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It’s only a Phase! Clinical Trials Part II


by Dr. Susan Shurin, MD Source: Spring 2003 CCCF Newsletter

How does your doctor know what treatments to recommend for your child? You are probably familiar with the idea that medicine is both an art and a science. The scientific basis of medicine requires understanding the underlying biology and chemistry of the human body, rigorous study of what causes diseases (pathology), and the effectiveness of treatments (therapeutics). The better we understand how things work, the more rationally we can prevent and treat diseases. Particularly in the treatment of cancer, where accurate categorization of the disease can be difficult, and where the combinations of different therapeutic approaches (surgery, irradiation and drugs) treatments may greatly affect the outcome.

Clinical trials are the means by which safety and efficacy of new therapies are determined. Laboratory studies of drugs in cell culture and laboratory animals (“pre-clinical tests”) are done first. Tests of how the drugs are metabolized and their side effects, termed “Phase I” studies, are done next. Then, drugs are studied in humans with a disease to determine whether there is activity against that disease. These are called “Phase II” studies. “Phase III” studies are done when a new treatment is compared to established treatments to determine which is best. All aspects of diagnosis and treatment on a clinical trial receive intense scrutiny, since decisions about treatments of future patients will be made on the basis of these results.


Researchers, physicians, patients and families are eager to develop new treatments when the outcomes of existing therapies are either ineffective or excessively toxic. In the United States, several government agencies are involved in regulating clinical trials, including the FDA and the NIH. Most of these studies are done at academic medical centers – hospitals and universities working together. The drugs themselves come from laboratories and pharmaceutical companies. Each of these is a complex system with its own bureaucracy. The ultimate goals of all groups are the same however: the development of improved treatments which can be made broadly available and improve the outcome for patients.

It is important to understand what is known and what is not known about a clinical trial when you are considering participation in a study. You should be an informed advocate for your child so that you are able to judge how much risk is acceptable to you, and how realistic it is for you to anticipate any benefit. These are important studies. Everyone involved in doing them has a primary interest – the benefit of the patient. Each institution and professional also has his or her own interests, which can have an impact on how a clinical trial is viewed.

The patient and the patient’s family are generally motivated by a desire to benefit from new therapies. People with serious diseases and few options make very personal and individual choices, which enable them to maintain hope. Some choose no treatment targeted at the disease, while others choose to focus on alternative or complementary therapies, and still others pursue new medical therapies. When you are invited to participate in a phase I or II clinical trial, your likelihood of benefiting from existing, proven therapies is very limited. It is perfectly appropriate to hope that you will benefit from a treatment at the same time that you understand logically that this is not very likely to happen.

The doctors who order the therapy, who may also be investigators who design and conduct the study, are motivated by desire to achieve several goals:

  • help their patients who participate in the study
  • improve treatments for all their patients, including future patients
  • publish articles in the medical literature, which enables them to get support for their research programs, build their own professional reputations, and build the reputations of their institutions.

The academic medical centers have extensive infrastructure, such as Clinical Research Centers and Institutional Review Boards, which must be supported to permit the safe conduct of research. Medical Centers develop their reputations by their leadership roles in clinical research, which requires attracting patients and being able to cover extensive costs of facilities, nursing, pharmacies, data management, and laboratory testing.

The pharmaceutical companies who make the drugs are in business to make money. Their reputations, long-term business strategies and profit margins flourish when they benefit patients, by developing new and effective drugs.

The governmental regulatory agencies – the Food and Drug Administration (FDA) and the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) – need to respond to multiple different constituencies, including the public, patient and professional groups, business interests, Congress and the Executive Branch of government. They are simultaneously criticized for moving too slowly and too rapidly; taking too few and too many risks; regulating too much and too little.


  1. Expertise: Many years of training are required: check out a few of the guidelines at (
  • The investigator must be a skilled clinician, respected scientist, and have administrative abilities which enable him or her to pull together a team and put in place the infrastructure to ensure that all the data are collected, accurate, and reported, that therapy is given as required, and that the patients and families are fully informed and supported.
  • All the professionals must know what to look for, what to do, how to report events, and know the complexities of the system in which they are working.
  1. Money:
  • Infrastructure: laboratory testing, data collection, data submission, data analysis (statisticians, computers, etc), and rapid review of any possible toxic events.
  • Time: The time of skilled scientists, pharmacists, nurses, clinical research associates and clinicians must be made available to devote to design and performance of the study and review of data. This must be a major commitment of the professionals, not a hobby.
  • Patient care resources. The patient or his insurance carrier must pay for all aspects of patient care except the experimental drug. With industrysponsored studies, some of these costs may be born by the pharmaceutical company.
  1. Institutional resources:
  • Space, professional time, computers, access to all of the complex resources of an academic medical center.
  1. Access to new agents:
  • An investigational new drug application, or IND, is required for anyone who has responsibility for testing new drugs.
  • If the drug is not approved, the investigator must have access to it, which means that the drug company or other provider, such as CTEP, must guarantee access.
  1. Partners:
  • Studies in humans with the relevant diseases are necessary to determine whether a new therapy is safe or effective. Without patients and their supportive families, these studies cannot be done.
  1. Ethical study design:
  • For studies of new therapies, it is important that no other potentially superior therapy be available. This concept is called “equipoise.”
  • Informed consent. The partner who brings the most important component to these studies – himself or herself – must understand what is planned, why, and what is involved. For new therapies, no promise of benefit can be offered or implied. That does not mean that all involved, including the investigators, do not hope for benefit.

Phase I studies are designed to determine the dose, administration schedule and side effects of new drugs. Fewer than 5% benefit from these therapies; fortunately, even are harmed.


  • The Institutional Review Board of the institution where the study is being done.
  • The Food and Drug Administration (FDA), if a new drug or a new combination of old drugs is being used.
  • The company which is providing a drug which has not been approved by the FDA, or if the company will provide an approved drug free of charge.
  • The Cancer Therapy Program (CTEP) at the National Cancer Institute (NCI), if it is a study which uses any of the resources of the cooperative group oncology program.


Industry-sponsored trials These are studies which are initiated and supported (paid for) by pharmaceutical companies, which design the study and provide the drug. The physician-investigators at the institutions which do these studies agree to enroll patients, do tests, collect and submit data to the company in exchange for payments which cover the costs of doing the research and usually provide a profit to the institution. Under most arrangements, the physician-investigators do not personally profit from these payments, but their institutions benefit, and other parts of a research or education program may be supported from these funds. In pediatrics, this arrangement is most commonly used for studies of supportive treatments such as antibiotics, growth factors or anti-nausea drugs, not for new cancer drug development. Many very important drugs have become available using this approach.

CTEP-approved trials The Cancer Therapy Evaluation Program, or CTEP, supports networks of institutions which pool their resources to bring new treatments to patients, and to facilitate cancer research. The cooperative oncology groups include the Children’s Oncology Group, which encompasses all of pediatric cancer ( To ensure coordination of use of resources, CTEP participates in the evaluation of proposed studies, and helps set research priorities.

Single institution studies Some institutions are able to develop new treatments on their own, usually in one or two focused disease areas. These early treatments are called “pilot” studies. These are done at institutions which have very large numbers of patients and a group of investigators with special interest in certain diseases or therapies. Examples include: leukemia studies at St. Jude’s Research Hospital in Memphis; bone tumor studies at Memorial Sloan Kettering Institute in New York; neuroblastoma studies at Children’s Hospital of Philadelphia; and bone marrow transplant studies at the Fred Hutchinson Cancer Center in Seattle.

These studies have been reviewed and approved by IRBs and various regulatory agencies. For pilot studies, there may be little data to suggest that the treatments are better than existing therapies, which may have unrecognized side effects. Successful single institution studies are the basis for development of larger clinical trials at multiple institutions. There is less data to show safety or efficacy at this very early stage of study development than there is for most studies which are part of the cooperative group mechanism.

Pilot studies often involve novel approaches, and may be a real departure from more proven therapies. Design of these approaches reflects the philosophy and interests of the investigators, and is less likely to involve the compromises seen when studies are designed by a committee. Toxicity is closely monitored. These studies take less time from concept to implementation than do studies involving multiple institutions.

Limited institution studies Some institutions which have investigators who work in closely related fields may offer some studies to patients only at those institutions. The start up time for these studies is shorter than for cooperative group studies. Because the numbers of patients are often greater, they may take less time to complete than single institution studies. Two consortia of ten institutions each whose combined research is supported by the NCI, by provision of support for data collection and analysis are the Pediatric Brain Tumor Consortium (PBTC), and the New Approaches to Neuroblastoma Therapy Consortium (NANT).

Cooperative group studies Children’s Oncology Group (COG) is a cooperative oncology research group with institutions across the US and Canada which take care of over 90% of children under 15 with cancer. COG and its predecessor groups have been in operation for 50 years, and together they are responsible for many of the great advances in the outcome for children with cancer. COG has both the benefits and the liabilities of size – it is difficult for a large institution to move rapidly, so that both start up and completion of trials entails organizational lag times. Extensive protocol review and patient safety protections are in place. A consortium of 20 COG institutions performs Phase I studies. COG brings state-of-the-art therapy to children across all of North America and a few other countries. The Group performs studies with adult oncology groups and European groups, when this approach answers important questions more rapidly.


Because of the amazing support of generations of parents and children who have been willing to partner with their nurses and doctors, take risks and try to beat odds in a terrible battle, three quarters of children diagnosed with cancer in 2003 will live to raise their own families and become productive adults. If you and your child are facing the tragic situations these families have faced, you should consider participating in this courageous experiment. A few suggestions may help with these decisions:

Ask lots of questions. You have the right to every available answer. Often, your doctor or nurse will not know, and may not be able to find the answer. That is the nature of this territory – often, we don’t know. You will help us learn.

Advocate for your child. Make lots of phone calls, be sure you understand your options. Understand that the professionals with whom you are dealing want only the best for your child, but are also operating in complex systems in which they are rewarded or punished for doing some things which seem irrational to you.

Listen to people you trust, but realize that there are no right answers. What works for others may not work for you.


Candlelighters would like to express our deepest gratitude to Dr. Susan Shurin for the writing of this important article on Clinical Trials.

Contact info for Dr. Shurin: Susan B. Shurin, MD Vice President and Secretary of the Corporation Professor of Pediatrics and Oncology Case Western Reserve University 10900 Euclid Avenue Cleveland OH 44106-7010