where continuation of the experiment seems to him to be impossible.¹

The principles of the Nuremberg Code were further expanded by the declaration of Helsinki, first adopted by the World Medical Assembly in 1964. The declaration was the first attempt by physicians to regulate research activities. Primary points of the declaration include:

1. The design and performance of each experimental protocol should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor.
2. Each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject’s freely-given informed consent, preferably in writing.

The declaration has been updated and revised on multiple occasions, most recently in 2004.²

In the 1980s the European Union (EU) initiated a process to harmonize regulatory requirements to develop guidelines for the quality, safety and efficacy of drugs. The guidelines developed are referred to as the International Conference on Harmonization (ICH) guidelines. The ultimate goal of these guidelines is to provide pharmaceutical firms a method to ensure simultaneous submission and rapid regulatory approval in the world’s major markets. Included in the ICH guidelines is section E6 relating to Good Clinical Practice. ICH E6 contains information relating to review by an Institutional Review Board/Independent Ethics Committee (IRB/IEC). The FDA has been very involved in the ICH guidelines and therefore the guidelines very closely mirror those of the U.S. system. More information about the history of regulation in the U.S. and resulting processes is presented below.³

Human Subjects Protections - U.S. Regulations
Laws governing human subject research in the U.S. developed in response to the discovery of inappropriate research techniques utilized in the Tuskegee Syphilis study. The Tuskegee Syphilis study involved observation of approximately 400 poor African-American males in rural Alabama. The non-intervention study continued even after effective treatments for the disease had been identified.

Following publication of the scandal, the U.S. Congress established the The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research which published the “Belmont Report” in 1979. The Belmont report identified three quintessential requirements for the ethical conduct of research using human Subjects:

1. Respect for persons
2. Beneficence
3. Justice⁴

In 1991, 16 Federal departments joined the U.S. Department of Health and Human Services (DHHS) in adopting 45CFR46 subpart A. This uniform set of regulations is the Federal Policy for the Protection of Human Subjects, informally known as the “Common Rule”. The Common Rule:

1. Defines the responsibilities of the Institutional Review Board (IRB)
2. Includes special regulations for protection of vulnerable populations including fetuses, pregnant women, prisoners and children
3. Provides guidelines for components of informed consent including:
   1. Purposes and Procedures
   2. Risks
   3. Benefits
   4. Alternatives
   5. Extent of confidentiality
   6. Compensation for injury
   7. Name, address and telephone number of a contact person
   8. Assurance that participation in the study is voluntary.⁵

Human Subjects Protections in Children
As stated above, children are considered to be a vulnerable population when included in research. If an IRB regularly reviews research that involves children, the IRB should include one or more individuals who are knowledgeable about and experienced in working with children. The criteria for IRB approval of research using children is codified in 45CFR46.401 (Subpart D). Subpart D identifies four categories of risk and associated benefits with corresponding consent requirements. All four categories require that children’s assent be obtained as appropriate. Assent is defined as the child’s affirmative agreement to participate in research and mere failure to object should not be construed as assent. The IRB must take into consideration the age, maturity, and psychological state of the children when determining whether children are capable of assenting to research. If the research holds out the prospect of direct benefit to children and the IRB determines that some or all of the children will not be capable of assent, obtaining assent will not necessarily be required in order to conduct the research. The method of obtaining and documenting assent is also determined by the IRB. In some situations age appropriate documents are utilized while in others parental documentation of the child’s assent is adequate. Many research studies have been done to try to determine the most effective method of obtaining assent however at this time there is no "gold standard".

Some level of parental permission is always required. The four categories and the level of parental consent follow:

Children who are wards of the state can be included in research that has more than minimal risk and no direct benefit to the subject only if the research is related to their status as wards or if it is conducted in settings where the majority of study subjects will not be wards. In these situations the child must have an advocate in addition to any other individual acting on behalf of the child as a guardian.⁵

In addition to the regulations specified by 45CFR46 (subpart D), numerous organizations and agencies have developed and released guidance documents relating to human subject research in children. Notable among these are documents released by the FDA such as the FDA Modernization Act,⁶ the FDA 1998 Pediatric Rule,⁷ and the Pediatric Research Equity Act,⁸ all of which encourage research in children in situations where therapeutic options are limited or sub-optimal.

The development and codification of ethical guidelines for human subject research is relatively recent. Finer tuning of issues such as protection of children in research is an even more recent development. It is likely that as the areas of research continue to expand, ethical guidelines governing such research will mature. Included in this process is likely to be a broadened focus on research in children and the proper way to conduct such research.

About the Authors

Bambi Grilley, RPh, CCRP, CCRC, CIP, is the Director of the Clinical Research Protocol Office. She assists investigators develop clinical protocols and the related regulatory documents. She also oversees the regulatory submissions for the over 300 clinical trials being conducted by Texas Children’s Cancer Center and Hematology Service and Baylor College of Medicine’s Center for Cell and Gene Therapy.

She has experience as an Investigational drug pharmacist, IRB administrator, IRB member, regulatory affairs professional and in the conduct of clinical trials. She has been working in the area of oncology for almost 20 years and has been working in the area of gene therapy for over 10 years. Bambi Grilley is an instructor of pediatrics at Baylor College of Medicine.

Dr. Stacey Berg's primary area of interest is pharmacology and experimental therapeutics, with a special emphasis on the development of new anticancer drugs for children. She also has a strong interest in clinical trial design and biomedical ethics. Berg is a professor of pediatrics at Baylor College of Medicine.

Cynthia Boudreaux, MEd, CCRP, is the lead regulatory coordinator of the Clinical Research Protocol Office. She supervises the regulatory staff and assists investigators from Texas Children’s Cancer Center and Hematology Service and Baylor’s Center for Cell and Gene Therapy develop clinical protocols and related regulatory documents. Boudreaux has eight years of clinical research experience in the areas of clinical research coordination, research compliance and regulatory affairs. She has also worked as an exercise physiologist with cardiac and cardiopulmonary patients.

References

1. The Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2, pp 181-182. Washington, DC: US Government Printing Office; September 1989.
2. The World Medical Association. Declaration of Helsinki [clarified 2000 cited 2004 March]. Available from http://www.wma.net/e/policy/b3.htm
3. International Conference on Harmonization [website on the Internet]. History and Future of ICH (revised 2000 cited 2004 Mar]. Available from www.ich.org
4. Food and Drug Administration. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research [updated 1998 cited 2004 Mar]Available from http://www.fda.gov/oc/ohrt/IRBS/belmont.html
5. United States Federal Government Code of Federal Regulations. 45CFR46 Washington DC [updated 2004 Apr 1 cited 2004 Sept 15]. Available from http://www.gpoaccess.gov/cfr/index.html
6. Food and Drug Administration. Food and Drug Administration Modernization Act of 1997 [1997 cited 2004 Mar]. Available from http://www.fda.gov
7. Food and Drug Administration. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule [1998 cited 2007 July]. Available from http://www.fda.gov/ohrms/dockets/98fr/120298c.txt
8. Food and Drug Administration. Pediatric Research Equity Act of 2003 [1998 cited 2007 July]. Available from http://www.fda.gov/cder/pediatric/S-650-PREA.pdf